WorldWideScience

Sample records for identifying toxic mechanisms

  1. Mechanisms of Phosphine Toxicity

    Directory of Open Access Journals (Sweden)

    Nisa S. Nath

    2011-01-01

    Full Text Available Fumigation with phosphine gas is by far the most widely used treatment for the protection of stored grain against insect pests. The development of high-level resistance in insects now threatens its continued use. As there is no suitable chemical to replace phosphine, it is essential to understand the mechanisms of phosphine toxicity to increase the effectiveness of resistance management. Because phosphine is such a simple molecule (PH3, the chemistry of phosphorus is central to its toxicity. The elements above and below phosphorus in the periodic table are nitrogen (N and arsenic (As, which also produce toxic hydrides, namely, NH3 and AsH3. The three hydrides cause related symptoms and similar changes to cellular and organismal physiology, including disruption of the sympathetic nervous system, suppressed energy metabolism and toxic changes to the redox state of the cell. We propose that these three effects are interdependent contributors to phosphine toxicity.

  2. Molecular toxicity mechanism of nanosilver

    Directory of Open Access Journals (Sweden)

    Danielle McShan

    2014-03-01

    Full Text Available Silver is an ancient antibiotic that has found many new uses due to its unique properties on the nanoscale. Due to its presence in many consumer products, the toxicity of nanosilver has become a hot topic. This review summarizes recent advances, particularly the molecular mechanism of nanosilver toxicity. The surface of nanosilver can easily be oxidized by O2 and other molecules in the environmental and biological systems leading to the release of Ag+, a known toxic ion. Therefore, nanosilver toxicity is closely related to the release of Ag+. In fact, it is difficult to determine what portion of the toxicity is from the nano-form and what is from the ionic form. The surface oxidation rate is closely related to the nanosilver surface coating, coexisting molecules, especially thiol-containing compounds, lighting conditions, and the interaction of nanosilver with nucleic acids, lipid molecules, and proteins in a biological system. Nanosilver has been shown to penetrate the cell and become internalized. Thus, nanosilver often acts as a source of Ag+ inside the cell. One of the main mechanisms of toxicity is that it causes oxidative stress through the generation of reactive oxygen species and causes damage to cellular components including DNA damage, activation of antioxidant enzymes, depletion of antioxidant molecules (e.g., glutathione, binding and disabling of proteins, and damage to the cell membrane. Several major questions remain to be answered: (1 the toxic contribution from the ionic form versus the nano-form; (2 key enzymes and signaling pathways responsible for the toxicity; and (3 effect of coexisting molecules on the toxicity and its relationship to surface coating.

  3. Molecular mechanisms of fluoride toxicity.

    Science.gov (United States)

    Barbier, Olivier; Arreola-Mendoza, Laura; Del Razo, Luz María

    2010-11-05

    Halfway through the twentieth century, fluoride piqued the interest of toxicologists due to its deleterious effects at high concentrations in human populations suffering from fluorosis and in in vivo experimental models. Until the 1990s, the toxicity of fluoride was largely ignored due to its "good reputation" for preventing caries via topical application and in dental toothpastes. However, in the last decade, interest in its undesirable effects has resurfaced due to the awareness that this element interacts with cellular systems even at low doses. In recent years, several investigations demonstrated that fluoride can induce oxidative stress and modulate intracellular redox homeostasis, lipid peroxidation and protein carbonyl content, as well as alter gene expression and cause apoptosis. Genes modulated by fluoride include those related to the stress response, metabolic enzymes, the cell cycle, cell-cell communications and signal transduction. The primary purpose of this review is to examine recent findings from our group and others that focus on the molecular mechanisms of the action of inorganic fluoride in several cellular processes with respect to potential physiological and toxicological implications. This review presents an overview of the current research on the molecular aspects of fluoride exposure with emphasis on biological targets and their possible mechanisms of involvement in fluoride cytotoxicity. The goal of this review is to enhance understanding of the mechanisms by which fluoride affects cells, with an emphasis on tissue-specific events in humans. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  4. Test systems to identify reproductive toxicants.

    Science.gov (United States)

    Riecke, K; Stahlmann, R

    2000-09-01

    Experience with drugs and other xenobiotics indicates that both animal testing and epidemiological studies are necessary to provide adequate data for an estimation of risks that might be associated with exposure to a chemical substance. In this review, the pros and cons of test systems for reproductive toxicity are discussed. Usually, several studies are performed to cover the different phases of the reproductive cycle. In the preclinical development of drugs, the three so-called 'segment testing protocols' have been used for several decades now. More recently, new testing concepts have been accepted internationally which include more flexibility in implementation. Several examples of compounds with the potential for reproductive toxicity are presented in more detail in a discussion of some pitfalls of the tests for fertility (phthalates and fluoroquinolones), teratogenicity (acyclovir and protease inhibitors) and postnatal developmental toxicity (fluoroquinolones). In addition, important aspects of kinetics and metabolism as a prerequisite for a rational interpretation of results from toxicological studies are briefly discussed. In vitro assays are useful for supplementing the routinely used in vivo approaches or for studying an expected or defined effect, but they are not suitable for revealing an unknown effect of a chemical on the complex reproductive process.

  5. Acute Toxicity of a Recently Identified Phenol-based Synthetic ...

    African Journals Online (AJOL)

    This paper reports on the acute toxicity of a new phenol based synthetic tsetse fly repellent recently identified at the International Centre for Insect Physiology and Ecology (patent No. ... The repellent can be classified as being highly toxic with central nervous system (CNS) involvement and a mild skin and eye irritant.

  6. Mechanisms of Silver Nanoparticle Toxicity

    DEFF Research Database (Denmark)

    Foldbjerg, Rasmus

    nanometers. At this size, materials begin to exhibit unique properties that affect physical, chemical, and biological behavior. However, the same characteristics which make nanomaterials attractive for exploitation in new products have led to concerns that nanomaterials may pose a risk for humans...... to their anti-microbial properties, high electrical conductivity, and optical properties. Information about the mechanisms involved in the cytotoxicity of Ag NPs is important in order to evaluate the potential hazards posed by these particles. Several studies have suggested oxidative stress to play a major role...... by transcriptional profiling and to investigate cellular processes such as oxidative stress, apoptosis, cell cycle and DNA damage, which may be involved in carcinogenesis. For this purpose, Ag NP suspensions were prepared from a commercial powder or synthesized in-house. The Ag NPs were characterized...

  7. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism

    Directory of Open Access Journals (Sweden)

    Xinmiao Yan

    2016-03-01

    Full Text Available Pyrrolizidine Alkaloids (PAs are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1 and glutathione peroxidase 1 (GPX1 targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  8. Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism.

    Science.gov (United States)

    Yan, Xinmiao; Kang, Hong; Feng, Jun; Yang, Yiyan; Tang, Kailin; Zhu, Ruixin; Yang, Li; Wang, Zhengtao; Cao, Zhiwei

    2016-03-07

    Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

  9. Mechanisms of chemotherapy-induced behavioral toxicities

    Directory of Open Access Journals (Sweden)

    Elisabeth G Vichaya

    2015-04-01

    Full Text Available While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms of chemotherapy include (i cognitive deficiencies such as problems with attention, memory and executive functioning; (ii fatigue and motivational deficit; and (iii neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

  10. Mechanisms of nickel toxicity in microorganisms

    Science.gov (United States)

    Macomber, Lee

    2014-01-01

    Summary Nickel has long been known to be an important human toxicant, including having the ability to form carcinomas, but until recently nickel was believed to be an issue only to microorganisms living in nickel-rich serpentine soils or areas contaminated by industrial pollution. This assumption was overturned by the discovery of a nickel defense system (RcnR/RcnA) found in microorganisms that live in a wide range of environmental niches, suggesting that nickel homeostasis is a general biological concern. To date, the mechanisms of nickel toxicity in microorganisms and higher eukaryotes are poorly understood. In this review, we summarize nickel homeostasis processes used by microorganisms and highlight in vivo and in vitro effects of exposure to elevated concentrations of nickel. On the basis of this evidence we propose four mechanisms of nickel toxicity: 1) nickel replaces the essential metal of metalloproteins, 2) nickel binds to catalytic residues of non-metalloenzymes; 3) nickel binds outside the catalytic site of an enzyme to inhibit allosterically, and 4) nickel indirectly causes oxidative stress. PMID:21799955

  11. Autophagy as a Possible Underlying Mechanism of Nanomaterial Toxicity

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    Vanessa Cohignac

    2014-07-01

    Full Text Available The rapid development of nanotechnologies is raising safety concerns because of the potential effects of engineered nanomaterials on human health, particularly at the respiratory level. Since the last decades, many in vivo studies have been interested in the pulmonary effects of different classes of nanomaterials. It has been shown that some of them can induce toxic effects, essentially depending on their physico-chemical characteristics, but other studies did not identify such effects. Inflammation and oxidative stress are currently the two main mechanisms described to explain the observed toxicity. However, the exact underlying mechanism(s still remain(s unknown and autophagy could represent an interesting candidate. Autophagy is a physiological process in which cytoplasmic components are digested via a lysosomal pathway. It has been shown that autophagy is involved in the pathogenesis and the progression of human diseases, and is able to modulate the oxidative stress and pro-inflammatory responses. A growing amount of literature suggests that a link between nanomaterial toxicity and autophagy impairment could exist. In this review, we will first summarize what is known about the respiratory effects of nanomaterials and we will then discuss the possible involvement of autophagy in this toxicity. This review should help understand why autophagy impairment could be taken as a promising candidate to fully understand nanomaterials toxicity.

  12. Biological Mechanism of Silver Nanoparticle Toxicity

    Science.gov (United States)

    Armstrong, Najealicka Nicole

    Silver nanoparticles (AgNPs), like almost all nanoparticles, are potentially toxic beyond a certain concentration because the survival of the organism is compromised due to scores of pathophysiological abnormalities above that concentration. However, the mechanism of AgNP toxicity remains undetermined. Instead of applying a toxic dose, these investigations were attempted to monitor the effects of AgNPs at a non-lethal concentration on wild type Drosophila melanogaster by exposing them to nanoparticles throughout their development. All adult flies raised in AgNP doped food indicated that of not more than 50 mg/L had no negative influence on median survival; however, these flies appeared uniformly lighter in body color due to the loss of melanin pigments in their cuticle. Additionally, fertility and vertical movement ability were compromised after AgNP feeding. The determination of the amount of free ionic silver (Ag+) indicated that the observed biological effects had resulted from the AgNPs and not from Ag+. Biochemical analysis suggests that the activity of copper dependent enzymes, namely tyrosinase and Cu-Zn superoxide dismutase, were decreased significantly following the consumption of AgNPs, despite the constant level of copper present in the tissue. Furthermore, copper supplementation restored the loss of AgNP induced demelanization, and the reduction of functional Ctr1 in Ctr1 heterozygous mutants caused the flies to be resistant to demelanization. Consequently, these studies proposed a mechanism whereby consumption of excess AgNPs in association with membrane bound copper transporter proteins cause sequestration of copper, thus creating a condition that resembles copper starvation. This model also explained the cuticular demelanization effect resulting from AgNP since tyrosinase activity is essential for melanin biosynthesis. Finally, these investigations demonstrated that Drosophila, an established genetic model system, can be well utilized for further

  13. Identifying links between origami and compliant mechanisms

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    H. C. Greenberg

    2011-12-01

    Full Text Available Origami is the art of folding paper. In the context of engineering, orimimetics is the application of folding to solve problems. Kinetic origami behavior can be modeled with the pseudo-rigid-body model since the origami are compliant mechanisms. These compliant mechanisms, when having a flat initial state and motion emerging out of the fabrication plane, are classified as lamina emergent mechanisms (LEMs. To demonstrate the feasibility of identifying links between origami and compliant mechanism analysis and design methods, four flat folding paper mechanisms are presented with their corresponding kinematic and graph models. Principles from graph theory are used to abstract the mechanisms to show them as coupled, or inter-connected, mechanisms. It is anticipated that this work lays a foundation for exploring methods for LEM synthesis based on the analogy between flat-folding origami models and linkage assembly.

  14. IDENTIFYING TOXIC LEADERSHIP BEHAVIORS AND TOOLS TO FACILITATE THEIR DISCOVERY

    Science.gov (United States)

    2016-01-31

    generic traits that describe toxic leadership. Broad characteristics of narcissism and cynicism are further reduced to descriptors of selfishness...abuse and tyranny. The persistent abusiveness, authoritarianism, narcissism and unpredictability can be displayed in two categories of toxicity...retention failure to the toxic leadership climate. These leaders are maladjusted, emphasizing narcissism and authoritarianism.25 The primary indicators of

  15. Alternative approaches for identifying acute systemic toxicity: Moving from research to regulatory testing.

    Science.gov (United States)

    Hamm, Jon; Sullivan, Kristie; Clippinger, Amy J; Strickland, Judy; Bell, Shannon; Bhhatarai, Barun; Blaauboer, Bas; Casey, Warren; Dorman, David; Forsby, Anna; Garcia-Reyero, Natàlia; Gehen, Sean; Graepel, Rabea; Hotchkiss, Jon; Lowit, Anna; Matheson, Joanna; Reaves, Elissa; Scarano, Louis; Sprankle, Catherine; Tunkel, Jay; Wilson, Dan; Xia, Menghang; Zhu, Hao; Allen, David

    2017-06-01

    Acute systemic toxicity testing provides the basis for hazard labeling and risk management of chemicals. A number of international efforts have been directed at identifying non-animal alternatives for in vivo acute systemic toxicity tests. A September 2015 workshop, Alternative Approaches for Identifying Acute Systemic Toxicity: Moving from Research to Regulatory Testing, reviewed the state-of-the-science of non-animal alternatives for this testing and explored ways to facilitate implementation of alternatives. Workshop attendees included representatives from international regulatory agencies, academia, nongovernmental organizations, and industry. Resources identified as necessary for meaningful progress in implementing alternatives included compiling and making available high-quality reference data, training on use and interpretation of in vitro and in silico approaches, and global harmonization of testing requirements. Attendees particularly noted the need to characterize variability in reference data to evaluate new approaches. They also noted the importance of understanding the mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Workshop breakout groups explored different approaches to reducing or replacing animal use for acute toxicity testing, with each group crafting a roadmap and strategy to accomplish near-term progress. The workshop steering committee has organized efforts to implement the recommendations of the workshop participants. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Mechanisms of internal emitter skeletal toxicity

    International Nuclear Information System (INIS)

    Jee, W.S.S.

    1985-01-01

    The purpose of this program is to determine the mechanisms for the induction of skeletal cancers in dogs and man by α-emitting bone-seeking radionuclides from the nuclear fuel cycle. The role of microdistribution of radium-226 and plutonium-239, bone metabolism, bone cell turnover, and localized bone cell dosimetry in bone can induction will be determined. The osteogenic cell dose will be measured in dogs to develop better quantitative dose response information. Skeletal carcinogenesis models will be developed by correlating the local dosimetry, tumor site and incidence, age-dependent skeletal biology (bone morphometry, bone cell at risk, bone cell turnover, residence time and fate, remodeling rate, growth pattern and rate, hormonal influences, manipulation of bone cell populations of the bone modeling and remodeling systems, etc.). The authors will test the hypothesis that the frequency of osteosarcomas is proportional to the average dose delivered to cells at risk. They will also attempt to explain experimentally found toxicity ratios between volume- and bone surface-seeking radionuclides on the basis of radiation dose ratios

  17. Creating mechanisms of toxic substances emission of combustion engines

    OpenAIRE

    Jankowski Antoni; Kowalski Mirosław

    2015-01-01

    The paper analyses the mechanisms of creation of toxic exhaust gases, which mainly derived from inexact fuel metering and improper air-fuel mixture preparation. The paper describes the process of creating toxic components in the exhaust gases of piston engines during engine operation, and impact on the emission of these components determining the composition of the fuel mixture determined equivalence factor Φ. The principal mechanisms of formation of toxic exhaust gases, in particular nitroge...

  18. Mechanisms of metal toxicity in plants

    Czech Academy of Sciences Publication Activity Database

    Küpper, Hendrik; Andresen, Elisa

    2016-01-01

    Roč. 8, č. 3 (2016), s. 269-285 ISSN 1756-5901 Institutional support: RVO:60077344 Keywords : Hyperaccumulator thlaspi-caerulescens * Induced oxidative stress * Iron toxicity Subject RIV: CE - Biochemistry Impact factor: 3.975, year: 2016

  19. Molecular Mechanisms of Microcystin Toxicity in Animal Cells

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    Alexandre Campos

    2010-01-01

    Full Text Available Microcystins (MC are potent hepatotoxins produced by the cyanobacteria of the genera Planktothrix, Microcystis, Aphanizomenon, Nostoc and Anabaena. These cyclic heptapeptides have strong affinity to serine/threonine protein phosphatases (PPs thereby acting as an inhibitor of this group of enzymes. Through this interaction a cascade of events responsible for the MC cytotoxic and genotoxic effects in animal cells may take place. Moreover MC induces oxidative stress in animal cells and together with the inhibition of PPs, this pathway is considered to be one of the main mechanisms of MC toxicity. In recent years new insights on the key enzymes involved in the signal-transduction and toxicity have been reported demonstrating the complexity of the interaction of these toxins with animal cells. Key proteins involved in MC up-take, biotransformation and excretion have been identified, demonstrating the ability of aquatic animals to metabolize and excrete the toxin. MC have shown to interact with the mitochondria. The consequences are the dysfunction of the organelle, induction of reactive oxygen species (ROS and cell apoptosis. MC activity leads to the differential expression/activity of transcriptional factors and protein kinases involved in the pathways of cellular differentiation, proliferation and tumor promotion activity. This activity may result from the direct inhibition of the protein phosphatases PP1 and PP2A. This review aims to summarize the increasing data regarding the molecular mechanisms of MC toxicity in animal systems, reporting for direct MC interacting proteins and key enzymes in the process of toxicity biotransformation/excretion of these cyclic peptides.

  20. Dose-dependent transitions in mechanisms of toxicity

    International Nuclear Information System (INIS)

    Slikker, William; Andersen, Melvin E.; Bogdanffy, Matthew S.; Bus, James S.; Cohen, Steven D.; Conolly, Rory B.; David, Raymond M.; Doerrer, Nancy G.; Dorman, David C.; Gaylor, David W.; Hattis, Dale; Rogers, John M.; Woodrow Setzer, R.; Swenberg, James A.; Wallace, Kendall

    2004-01-01

    Scientists and decision makers from all sectors agree that risk assessments should be based on the best available science. Several years ago, the Health and Environmental Sciences Institute (HESI), a global branch of the International Life Sciences Institute (ILSI), identified the need for better scientific understanding of dose-dependent transitions in mechanisms of toxicity as one avenue by which the best and latest science can be integrated into the decision making process. In July 2001, the HESI Project Committee on Dose-Dependent Transitions in Mechanisms of Toxicity established a group of academic, government, and industry scientists to engage in active technical discourse on the issue of dose-dependent transitions in mechanisms of toxicity. Over the next 18 months, case studies were examined. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, the peroxisome proliferator-activated receptor, progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc (Slikker, W., Jr., Andersen, M.E., Bogdanffy, M.S., Bus, J.S., Cohen, S.D., Conolly, R.B., David, R.M., Doerrer, N.G., Dorman, D.C., Gaylor, D.W., Hattis, D., Rogers, J.M., Setzer, R.W., Swenberg, J.A., Wallace, K., 2004. Dose-dependent transitions in mechanisms of toxicity: case studies. Toxicol. Appl. Pharmacol. 201(3), 226-294 (this issue)). The HESI Project Committee sponsored two technical workshops in 2003. The first of these workshops took place on February 12-13, 2003, and was co-sponsored by the Agency for Toxic Substances and Disease Registry, the American Chemistry Council, the National Institute of Environmental Health Sciences, the Society of Toxicology, and the U.S. Environmental Protection Agency. Additional support was provided by Health Canada. Invited experts from government, academia, and industry provided scientific perspectives and recommendations at the workshop. The purpose of

  1. A review of acrylamide toxicity and its mechanism

    Directory of Open Access Journals (Sweden)

    Ehsan Zamani

    2017-05-01

    Full Text Available Acrylamide (AA is an important industrial chemical agent that is mainly used in the production of polymers and copolymers. Recently it has been attention because of its production in the diet at high-temperature (>120 ºC processes such as cooking, frying, toasting, roasting or baking of high carbohydrate foods. According to high exposure to acrylamide, recognition of its toxic effect is necessary. Neurotoxicity, reproductive toxicity and immunotoxicity of AA were observed in several studies. There isn’t a clear mechanism that justifies this toxicity. In this study we reviewed the mechanisms of AA toxicity especially oxidative stress and apoptosis. AA can cause neurotoxicity, reproductive toxicity and genotoxicity on animal models. It showed neurotoxicity in human. We suggested the oxidative stress is the main factor for inducing of acrylamide toxicities. We advised that modifying of food processing methods can be as a good way for decreasing of AA production in foods.

  2. Identifying developmental vascular disruptor compounds using a predictive signature and alternative toxicity models

    Science.gov (United States)

    Identifying Developmental Vascular Disruptor Compounds Using a Predictive Signature and Alternative Toxicity Models Presenting Author: Tamara Tal Affiliation: U.S. EPA/ORD/ISTD, RTP, NC, USA Chemically induced vascular toxicity during embryonic development can result in a wide...

  3. Mechanisms of nickel toxicity in microorganisms

    OpenAIRE

    Macomber, Lee; Hausinger, Robert P.

    2011-01-01

    Nickel has long been known to be an important human toxicant, including having the ability to form carcinomas, but until recently nickel was believed to be an issue only to microorganisms living in nickel-rich serpentine soils or areas contaminated by industrial pollution. This assumption was overturned by the discovery of a nickel defense system (RcnR/RcnA) found in microorganisms that live in a wide range of environmental niches, suggesting that nickel homeostasis is a general biological co...

  4. The toxic effects of chlorophenols and associated mechanisms in fish

    International Nuclear Information System (INIS)

    Ge, Tingting; Han, Jiangyuan; Qi, Yongmei; Gu, Xueyan; Ma, Lin; Zhang, Chen; Naeem, Sajid; Huang, Dejun

    2017-01-01

    Highlights: • We review the toxic effects of chlorophenols (CPs) and underlying mechanisms in fish. • CPs induce lethal effects, oxidative stress, endocrine disruption, reproductive toxicity and apoptosis in fish. • CPs exhibit toxicity through multiple signaling pathways in fish and different pathways co-exist under the same conditions. • Studies on DNA methylation provide new insights into our understanding of epigenetic mechanisms of CPs-induced toxicity. • Mechanisms studies on CPs toxicity performed under environmental concentrations need more attentions. - Abstract: Chlorophenols (CPs) are ubiquitous contaminants in the environment primarily released from agricultural and industrial wastewater. These compounds are not readily degraded naturally, and easily accumulate in organs, tissues and cells via food chains, further leading to acute and chronic toxic effects on aquatic organisms. Herein, we review the available literature regarding CP toxicity in fish, with special emphasis on the potential toxic mechanisms. CPs cause oxidative stress via generation of reactive oxygen species, induction of lipid peroxidation and/or oxidative DNA damage along with inhibition of antioxidant systems. CPs affect immune system by altering the number of mature B cells and macrophages, while suppressing phagocytosis and down-regulating the expression of immune factors. CPs also disrupt endocrine function by affecting hormone levels, or inducing abnormal gene expression and interference with hormone receptors. CPs at relatively higher concentrations induce apoptosis via mitochondria-mediated pathway, cell death receptor-mediated pathway, and/or DNA damage-mediated pathway. CPs at relatively lower concentrations promote cell proliferation, and foster cancers-prone environment by increasing the rate of point mutations and oxidative DNA lesions. These toxic effects in fish are induced directly by CPs per se or indirectly by their metabolic products. In addition, recent

  5. The toxic effects of chlorophenols and associated mechanisms in fish

    Energy Technology Data Exchange (ETDEWEB)

    Ge, Tingting; Han, Jiangyuan; Qi, Yongmei; Gu, Xueyan; Ma, Lin; Zhang, Chen; Naeem, Sajid; Huang, Dejun, E-mail: huangdj@lzu.edu.cn

    2017-03-15

    Highlights: • We review the toxic effects of chlorophenols (CPs) and underlying mechanisms in fish. • CPs induce lethal effects, oxidative stress, endocrine disruption, reproductive toxicity and apoptosis in fish. • CPs exhibit toxicity through multiple signaling pathways in fish and different pathways co-exist under the same conditions. • Studies on DNA methylation provide new insights into our understanding of epigenetic mechanisms of CPs-induced toxicity. • Mechanisms studies on CPs toxicity performed under environmental concentrations need more attentions. - Abstract: Chlorophenols (CPs) are ubiquitous contaminants in the environment primarily released from agricultural and industrial wastewater. These compounds are not readily degraded naturally, and easily accumulate in organs, tissues and cells via food chains, further leading to acute and chronic toxic effects on aquatic organisms. Herein, we review the available literature regarding CP toxicity in fish, with special emphasis on the potential toxic mechanisms. CPs cause oxidative stress via generation of reactive oxygen species, induction of lipid peroxidation and/or oxidative DNA damage along with inhibition of antioxidant systems. CPs affect immune system by altering the number of mature B cells and macrophages, while suppressing phagocytosis and down-regulating the expression of immune factors. CPs also disrupt endocrine function by affecting hormone levels, or inducing abnormal gene expression and interference with hormone receptors. CPs at relatively higher concentrations induce apoptosis via mitochondria-mediated pathway, cell death receptor-mediated pathway, and/or DNA damage-mediated pathway. CPs at relatively lower concentrations promote cell proliferation, and foster cancers-prone environment by increasing the rate of point mutations and oxidative DNA lesions. These toxic effects in fish are induced directly by CPs per se or indirectly by their metabolic products. In addition, recent

  6. Identifying and designing chemicals with minimal acute aquatic toxicity.

    Science.gov (United States)

    Kostal, Jakub; Voutchkova-Kostal, Adelina; Anastas, Paul T; Zimmerman, Julie Beth

    2015-05-19

    Industrial ecology has revolutionized our understanding of material stocks and flows in our economy and society. For this important discipline to have even deeper impact, we must understand the inherent nature of these materials in terms of human health and the environment. This paper focuses on methods to design synthetic chemicals to reduce their intrinsic ability to cause adverse consequence to the biosphere. Advances in the fields of computational chemistry and molecular toxicology in recent decades allow the development of predictive models that inform the design of molecules with reduced potential to be toxic to humans or the environment. The approach presented herein builds on the important work in quantitative structure-activity relationships by linking toxicological and chemical mechanistic insights to the identification of critical physical-chemical properties needed to be modified. This in silico approach yields design guidelines using boundary values for physiochemical properties. Acute aquatic toxicity serves as a model endpoint in this study. Defining value ranges for properties related to bioavailability and reactivity eliminates 99% of the chemicals in the highest concern for acute aquatic toxicity category. This approach and its future implementations are expected to yield very powerful tools for life cycle assessment practitioners and molecular designers that allow rapid assessment of multiple environmental and human health endpoints and inform modifications to minimize hazard.

  7. Detoxification Mechanisms of Mercury Toxicity in Plants: A Review

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    Shilpa Shrivastava

    2015-12-01

    Full Text Available Mercury is one of the most toxic heavy metals present in the earth’s crust. It has been considered as environmental pollutant because of its potent toxicity to plants and humans. In this review, we discuss mercury toxicity responses on plant metabolism and its detoxification mechanism by phytochelatins and antioxidant enzymes. Some light is also shed on selenium antagonistic study with mercury. Due to its potential toxicity, it has attracted attention in fields of soil science and plant nutrition. Mercury has harmful toxic effects on the molecular and physiobiochemical behavior of plants. Mostly research work has been done on seed germination, and shoot, root, and leaf morphology. Enzyme responses with respect to mercury as a result Hg accumulated in food chain is also reviewed here. Hence, this review may provide a compiled data for other researches in this direction, to provide a better mechanism or details about mercury’s noxious effect in the ecosystem.

  8. Acute toxicity and associated mechanisms of four strobilurins in algae.

    Science.gov (United States)

    Liu, Xiaoxu; Wang, Yu; Chen, Hao; Zhang, Junli; Wang, Chengju; Li, Xuefeng; Pang, Sen

    2018-04-03

    Strobilurins have been reported highly toxic to non-target aquatic organisms but few illustrated how they cause toxic effects on algae. This study investigated the acute toxicity of Kresoxim-methy (KRE), Pyraclostrobin (PYR), Trifloxystrobin (TRI) and Picoxystrobin (PIC) on two algae and their toxicity mechanisms. Four strobilurins showed lower toxic effects on Chlorella pyrenoidsa but higher on Chlorella vulgaris. bc1 complex activities in C. vulgaris were significantly inhibited by all strobilurins, suggesting bc 1 complex might be the target of strobilurin toxicity in algae. Moreover, SOD, CAT and POD activities were significantly up-regulated by all doses of KRE, PYR and PIC. In contrast, low concentrations of TRI stimulated SOD and POD activities but highest concentration significantly inhibited those activities. Comet assays showed damaged DNA in C. vulgaris by four strobulirins, suggesting their potential genotoxic threats to algae. The results illustrated acute toxicity by strobulirins on algae and their possible toxicity mechanisms. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. Creating mechanisms of toxic substances emission of combustion engines

    Directory of Open Access Journals (Sweden)

    Jankowski Antoni

    2015-12-01

    Full Text Available The paper analyses the mechanisms of creation of toxic exhaust gases, which mainly derived from inexact fuel metering and improper air-fuel mixture preparation. The paper describes the process of creating toxic components in the exhaust gases of piston engines during engine operation, and impact on the emission of these components determining the composition of the fuel mixture determined equivalence factor Φ. The principal mechanisms of formation of toxic exhaust gases, in particular nitrogen oxides, carbon monoxide and hydrocarbons, and also essential according to create each of toxic exhaust gases are the subject of the paper. Moreover, empirical relationships, by means of which it is possible to determine the time of creation of the individual components of toxic exhaust gases, are presented. For example, one of the mechanisms for prompt formation of nitrogen oxides and hydrocarbons graphic illustration of formation as a function of crank angle is described. At the conclusion, the summary and significance of information on creation mechanisms of toxic components in the exhaust gases of piston engines are presented.

  10. Understanding mechanisms of toxicity: Insights from drug discovery research

    International Nuclear Information System (INIS)

    Houck, Keith A.; Kavlock, Robert J.

    2008-01-01

    Toxicology continues to rely heavily on use of animal testing for prediction of potential for toxicity in humans. Where mechanisms of toxicity have been elucidated, for example endocrine disruption by xenoestrogens binding to the estrogen receptor, in vitro assays have been developed as surrogate assays for toxicity prediction. This mechanistic information can be combined with other data such as exposure levels to inform a risk assessment for the chemical. However, there remains a paucity of such mechanistic assays due at least in part to lack of methods to determine specific mechanisms of toxicity for many toxicants. A means to address this deficiency lies in utilization of a vast repertoire of tools developed by the drug discovery industry for interrogating the bioactivity of chemicals. This review describes the application of high-throughput screening assays as experimental tools for profiling chemicals for potential for toxicity and understanding underlying mechanisms. The accessibility of broad panels of assays covering an array of protein families permits evaluation of chemicals for their ability to directly modulate many potential targets of toxicity. In addition, advances in cell-based screening have yielded tools capable of reporting the effects of chemicals on numerous critical cell signaling pathways and cell health parameters. Novel, more complex cellular systems are being used to model mammalian tissues and the consequences of compound treatment. Finally, high-throughput technology is being applied to model organism screens to understand mechanisms of toxicity. However, a number of formidable challenges to these methods remain to be overcome before they are widely applicable. Integration of successful approaches will contribute towards building a systems approach to toxicology that will provide mechanistic understanding of the effects of chemicals on biological systems and aid in rationale risk assessments

  11. Toxicity and Carcinogenicity Mechanisms of Fibrous Antigorite

    Directory of Open Access Journals (Sweden)

    Michael Balazy

    2007-03-01

    Full Text Available We studied the effects of fibrous antigorite on mesothelial MeT-5A and monocyte-macrophage J774 cell lines to further understand cellular mechanisms induced by asbestos fibers leading to lung damage and cancer. Antigorite is a mineral with asbestiform properties, which tends to associate with chrysotile or tremolite, and frequently occurs as the predominant mineral in the veins of several serpentinite rocks found abundantly in the Western Alps. Particles containing antigorite are more abundant in the breathing air of this region than those typically found in urban ambient air. Exposure of MeT-5A and J774 cells to fibrous antigorite at concentrations of 5-100 μg/ml for 72 hr induced dose-dependent cytotoxicity. Antigorite also stimulated the ROS production, induced the generation of nitrite and PGE2. MeT-5A cells were more sensitive to antigorite than J774 cells. The results of this study revealed that the fibrous antigorite stimulates cyclooxygenase and formation of hydroxyl and nitric oxide radicals. These changes represent early cellular responses to antigorite fibers, which lead to a host of pathological and neoplastic conditions because free radicals and PGE2 play important roles as mediators of tumor pathogenesis. Understanding the mechanisms of the cellular responses to antigorite and other asbestos particles should be helpful in designing rational prevention and treatment approaches.

  12. Identifying genes that mediate anthracyline toxicity in immune cells

    Directory of Open Access Journals (Sweden)

    Amber eFrick

    2015-04-01

    Full Text Available The role of the immune system in response to chemotherapeutic agents remains elusive. The interpatient variability observed in immune and chemotherapeutic cytotoxic responses is likely, at least in part, due to complex genetic differences. Through the use of a panel of genetically diverse mouse inbred strains, we developed a drug screening platform aimed at identifying genes underlying these chemotherapeutic cytotoxic effects on immune cells. Using genome-wide association studies (GWAS, we identified four genome-wide significant quantitative trait loci (QTL that contributed to the sensitivity of doxorubicin and idarubicin in immune cells. Of particular interest, a locus on chromosome 16 was significantly associated with cell viability following idarubicin administration (p = 5.01x10-8. Within this QTL lies App, which encodes amyloid beta precursor protein. Comparison of dose-response curves verified that T-cells in App knockout mice were more sensitive to idarubicin than those of C57BL/6J control mice (p < 0.05.In conclusion, the cellular screening approach coupled with GWAS led to the identification and subsequent validation of a gene involved in T-cell viability after idarubicin treatment. Previous studies have suggested a role for App in in vitro and in vivo cytotoxicity to anticancer agents; the overexpression of App enhances resistance, while the knockdown of this gene is deleterious to cell viability. Thus, further investigations should include performing mechanistic studies, validating additional genes from the GWAS, including Ppfia1 and Ppfibp1, and ultimately translating the findings to in vivo and human studies.

  13. Dose-dependent transitions in mechanisms of toxicity: case studies

    International Nuclear Information System (INIS)

    Slikker, William; Andersen, Melvin E.; Bogdanffy, Matthew S.; Bus, James S.; Cohen, Steven D.; Conolly, Rory B.; David, Raymond M.; Doerrer, Nancy G.; Dorman, David C.; Gaylor, David W.; Hattis, Dale; Rogers, John M.; Setzer, R. Woodrow; Swenberg, James A.; Wallace, Kendall

    2004-01-01

    Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed with increasing exposures, signaling the emergence of new modalities of toxic tissue injury at these higher doses. Therefore, dose-dependent transitions in principal mechanisms of toxicity may occur, and could have significant impact on the interpretation of reference data sets for risk assessment. To illustrate the existence of dose-dependent transitions in mechanisms of toxicity, a group of academic, government, and industry scientists, formed under the leadership of the ILSI Health and Environmental Sciences Institute (HESI), developed a series of case studies. These case studies included acetaminophen, butadiene, ethylene glycol, formaldehyde, manganese, methylene chloride, peroxisome proliferator-activated receptor (PPAR), progesterone/hydroxyflutamide, propylene oxide, vinyl acetate, vinyl chloride, vinylidene chloride, and zinc. The case studies formed the basis for technical discourse at two scientific workshops in 2003

  14. POTENTIAL PATHOPHYSIOLOGICAL MECHANISMS OF ULTRAFINE PARTICLE TOXIC EFFECTS IN HUMANS

    Directory of Open Access Journals (Sweden)

    JASMINA JOVIĆ-STOŠIĆ

    2008-03-01

    Full Text Available Epidemiological and clinical studies suggested the association of the particulate matter ambient air pollution and the increased morbidity and mortality, mainly from respiratory and cardiovascular diseases. The size of particles has great influence on their toxicity, because it determines the site in the respiratory tract where they deposit. The most well established theory explaining the mechanisms behind the increased toxicity of ultrafine particles (UFP, < 0.1 µm is that it has to do with the increased surface area and/or the combination with the increased number of particles. Biological effects of UFP are also determined by their shape and chemical composition, so it is not possible to estimate their toxicity in a general way. General hypothesis suggested that exposure to inhaled particles induces pulmonary alveolar inflammation as a basic pathophysiological event, triggering release of various proinflammatory cytokines. Chronic inflammation is a very important underlying mechanism in the genesis of atherosclerosis and cardiovascular diseases. UFP can freely move through the circulation, but their effects on the secondary organs are not known yet, so more studies on recognizing toxicological endpoints of UFP are needed. Determination of UFP toxicity and the estimation of their internal and biologically active dose are necessary for the evidence based conclusions connecting air pollution by UFP and human diseases.

  15. Genomic interrogation of mechanism(s) underlying cellular responses to toxicants

    International Nuclear Information System (INIS)

    Amin, Rupesh P.; Hamadeh, Hisham K.; Bushel, Pierre R.; Bennett, Lee; Afshari, Cynthia A.; Paules, Richard S.

    2002-01-01

    Assessment of the impact of xenobiotic exposure on human health and disease progression is complex. Knowledge of mode(s) of action, including mechanism(s) contributing to toxicity and disease progression, is valuable for evaluating compounds. Toxicogenomics, the subdiscipline which merges genomics with toxicology, holds the promise to contributing significantly toward the goal of elucidating mechanism(s) by studying genome-wide effects of xenobiotics. Global gene expression profiling, revolutionized by microarray technology and a crucial aspect of a toxicogenomic study, allows measuring transcriptional modulation of thousands of genes following exposure to a xenobiotic. We use our results from previous studies on compounds representing two different classes of xenobiotics (barbiturate and peroxisome proliferator) to discuss the application of computational approaches for analyzing microarray data to elucidate mechanism(s) underlying cellular responses to toxicants. In particular, our laboratory demonstrated that chemical-specific patterns of gene expression can be revealed using cDNA microarrays. Transcript profiling provides discrimination between classes of toxicants, as well as, genome-wide insight into mechanism(s) of toxicity and disease progression. Ultimately, the expectation is that novel approaches for predicting xenobiotic toxicity in humans will emerge from such information

  16. Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity

    Directory of Open Access Journals (Sweden)

    Stern Stephan T

    2012-06-01

    Full Text Available Abstract The study of the potential risks associated with the manufacture, use, and disposal of nanoscale materials, and their mechanisms of toxicity, is important for the continued advancement of nanotechnology. Currently, the most widely accepted paradigms of nanomaterial toxicity are oxidative stress and inflammation, but the underlying mechanisms are poorly defined. This review will highlight the significance of autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Most endocytic routes of nanomaterial cell uptake converge upon the lysosome, making the lysosomal compartment the most common intracellular site of nanoparticle sequestration and degradation. In addition to the endo-lysosomal pathway, recent evidence suggests that some nanomaterials can also induce autophagy. Among the many physiological functions, the lysosome, by way of the autophagy (macroautophagy pathway, degrades intracellular pathogens, and damaged organelles and proteins. Thus, autophagy induction by nanoparticles may be an attempt to degrade what is perceived by the cell as foreign or aberrant. While the autophagy and endo-lysosomal pathways have the potential to influence the disposition of nanomaterials, there is also a growing body of literature suggesting that biopersistent nanomaterials can, in turn, negatively impact these pathways. Indeed, there is ample evidence that biopersistent nanomaterials can cause autophagy and lysosomal dysfunctions resulting in toxicological consequences.

  17. Sources of toxicity and exposure information for identifying chemicals of high concern to children

    International Nuclear Information System (INIS)

    Stone, Alex; Delistraty, Damon

    2010-01-01

    Due to the large number of chemicals in commerce without adequate toxicity characterization data, coupled with an ineffective federal policy for chemical management in the United States, many states are grappling with the challenge to identify toxic chemicals that may pose a risk to human health and the environment. Specific populations (e.g., children, elderly) are particularly sensitive to these toxic chemicals. In 2008, the Children's Safe Product Act (CSPA) was passed in Washington State. The CSPA included specific requirements to identify High Priority Chemicals (HPCs) and Chemicals of High Concern to Children (CHCCs). To implement this legislation, a methodology was developed to identify HPCs from authoritative scientific and regulatory sources on the basis of toxicity criteria. Another set of chemicals of concern was then identified from authoritative sources, based on their potential exposure to children. Exposure potential was evaluated by identifying chemicals detected in biomonitoring studies (i.e., human tissues), as well as those present in residential exposure media (e.g., indoor air, house dust, drinking water, consumer products). Accordingly, CHCCs were defined as HPCs that also appear in biomonitoring studies or relevant exposure media. For chemicals with unique Chemical Abstracts Service (CAS) numbers, we identified 2044 HPCs and 2219 chemicals with potential exposure to children, resulting in 476 CHCCs. The process of chemical identification is dynamic, so that chemicals may be added or subtracted as new information becomes available. Although beyond the scope of this paper, the 476 CHCCs will be prioritized in a more detailed assessment, based on the strength and weight of evidence of toxicity and exposure data. Our approach was developed to be flexible which allows the addition or removal of specific sources of toxicity or exposure information, as well as transparent to allow clear identification of inputs. Although the methodology was

  18. Neurodevelopmental Disorders and Environmental Toxicants: Epigenetics as an Underlying Mechanism

    Directory of Open Access Journals (Sweden)

    Nguyen Quoc Vuong Tran

    2017-01-01

    Full Text Available The increasing prevalence of neurodevelopmental disorders, especially autism spectrum disorders (ASD and attention deficit hyperactivity disorder (ADHD, calls for more research into the identification of etiologic and risk factors. The Developmental Origin of Health and Disease (DOHaD hypothesizes that the environment during fetal and childhood development affects the risk for many chronic diseases in later stages of life, including neurodevelopmental disorders. Epigenetics, a term describing mechanisms that cause changes in the chromosome state without affecting DNA sequences, is suggested to be the underlying mechanism, according to the DOHaD hypothesis. Moreover, many neurodevelopmental disorders are also related to epigenetic abnormalities. Experimental and epidemiological studies suggest that exposure to prenatal environmental toxicants is associated with neurodevelopmental disorders. In addition, there is also evidence that environmental toxicants can result in epigenetic alterations, notably DNA methylation. In this review, we first focus on the relationship between neurodevelopmental disorders and environmental toxicants, in particular maternal smoking, plastic-derived chemicals (bisphenol A and phthalates, persistent organic pollutants, and heavy metals. We then review studies showing the epigenetic effects of those environmental factors in humans that may affect normal neurodevelopment.

  19. Neurodevelopmental Disorders and Environmental Toxicants: Epigenetics as an Underlying Mechanism

    Science.gov (United States)

    2017-01-01

    The increasing prevalence of neurodevelopmental disorders, especially autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD), calls for more research into the identification of etiologic and risk factors. The Developmental Origin of Health and Disease (DOHaD) hypothesizes that the environment during fetal and childhood development affects the risk for many chronic diseases in later stages of life, including neurodevelopmental disorders. Epigenetics, a term describing mechanisms that cause changes in the chromosome state without affecting DNA sequences, is suggested to be the underlying mechanism, according to the DOHaD hypothesis. Moreover, many neurodevelopmental disorders are also related to epigenetic abnormalities. Experimental and epidemiological studies suggest that exposure to prenatal environmental toxicants is associated with neurodevelopmental disorders. In addition, there is also evidence that environmental toxicants can result in epigenetic alterations, notably DNA methylation. In this review, we first focus on the relationship between neurodevelopmental disorders and environmental toxicants, in particular maternal smoking, plastic-derived chemicals (bisphenol A and phthalates), persistent organic pollutants, and heavy metals. We then review studies showing the epigenetic effects of those environmental factors in humans that may affect normal neurodevelopment. PMID:28567415

  20. A pharmacologically-based array to identify targets of cyclosporine A-induced toxicity in cultured renal proximal tubule cells

    International Nuclear Information System (INIS)

    Sarró, Eduard; Jacobs-Cachá, Conxita; Itarte, Emilio; Meseguer, Anna

    2012-01-01

    Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule cells (PTC), a comprehensive view of events occurring after CsA exposure remains to be described. For this purpose, we applied a pharmacologic approach based on the use of known activities of a large panel of potentially protective compounds and evaluated their efficacy in preventing CsA toxicity in cultured mouse PTC. Our results show that compounds that blocked protein synthesis and apoptosis, together with the CK2 inhibitor DMAT and the PI3K inhibitor apigenin, were the most efficient in preventing CsA toxicity. We also identified GSK3, MMPs and PKC pathways as potential targets to prevent CsA damage. Additionally, heparinase-I and MAPK inhibitors afforded partial but significant protection. Interestingly, antioxidants and calcium metabolism-related compounds were unable to ameliorate CsA-induced cytotoxicity. Subsequent experiments allowed us to clarify the hierarchical relationship of targeted pathways after CsA treatment, with ER stress identified as an early effector of CsA toxicity, which leads to ROS generation, phenotypical changes and cell death. In summary, this work presents a novel experimental approach to characterizing cellular responses to cytotoxics while pointing to new targets to prevent CsA-induced toxicity in proximal tubule cells. Highlights: ► We used a novel pharmacological approach to elucidate cyclosporine (CsA) toxicity. ► The ability of a broad range of compounds to prevent CsA toxicity was evaluated. ► CsA toxicity was monitored using LDH release assay and PARP cleavage. ► Protein synthesis, PI3K, GSK3, MMP, PKC and caspase inhibitors prevented CsA toxicity. ► We also identified ER

  1. A pharmacologically-based array to identify targets of cyclosporine A-induced toxicity in cultured renal proximal tubule cells

    Energy Technology Data Exchange (ETDEWEB)

    Sarró, Eduard, E-mail: eduard.sarro@vhir.org [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Jacobs-Cachá, Conxita, E-mail: conxita.jacobs@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Itarte, Emilio, E-mail: emili.itarte@uab.es [Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain); Meseguer, Anna, E-mail: ana.meseguer@vhir.org [Renal Physiopathology, CIBBIM-Nanomedicine, Vall d' Hebron Research Institute (VHIR), 08035 Barcelona (Spain); Departament de Bioquimica i Biologia Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra (Barcelona) (Spain)

    2012-01-15

    Mechanisms of cyclosporine A (CsA)-induced nephrotoxicity were generally thought to be hemodynamic in origin; however, there is now accumulating evidence of a direct tubular effect. Although genomic and proteomic experiments by our group and others provided overall information on genes and proteins up- or down-regulated by CsA in proximal tubule cells (PTC), a comprehensive view of events occurring after CsA exposure remains to be described. For this purpose, we applied a pharmacologic approach based on the use of known activities of a large panel of potentially protective compounds and evaluated their efficacy in preventing CsA toxicity in cultured mouse PTC. Our results show that compounds that blocked protein synthesis and apoptosis, together with the CK2 inhibitor DMAT and the PI3K inhibitor apigenin, were the most efficient in preventing CsA toxicity. We also identified GSK3, MMPs and PKC pathways as potential targets to prevent CsA damage. Additionally, heparinase-I and MAPK inhibitors afforded partial but significant protection. Interestingly, antioxidants and calcium metabolism-related compounds were unable to ameliorate CsA-induced cytotoxicity. Subsequent experiments allowed us to clarify the hierarchical relationship of targeted pathways after CsA treatment, with ER stress identified as an early effector of CsA toxicity, which leads to ROS generation, phenotypical changes and cell death. In summary, this work presents a novel experimental approach to characterizing cellular responses to cytotoxics while pointing to new targets to prevent CsA-induced toxicity in proximal tubule cells. Highlights: ► We used a novel pharmacological approach to elucidate cyclosporine (CsA) toxicity. ► The ability of a broad range of compounds to prevent CsA toxicity was evaluated. ► CsA toxicity was monitored using LDH release assay and PARP cleavage. ► Protein synthesis, PI3K, GSK3, MMP, PKC and caspase inhibitors prevented CsA toxicity. ► We also identified ER

  2. Molecular mechanisms of acrolein toxicity: relevance to human disease.

    Science.gov (United States)

    Moghe, Akshata; Ghare, Smita; Lamoreau, Bryan; Mohammad, Mohammad; Barve, Shirish; McClain, Craig; Joshi-Barve, Swati

    2015-02-01

    Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and its potential as a serious environmental health threat is beginning to be recognized. Humans are exposed to acrolein per oral (food and water), respiratory (cigarette smoke, automobile exhaust, and biocide use) and dermal routes, in addition to endogenous generation (metabolism and lipid peroxidation). Acrolein has been suggested to play a role in several disease states including spinal cord injury, multiple sclerosis, Alzheimer's disease, cardiovascular disease, diabetes mellitus, and neuro-, hepato-, and nephro-toxicity. On the cellular level, acrolein exposure has diverse toxic effects, including DNA and protein adduction, oxidative stress, mitochondrial disruption, membrane damage, endoplasmic reticulum stress, and immune dysfunction. This review addresses our current understanding of each pathogenic mechanism of acrolein toxicity, with emphasis on the known and anticipated contribution to clinical disease, and potential therapies. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Acute toxicity tests and meta-analysis identify gaps in tropical ecotoxicology for amphibians.

    Science.gov (United States)

    Ghose, Sonia L; Donnelly, Maureen A; Kerby, Jacob; Whitfield, Steven M

    2014-09-01

    Amphibian populations are declining worldwide, particularly in tropical regions where amphibian diversity is highest. Pollutants, including agricultural pesticides, have been identified as a potential contributor to decline, yet toxicological studies of tropical amphibians are very rare. The present study assesses toxic effects on amphibians of 10 commonly used commercial pesticides in tropical agriculture using 2 approaches. First, the authors conducted 8-d toxicity assays with formulations of each pesticide using individually reared red-eyed tree frog (Agalychnis callidryas) tadpoles. Second, they conducted a review of available data for the lethal concentration to kill 50% of test animals from the US Environmental Protection Agency's ECOTOX database to allow comparison with their findings. Lethal concentration estimates from the assays ranged over several orders of magnitude. The nematicides terbufos and ethoprophos and the fungicide chlorothalonil were very highly toxic, with evident effects within an order of magnitude of environmental concentrations. Acute toxicity assays and meta-analysis show that nematicides and fungicides are generally more toxic than herbicides yet receive far less research attention than less toxic herbicides. Given that the tropics have a high diversity of amphibians, the findings emphasize the need for research into the effects of commonly used pesticides in tropical countries and should help guide future ecotoxicological research in tropical regions. © 2014 SETAC.

  4. Dynamic zebrafish interactome reveals transcriptional mechanisms of dioxin toxicity.

    Directory of Open Access Journals (Sweden)

    Andrey Alexeyenko

    2010-05-01

    Full Text Available In order to generate hypotheses regarding the mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin causes toxicity, we analyzed global gene expression changes in developing zebrafish embryos exposed to this potent toxicant in the context of a dynamic gene network. For this purpose, we also computationally inferred a zebrafish (Danio rerio interactome based on orthologs and interaction data from other eukaryotes.Using novel computational tools to analyze this interactome, we distinguished between dioxin-dependent and dioxin-independent interactions between proteins, and tracked the temporal propagation of dioxin-dependent transcriptional changes from a few genes that were altered initially, to large groups of biologically coherent genes at later times. The most notable processes altered at later developmental stages were calcium and iron metabolism, embryonic morphogenesis including neuronal and retinal development, a variety of mitochondria-related functions, and generalized stress response (not including induction of antioxidant genes. Within the interactome, many of these responses were connected to cytochrome P4501A (cyp1a as well as other genes that were dioxin-regulated one day after exposure. This suggests that cyp1a may play a key role initiating the toxic dysregulation of those processes, rather than serving simply as a passive marker of dioxin exposure, as suggested by earlier research.Thus, a powerful microarray experiment coupled with a flexible interactome and multi-pronged interactome tools (which are now made publicly available for microarray analysis and related work suggest the hypothesis that dioxin, best known in fish as a potent cardioteratogen, has many other targets. Many of these types of toxicity have been observed in mammalian species and are potentially caused by alterations to cyp1a.

  5. Thallium Toxicity: General Issues, Neurological Symptoms, and Neurotoxic Mechanisms.

    Science.gov (United States)

    Osorio-Rico, Laura; Santamaria, Abel; Galván-Arzate, Sonia

    2017-01-01

    Thallium (Tl + ) is a ubiquitous natural trace metal considered as the most toxic among heavy metals. The ionic ratio of Tl + is similar to that of potassium (K + ), therefore accounting for the replacement of the latter during enzymatic reactions. The principal organelle damaged after Tl + exposure is mitochondria. Studies on the mechanisms of Tl + include intrinsic pathways altered and changes in antiapoptotic and proapoptotic proteins, cytochrome c, and caspases. Oxidative damage pathways increase after Tl + exposure to produce reactive oxygen species (ROS), changes in physical properties of the cell membrane caused by lipid peroxidation, and concomitant activation of antioxidant mechanisms. These processes are likely to account for the neurotoxic effects of the metal. In humans, Tl + is absorbed through the skin and mucous membranes and then is widely distributed throughout the body to be accumulated in bones, renal medulla, liver, and the Central Nervous System. Given the growing relevance of Tl + intoxication, in recent years there is a notorious increase in the number of reports attending Tl + pollution in different countries. In this sense, the neurological symptoms produced by Tl + and its neurotoxic effects are gaining attention as they represent a serious health problem all over the world. Through this review, we present an update to general information about Tl + toxicity, making emphasis on some recent data about Tl + neurotoxicity, as a field requiring attention at the clinical and preclinical levels.

  6. Toxic polyacetylenes in the genus Bupleurum (Apiaceae) - Distribution, toxicity, molecular mechanism and analysis.

    Science.gov (United States)

    Lin, Meiyu; Zhang, Weidong; Su, Juan

    2016-12-04

    The genus Bupleurum includes approximately 200 species that are widely distributed in the Northern Hemisphere, Eurasia and North Africa. Certain species of this genus have long been used as antiphlogistic, antipyretic and analgesic agents in traditional folk medicine. As described in the Chinese Pharmacopoeia, the roots of Bupleurum chinense DC. and B. scorzonerifolium Willd. are the herbal materials that compose Chaihu (Radix Bupleuri), a well-known TCM herb. This review aims to provide up-to-date and comprehensive information regarding the distribution, toxicity, molecular mechanism and relatively new methods for the qualitative and quantitative determination of polyacetylenes in different Bupleurum species. The information needed for this paper were sourced from publishing sites such as Elsevier, science Direct, PubMed; electronic search engines such as Scopus and Web of Science, Google scholar; other scientific database sites for chemicals such as ChemSpider, PubChem, SciFinder, and also from on line books. Polyacetylenes, which are widely distributed in genus Bupleurum of the Apiaceae family, have high toxicity. Among polyacetylenes, bupleurotoxin, acetylbupleurotoxin and oenanthotoxin have strong neurotoxicity. Through previous research, it was found that the toxicity of Bupleurum polyacetylenes manifested as epileptic seizures, with the target of toxicity being the brain. The neurotoxicity of polyacetylenes exhibits a relationship with the γ-aminobutyric acid (GABA) receptor pathway, and polyacetylenes have been shown to inhibit GABA-induced currents (I GABA ) in a competitive manner. The plants of genus Bupleurum have been used in traditional medicine for thousands of years. However, certain species of this genus are poisonous, and it was attributed to the high content of polyacetylenes. The present review indicates that certain polyacetylenes in the genus Bupleurum have highly neurotoxic effects. The major challenge with regard to toxic polyacetylenes is

  7. Toxicity of ozone and nitrogen dioxide to alveolar macrophages: comparative study revealing differences in their mechanism of toxic action

    NARCIS (Netherlands)

    Rietjens, I. M.; Poelen, M. C.; Hempenius, R. A.; Gijbels, M. J.; Alink, G. M.

    1986-01-01

    The toxicity of ozone and nitrogen dioxide is generally ascribed to their oxidative potential. In this study their toxic mechanism of action was compared using an intact cell model. Rat alveolar macrophages were exposed by means of gas diffusion through a Teflon film. In this in vitro system, ozone

  8. An epigenetic signal encoded protection mechanism is activated by graphene oxide to inhibit its induced reproductive toxicity in Caenorhabditis elegans.

    Science.gov (United States)

    Zhao, Yunli; Wu, Qiuli; Wang, Dayong

    2016-02-01

    Although many studies have suggested the adverse effects of engineered nanomaterials (ENMs), the self-protection mechanisms for organisms against ENMs toxicity are still largely unclear. Using Caenorhabditis elegans as an in vivo assay system, our results suggest the toxicity of graphene oxide in reducing reproductive capacity by inducing damage on gonad development. The observed reproductive toxicity of GO on gonad development was due to the combinational effect of germline apoptosis and cell cycle arrest, and DNA damage activation might act as an inducer for this combinational effect. For the underlying molecular mechanism of reproductive toxicity of GO, we raised a signaling cascade of HUS-1/CLK-2-CEP-1-EGL-1-CED-4-CED-3 to explain the roles of core apoptosis signaling pathway and DNA damage checkpoints. Moreover, we identified a miRNA regulation mechanism activated by GO to suppress its induced reproductive toxicity. A mir-360 regulation mechanism was activated by GO to suppress its induced DNA damage-apoptosis signaling cascade through affecting component of CEP-1. Our identified epigenetic signal encoded protection mechanism activated by GO suggests a novel self-protection mechanism for organisms against the ENMs toxicity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. In vitro functional screening as a means to identify new plasticizers devoid of reproductive toxicity

    International Nuclear Information System (INIS)

    Boisvert, Annie; Jones, Steven; Issop, Leeyah; Erythropel, Hanno C.; Papadopoulos, Vassilios; Culty, Martine

    2016-01-01

    Plasticizers are indispensable additives providing flexibility and malleability to plastics. Among them, several phthalates, including di (2-ethylhexyl) phthalate (DEHP), have emerged as endocrine disruptors, leading to their restriction in consumer products and creating a need for new, safer plasticizers. The goal of this project was to use in vitro functional screening tools to select novel non-toxic plasticizers suitable for further in vivo evaluation. A panel of novel compounds with satisfactory plasticizer properties and biodegradability were tested, along with several commercial plasticizers, such as diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®). MEHP, the monoester metabolite of DEHP was also included as reference compound. Because phthalates target mainly testicular function, including androgen production and spermatogenesis, we used the mouse MA-10 Leydig and C18-4 spermatogonial cell lines as surrogates to examine cell survival, proliferation, steroidogenesis and mitochondrial integrity. The most promising compounds were further assessed on organ cultures of rat fetal and neonatal testes, corresponding to sensitive developmental windows. Dose-response studies revealed the toxicity of most maleates and fumarates, while identifying several dibenzoate and succinate plasticizers as innocuous on Leydig and germ cells. Interestingly, DINCH®, a plasticizer marketed as a safe alternative to phthalates, exerted a biphasic effect on steroid production in MA-10 and fetal Leydig cells. MEHP was the only plasticizer inducing the formation of multinucleated germ cells (MNG) in organ culture. Overall, organ cultures corroborated the cell line data, identifying one dibenzoate and one succinate as the most promising candidates. The adoption of such collaborative approaches for developing new chemicals should help prevent the development of compounds potentially harmful to human health. - Highlights: • Phthalate plasticizers exert toxic effects on male reproduction

  10. In vitro functional screening as a means to identify new plasticizers devoid of reproductive toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Boisvert, Annie; Jones, Steven; Issop, Leeyah [The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada H4A 3J1 (Canada); Department of Medicine, McGill University, Montreal, Quebec, Canada H4A 3J1 (Canada); Erythropel, Hanno C. [Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada H4A 3J1 (Canada); Papadopoulos, Vassilios [The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada H4A 3J1 (Canada); Department of Medicine, McGill University, Montreal, Quebec, Canada H4A 3J1 (Canada); Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada H4A 3J1 (Canada); Culty, Martine, E-mail: martine.culty@mcgill.ca [The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada H4A 3J1 (Canada); Department of Medicine, McGill University, Montreal, Quebec, Canada H4A 3J1 (Canada); Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada H4A 3J1 (Canada)

    2016-10-15

    Plasticizers are indispensable additives providing flexibility and malleability to plastics. Among them, several phthalates, including di (2-ethylhexyl) phthalate (DEHP), have emerged as endocrine disruptors, leading to their restriction in consumer products and creating a need for new, safer plasticizers. The goal of this project was to use in vitro functional screening tools to select novel non-toxic plasticizers suitable for further in vivo evaluation. A panel of novel compounds with satisfactory plasticizer properties and biodegradability were tested, along with several commercial plasticizers, such as diisononyl-cyclohexane-1,2-dicarboxylate (DINCH®). MEHP, the monoester metabolite of DEHP was also included as reference compound. Because phthalates target mainly testicular function, including androgen production and spermatogenesis, we used the mouse MA-10 Leydig and C18-4 spermatogonial cell lines as surrogates to examine cell survival, proliferation, steroidogenesis and mitochondrial integrity. The most promising compounds were further assessed on organ cultures of rat fetal and neonatal testes, corresponding to sensitive developmental windows. Dose-response studies revealed the toxicity of most maleates and fumarates, while identifying several dibenzoate and succinate plasticizers as innocuous on Leydig and germ cells. Interestingly, DINCH®, a plasticizer marketed as a safe alternative to phthalates, exerted a biphasic effect on steroid production in MA-10 and fetal Leydig cells. MEHP was the only plasticizer inducing the formation of multinucleated germ cells (MNG) in organ culture. Overall, organ cultures corroborated the cell line data, identifying one dibenzoate and one succinate as the most promising candidates. The adoption of such collaborative approaches for developing new chemicals should help prevent the development of compounds potentially harmful to human health. - Highlights: • Phthalate plasticizers exert toxic effects on male reproduction

  11. The Simplest Flowchart Stating the Mechanisms for Organic Xenobiotics-induced Toxicity: Can it Possibly be Accepted as a "Central Dogma" for Toxic Mechanisms?

    Science.gov (United States)

    Park, Yeong-Chul; Lee, Sundong; Cho, Myung-Haing

    2014-09-01

    Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems.

  12. An improved anti-leech mechanism based on session identifier

    Science.gov (United States)

    Zhang, Jianbiao; Zhu, Tong; Zhang, Han; Lin, Li

    2012-01-01

    With the rapid development of information technology and extensive requirement of network resource sharing, plenty of resource hotlinking phenomenons appear on the internet. The hotlinking problem not only harms the interests of legal websites but also leads to a great affection to fair internet environment. The anti-leech technique based on session identifier is highly secure, but the transmission of session identifier in plaintext form causes some security flaws. In this paper, a proxy hotlinking technique based on session identifier is introduced firstly to illustrate these security flaws; next, this paper proposes an improved anti-leech mechanism based on session identifier, the mechanism takes the random factor as the core and detects hotlinking request using a map table that contains random factor, user's information and time stamp; at last the paper analyzes the security of mechanism in theory. The result reveals that the improved mechanism has the merits of simple realization, high security and great flexibility.

  13. Metal and pharmaceutical mixtures: Is ion loss the mechanism underlying acute toxicity and widespread additive toxicity in zebrafish?

    International Nuclear Information System (INIS)

    Alsop, Derek; Wood, Chris M.

    2013-01-01

    Highlights: •Zebrafish larvae were used to test the acute toxicity of contaminant mixtures. •Interactions were observed between metals, ammonia and pharmaceuticals. •Larval Na + loss was observed with exposure to all acutely toxic contaminants tested. •Water quality criteria should recognize the toxic interactions between contaminants. -- Abstract: The acute toxicities and mechanisms of action of a variety of environmental contaminants were examined using zebrafish larvae (Danio rerio; 4–8 days post fertilization). Toxic interactions were observed between metals. For example, the addition of a sublethal level of nickel (15% of the LC 50 , one third of the LC 01 ) to all copper treatments decreased the copper 96 h LC 50 by 58%, while sublethal copper exposure (6% of the copper LC 50 , 13% of the LC 01 ) decreased the cadmium 96 h LC 50 by 47%. Two predictive models were assessed, the concentration addition (CA) model, which assumes similar mechanisms of action, and the independent action (IA) model, which assumes different mechanisms of action. Quantitative comparisons indicated the CA model performed better than the IA model; the latter tended to underestimate combined toxicity to a greater extent. The effects of mixtures with nickel or ammonia were typically additive, while mixtures with copper or cadmium were typically greater than additive. Larvae exposed to cadmium, copper or nickel experienced whole body ion loss. Decreases were greatest for Na + followed by K + (as high as 19% and 9%, respectively, in 24 h). Additive toxicity between copper and other pharmaceutical compounds such as fluoxetine (Prozac™), β-naphthoflavone, estrogen and 17α-ethinylestradiol were also observed. Similar to metals, acutely toxic concentrations of fluoxetine, β-naphthoflavone and ammonia all decreased whole body Na + and K + . Overall, whole body Na + loss showed the greatest correlation with mortality across a variety of toxicants. We theorize that a disruption of

  14. Drug metabolizing enzyme systems and their relationship to toxic mechanisms

    International Nuclear Information System (INIS)

    Boyd, M.R.; Ravindranath, V.; Burka, L.T.

    1983-01-01

    The metabolism and toxicity of 3-methylfuran (3-MF) are described. The major product of metabolic activation of 3-MF appears to be disemicarbazones. Cursory description of toxic effects of 3-MF on lung and kidneys are provided. 18 refs

  15. Mechanisms of reduction of antitumor drug toxicity by liposome encapsulation

    Energy Technology Data Exchange (ETDEWEB)

    Rahman, Y. E.; Hanson, W. R.; Bharucha, J.; Ainsworth, E. J.; Jaroslow, B.

    1977-01-01

    The antitumor drug Actinomycin D is effective against the growth of some human solid tumors but its use is limited by its extreme toxicity. The development of a method of administering Act. D to reduce its systemic toxicity by incorporating the drug within liposomes reduced its toxicity but its tumoricidal activity was retained.

  16. Evaluation of pesticide toxicities with differing mechanisms using Caenorhabditis elegans.

    Science.gov (United States)

    Ruan, Qin-Li; Ju, Jing-Juan; Li, Yun-Hui; Liu, Ran; Pu, Yue-Pu; Yin, Li-Hong; Wang, Da-Yong

    2009-01-01

    The aim of this study was to (1) determine whether model organism Caenorhabditis elegans was sensitive to pesticides at the maximum concentration limits regulated by national agency standards, and (2) examine the multi-biological toxicities occurring as a result of exposure to pesticides. Five pesticides, namely, chlorpyrifos, imibacloprid, buprofezin, cyhalothrin, and glyphosate, with four different mechanisms of action were selected for the investigation. In accordance with national agency requirements, 4 exposed groups were used for each tested pesticide with the concentration scales ranging from 1.0 x 10(-3) to 1 mg/L. L4 larvae were exposed for 24 and 72 h, respectively. Endpoints of locomotion, propagation, and development were selected for the assay as parameters of toxicity. After exposure for 24 h, both the body bend frequency and head thrash frequency of nematodes exposed to chlorpyrifos, imibacloprid, and cyhalothrin decreased in a concentration-dependent manner, and there were significant differences between exposed groups at maximum concentration level (MCL) compared to control. The generation time of nematodes exposed to buprofezin 24 h significantly increased in a concentration-dependent manner in the highest exposed group. When exposed for 72 h, the body bend frequency and head thrash frequency of nematodes exposed to cyhalothrin markedly decreased at MCL. The generation time and brood size of nematodes exposed to buprofezin were reduced in a concentration-dependent manner. The behavior of nematodes was sensitive to pesticides with neurotoxic properties, while pesticides affecting insect growth modified the reproductive system. The effects of pesticides on nematodes exposed for 24 h appeared more sensitive than with exposure for 72 h. Caenorhabditis elegans may thus be used for assessing the adverse effects of pesticide residues in aquatic environment.

  17. Potential of isotope analysis (C, Cl) to identify dechlorination mechanisms

    Science.gov (United States)

    Cretnik, Stefan; Thoreson, Kristen; Bernstein, Anat; Ebert, Karin; Buchner, Daniel; Laskov, Christine; Haderlein, Stefan; Shouakar-Stash, Orfan; Kliegman, Sarah; McNeill, Kristopher; Elsner, Martin

    2013-04-01

    Chloroethenes are commonly used in industrial applications, and detected as carcinogenic contaminants in the environment. Their dehalogenation is of environmental importance in remediation processes. However, a detailed understanding frequently accounted problem is the accumulation of toxic degradation products such as cis-dichloroethylene (cis-DCE) at contaminated sites. Several studies have addressed the reductive dehalogenation reactions using biotic and abiotic model systems, but a crucial question in this context has remained open: Do environmental transformations occur by the same mechanism as in their corresponding in vitro model systems? The presented study shows the potential to close this research gap using the latest developments in compound specific chlorine isotope analysis, which make it possible to routinely measure chlorine isotope fractionation of chloroethenes in environmental samples and complex reaction mixtures.1,2 In particular, such chlorine isotope analysis enables the measurement of isotope fractionation for two elements (i.e., C and Cl) in chloroethenes. When isotope values of both elements are plotted against each other, different slopes reflect different underlying mechanisms and are remarkably insensitive towards masking. Our results suggest that different microbial strains (G. lovleyi strain SZ, D. hafniense Y51) and the isolated cofactor cobalamin employ similar mechanisms of reductive dechlorination of TCE. In contrast, evidence for a different mechanism was obtained with cobaloxime cautioning its use as a model for biodegradation. The study shows the potential of the dual isotope approach as a tool to directly compare transformation mechanisms of environmental scenarios, biotic transformations, and their putative chemical lab scale systems. Furthermore, it serves as an essential reference when using the dual isotope approach to assess the fate of chlorinated compounds in the environment.

  18. Molecular mechanisms of toxicity of important food-borne phytotoxins.

    Science.gov (United States)

    Rietjens, Ivonne M C M; Martena, Martijn J; Boersma, Marelle G; Spiegelenberg, Wim; Alink, Gerrit M

    2005-02-01

    At present, there is an increasing interest for plant ingredients and their use in drugs, for teas, or in food supplements. The present review describes the nature and mechanism of action of the phytochemicals presently receiving increased attention in the field of food toxicology. This relates to compounds including aristolochic acids, pyrrolizidine alkaloids, beta-carotene, coumarin, the alkenylbenzenes safrole, methyleugenol and estragole, ephedrine alkaloids and synephrine, kavalactones, anisatin, St. John's wort ingredients, cyanogenic glycosides, solanine and chaconine, thujone, and glycyrrhizinic acid. It can be concluded that several of these phytotoxins cause concern, because of their bioactivation to reactive alkylating intermediates that are able to react with cellular macromolecules causing cellular toxicity, and, upon their reaction with DNA, genotoxicity resulting in tumors. Another group of the phytotoxins presented is active without the requirement for bioactivation and, in most cases, these compounds appear to act as neurotoxins interacting with one of the neurotransmitter systems. Altogether, the examples presented illustrate that natural does not equal safe and that in modern society adverse health effects, upon either acute or chronic exposure to phytochemicals, can occur as a result of use of plant- or herb-based foods, teas, or other extracts.

  19. TOXIC METAL EMISSIONS FROM INCINERATION: MECHANISMS AND CONTROL

    Science.gov (United States)

    Toxic metals appear in the effluents of many combustion processes, and their release into the environment has come under regulatory scrutiny. This paper reviews the nature of the problems associated with toxic metals in combustion processes, and describes where these problems occ...

  20. Metal and pharmaceutical mixtures: Is ion loss the mechanism underlying acute toxicity and widespread additive toxicity in zebrafish?

    Energy Technology Data Exchange (ETDEWEB)

    Alsop, Derek, E-mail: alsopde@mcmaster.ca; Wood, Chris M.

    2013-09-15

    Highlights: •Zebrafish larvae were used to test the acute toxicity of contaminant mixtures. •Interactions were observed between metals, ammonia and pharmaceuticals. •Larval Na{sup +} loss was observed with exposure to all acutely toxic contaminants tested. •Water quality criteria should recognize the toxic interactions between contaminants. -- Abstract: The acute toxicities and mechanisms of action of a variety of environmental contaminants were examined using zebrafish larvae (Danio rerio; 4–8 days post fertilization). Toxic interactions were observed between metals. For example, the addition of a sublethal level of nickel (15% of the LC{sub 50}, one third of the LC{sub 01}) to all copper treatments decreased the copper 96 h LC{sub 50} by 58%, while sublethal copper exposure (6% of the copper LC{sub 50}, 13% of the LC{sub 01}) decreased the cadmium 96 h LC{sub 50} by 47%. Two predictive models were assessed, the concentration addition (CA) model, which assumes similar mechanisms of action, and the independent action (IA) model, which assumes different mechanisms of action. Quantitative comparisons indicated the CA model performed better than the IA model; the latter tended to underestimate combined toxicity to a greater extent. The effects of mixtures with nickel or ammonia were typically additive, while mixtures with copper or cadmium were typically greater than additive. Larvae exposed to cadmium, copper or nickel experienced whole body ion loss. Decreases were greatest for Na{sup +} followed by K{sup +} (as high as 19% and 9%, respectively, in 24 h). Additive toxicity between copper and other pharmaceutical compounds such as fluoxetine (Prozac™), β-naphthoflavone, estrogen and 17α-ethinylestradiol were also observed. Similar to metals, acutely toxic concentrations of fluoxetine, β-naphthoflavone and ammonia all decreased whole body Na{sup +} and K{sup +}. Overall, whole body Na{sup +} loss showed the greatest correlation with mortality across a

  1. Developmental mechanisms of arsenite toxicity in zebrafish (Danio rerio) embryos

    International Nuclear Information System (INIS)

    Li Dan; Lu Cailing; Wang Ju; Hu Wei; Cao Zongfu; Sun Daguang; Xia Hongfei; Ma Xu

    2009-01-01

    Arsenic usually accumulates in soil, water and airborne particles, from which it is taken up by various organisms. Exposure to arsenic through food and drinking water is a major public health problem affecting some countries. At present there are limited laboratory data on the effects of arsenic exposure on early embryonic development and the mechanisms behind its toxicity. In this study, we used zebrafish as a model system to investigate the effects of arsenite on early development. Zebrafish embryos were exposed to a range of sodium arsenite concentrations (0-10.0 mM) between 4 and 120 h post-fertilization (hpf). Survival and early development of the embryos were not obviously influenced by arsenite concentrations below 0.5 mM. However, embryos exposed to higher concentrations (0.5-10.0 mM) displayed reduced survival and abnormal development including delayed hatching, retarded growth and changed morphology. Alterations in neural development included weak tactile responses to light (2.0-5.0 mM, 30 hpf), malformation of the spinal cord and disordered motor axon projections (2.0 mM, 48 hpf). Abnormal cardiac function was observed as bradycardia (0.5-2.0 mM, 60 hpf) and altered ventricular shape (2.0 mM, 48 hpf). Furthermore, altered cell proliferation (2.0 mM, 24 hpf) and apoptosis status (2.0 mM, 24 and 48 hpf), as well as abnormal genomic DNA methylation patterning (2.0 mM, 24 and 48 hpf) were detected in the arsenite-treated embryos. All of these indicate a possible relationship between arsenic exposure and developmental failure in early embryogenesis. Our studies suggest that the negative effects of arsenic on vertebrate embryogenesis are substantial

  2. Multiple mitigation mechanisms: Effects of submerged plants on the toxicity of nine insecticides to aquatic animals.

    Science.gov (United States)

    Brogan, William R; Relyea, Rick A

    2017-01-01

    Understanding the processes that regulate contaminant impacts in nature is an increasingly important challenge. For insecticides in surface waters, the ability of aquatic plants to sorb, or bind, hydrophobic compounds has been identified as a primary mechanism by which toxicity can be mitigated (i.e. the sorption-based model). However, recent research shows that submerged plants can also rapidly mitigate the toxicity of the less hydrophobic insecticide malathion via alkaline hydrolysis (i.e. the hydrolysis-based model) driven by increased water pH resulting from photosynthesis. However, it is still unknown how generalizable these mitigation mechanisms are across the wide variety of insecticides applied today, and whether any general rules can be ascertained about which types of chemicals may be mitigated by each mechanism. We quantified the degree to which the submerged plant Elodea canadensis mitigated acute (48-h) toxicity to Daphnia magna using nine commonly applied insecticides spanning three chemical classes (carbamates: aldicarb, carbaryl, carbofuran; organophosphates: malathion, diazinon, chlorpyrifos; pyrethroids: permethrin, bifenthrin, lambda-cyhalothrin). We found that insecticides possessing either high octanol-water partition coefficients (log K ow ) values (i.e. pyrethroids) or high susceptibility to alkaline hydrolysis (i.e. carbamates and malathion) were all mitigated to some degree by E. canadensis, while the plant had no effect on insecticides possessing intermediate log K ow values and low susceptibility to hydrolysis (i.e. chlorpyrifos and diazinon). Our results provide the first general insights into which types of insecticides are likely to be mitigated by different mechanisms based on known chemical properties. We suggest that current models and mitigation strategies would be improved by the consideration of both mitigation models. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. The Simplest Flowchart Stating the Mechanisms for Organic Xenobiotics-induced Toxicity: Can it Possibly be Accepted as a “Central Dogma” for Toxic Mechanisms?

    Science.gov (United States)

    Lee, Sundong; Cho, Myung-Haing

    2014-01-01

    Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems. PMID:25343011

  4. Toxic mechanisms of copper oxide nanoparticles in epithelial kidney cells

    DEFF Research Database (Denmark)

    Thit, Amalie; Selck, Henriette; Bjerregaard, Henning F.

    2015-01-01

    and levels of reduced glutathione (GSH) and eventually cell death. We show that ROS (Reactive Oxygen Species) generation plays a key role and occurs early in Poly toxicity as Poly-induced DNA damage and cell death could be mitigated by the antioxidant NAC (N-acetyl-cysteine). Here we propose a model...

  5. Triclosan: environmental exposure, toxicity and mechanisms of action.

    Science.gov (United States)

    Dann, Andrea B; Hontela, Alice

    2011-05-01

    Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol; TCS] is a broad spectrum antibacterial agent used in personal care, veterinary, industrial and household products. TCS is commonly detected in aquatic ecosystems, as it is only partially removed during the wastewater treatment process. Sorption, biodegradation and photolytic degradation mitigate the availability of TCS to aquatic biota; however the by-products such as methyltriclosan and other chlorinated phenols may be more resistant to degradation and have higher toxicity than the parent compound. The continuous exposure of aquatic organisms to TCS, coupled with its bioaccumulation potential, have led to detectable levels of the antimicrobial in a number of aquatic species. TCS has been also detected in breast milk, urine and plasma, with levels of TCS in the blood correlating with consumer use patterns of the antimicrobial. Mammalian systemic toxicity studies indicate that TCS is neither acutely toxic, mutagenic, carcinogenic, nor a developmental toxicant. Recently, however, concern has been raised over TCS's potential for endocrine disruption, as the antimicrobial has been shown to disrupt thyroid hormone homeostasis and possibly the reproductive axis. Moreover, there is strong evidence that aquatic species such as algae, invertebrates and certain types of fish are much more sensitive to TCS than mammals. TCS is highly toxic to algae and exerts reproductive and developmental effects in some fish. The potential for endocrine disruption and antibiotic cross-resistance highlights the importance of the judicious use of TCS, whereby the use of TCS should be limited to applications where it has been shown to be effective. Copyright © 2011 John Wiley & Sons, Ltd.

  6. Regulation of mRNA Translation Is a Novel Mechanism for Phthalate Toxicity.

    Directory of Open Access Journals (Sweden)

    Jun Ling

    Full Text Available Phthalates are a group of plasticizers that are widely used in many consumer products and medical devices, thus generating a huge burden to human health. Phthalates have been known to cause a number of developmental and reproductive disorders functioning as endocrine modulators. They are also involved in carcinogenesis with mechanisms less understood. To further understand the molecular mechanisms of phthalate toxicity, in this study we reported a new effect of phthalates on mRNA translation/protein synthesis, a key regulatory step of gene expression. Butyl benzyl phthalate (BBP was found to directly inhibit mRNA translation in vitro but showed a complicated pattern of affecting mRNA translation in cells. In human kidney embryonic cell (HEK-293T, BBP increased cap-dependent mRNA translation at lower concentrations but showed inhibitory effect at higher concentrations. Cap-independent translation was not affected. On the other hand, mono (2-ethylhexyl phthalate (MEHP as a major metabolite of another important phthalate di (2-ethylhexyl phthalate (DEHP inhibited both can-dependent and -independent mRNA translation in vivo. In contrast, BBP and MEHP exhibited an overall promoting effect on mRNA translation in cancer cells. Mechanistic studies identified that the level and phosphorylation of eIF4E-BP (eIF4E binding protein and the amount of eIF4GI in eIF4F complex were altered in accordance with the effect of BBP on translation. BBP was also identified to directly bind to eIF4E, providing a further mechanism underlying the regulation of mRNA by phthalate. At the cellular level BBP inhibited normal cell growth but slightly promoted cancer cells (HT29 growth. Overall, this study provides the first evidence that phthalates can directly regulate mRNA translation as a novel mechanism to mediate their biological toxicities.

  7. A general mechanism for intracellular toxicity of metal-containing nanoparticles

    KAUST Repository

    Sabella, Stefania

    2014-04-09

    The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment-where particles are abundantly internalized-is responsible for the cascading events associated with nanoparticles-induced intracellular toxicity. We call this mechanism a "lysosome-enhanced Trojan horse effect" since, in the case of nanoparticles, the protective cellular machinery designed to degrade foreign objects is actually responsible for their toxicity. To test our hypothesis, we compare the toxicity of similar gold particles whose main difference is in the internalization pathways. We show that particles known to pass directly through cell membranes become more toxic when modified so as to be mostly internalized by endocytosis. Furthermore, using experiments with chelating and lysosomotropic agents, we found that the toxicity mechanism for different metal containing NPs (such as metallic, metal oxide, and semiconductor NPs) is mainly associated with the release of the corresponding toxic ions. Finally, we show that particles unable to release toxic ions (such as stably coated NPs, or diamond and silica NPs) are not harmful to intracellular environments. The Royal Society of Chemistry 2014.

  8. A general mechanism for intracellular toxicity of metal-containing nanoparticles

    KAUST Repository

    Sabella, Stefania; Carney, Randy P.; Brunetti, Virgilio; Malvindi, Maria Ada; Al-Juffali, Noura; Vecchio, Giuseppe; Janes, Sam M.; Bakr, Osman; Cingolani, Roberto; Stellacci, Francesco; Pompa, Pier Paolo

    2014-01-01

    The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment-where particles are abundantly internalized-is responsible for the cascading events associated with nanoparticles-induced intracellular toxicity. We call this mechanism a "lysosome-enhanced Trojan horse effect" since, in the case of nanoparticles, the protective cellular machinery designed to degrade foreign objects is actually responsible for their toxicity. To test our hypothesis, we compare the toxicity of similar gold particles whose main difference is in the internalization pathways. We show that particles known to pass directly through cell membranes become more toxic when modified so as to be mostly internalized by endocytosis. Furthermore, using experiments with chelating and lysosomotropic agents, we found that the toxicity mechanism for different metal containing NPs (such as metallic, metal oxide, and semiconductor NPs) is mainly associated with the release of the corresponding toxic ions. Finally, we show that particles unable to release toxic ions (such as stably coated NPs, or diamond and silica NPs) are not harmful to intracellular environments. The Royal Society of Chemistry 2014.

  9. Toxicity of zinc oxide nanoparticles to zebrafish embryo: a physicochemical study of toxicity mechanism

    International Nuclear Information System (INIS)

    Bai Wei; Zhang Zhiyong; Tian Wenjing; He Xiao; Ma Yuhui; Zhao Yuliang; Chai Zhifang

    2010-01-01

    The biological impact of engineered nanomaterials released into the aquatic environment is a major concern. In this work, the properties of ZnO nanoparticles (nano-ZnO, 30 nm) were characterized in a water suspension (E3 medium), and a zebrafish 96-h post fertilization (hpf) embryo-larval test was performed to assess the toxicity of nano-ZnO suspension. Nano-ZnO was found to readily form aggregates with different sizes; small aggregates (142.4-517.7 nm) were still suspended in E3 medium, but large aggregates (>1 μm) quickly deposited on the bottom of 24-well plates; nano-ZnO was partially dissolved to Zn species (Zn (dis) ) in E3 medium. In the nano-ZnO suspension, small aggregates, Zn (dis) , and large aggregates might jointly exert influence on the development of zebrafish embryos. The embryo toxicity test revealed that nano-ZnO killed zebrafish embryos (50 and 100 mg/L), retarded the embryo hatching (1-25 mg/L), reduced the body length of larvae, and caused tail malformation after the 96 hpf exposure. Zn (dis) only partially contributed to the toxicity of nano-ZnO. This research highlights the need to further investigate the ecotoxicity of nano-ZnO in the water environment.

  10. Ecotoxicological evaluation of leachate from the Limeira sanitary landfill with a view to identifying acute toxicity

    OpenAIRE

    José Euclides Stipp Paterniani; Ronaldo Teixeira Pelegrini; Núbia Natália de Brito Pelegrini

    2007-01-01

    Final disposal of solid waste is still a cause for serious impacts on the environment. In sanitary landfills, waste undergoes physical, chemical, and biological decomposition, generating biogas and leachate. Leachate is a highly toxic liquid with a very high pollution potential. The purpose of this work is to evaluate toxicity of in natura leachate samples collected from Limeira Sanitary Landfill, in Limeira, SP. The ecotoxicological evaluation comprised acute toxicity assays using as test or...

  11. Mechanisms for regulating oxygen toxicity in phytophagous insects.

    Science.gov (United States)

    Ahmad, S; Pardini, R S

    1990-01-01

    The antioxidant enzymatic defense of insects for the regulation of oxygen toxicity was investigated. Insect species examined were lepidopterous larvae of the cabbage looper (Trichoplusia ni), southern armyworm (Spodoptera eridania), and black swallowtail (Papilio polyxenes). These phytophagous species are subject to both endogenous and exogenous sources of oxidative stress from toxic oxygen radicals, hydrogen peroxide (H2O2) and lipid peroxides (LOOH). In general, the constitutive levels of the enzymes superoxide dismutase (SOD), catalase (CAT), glutathione transferase (GT), and its peroxidase activity (GTpx), and glutathione reductase (GR), correlate well with natural feeding habits of these insects and their relative susceptibility to prooxidant plant allelochemicals, quercetin (a flavonoid), and xanthotoxin (a photoactive furanocoumarin). Induction of SOD activity which rapidly destroys superoxide radicals, appears to be the main response to dietary prooxidant exposure. A unique observation includes high constitutive activity of CAT and a broader subcellular distribution in all three insects than observed in most mammalian species. These attributes of CAT appear to be important in the prevention of excessive accumulation of cytotoxic H2O2. Unlike mammalian species, insects possess very low levels of a GPOX-like activity toward H2O2. Irrefutable proof that this activity is due to a selenium-dependent GPOX found in mammals, is lacking at this time. However, the activity of selenium-independent GTpx is unusually high in insects, suggesting that GTpx and not GPOX plays a prominent role in scavenging deleterious LOOHs. The GSSG generated from the GPOX and GTpx reactions may be reduced to GSH by GR activity. A key role of SOD in protecting insects from prooxidant toxicity was evident when its inhibition resulted in enhanced toxicity towards prooxidants. The role of antioxidant compounds in protecting these insects from toxic forms of oxygen has not been explored in

  12. 5-fluorouracil Toxicity Mechanism Determination in Human Keratinocytes: in vitro Study on HaCaT

    Directory of Open Access Journals (Sweden)

    Jan Hartinger

    2018-01-01

    Full Text Available 5-fluorouracil (5-FU and capecitabine therapy is often accompanied by palmar-plantar erythrodysesthesia (PPE which is manifestation of 5-FU toxicity in keratinocytes. The main mechanisms of 5-FU action are thymidylate synthase (TS inhibition which can be abrogated by thymidine and strengthened by calciumfolinate (CF and incorporation of fluorouridinetriphosphate into RNA which can be abrogated by uridine. For proper PPE treatment 5-FU mechanism of action in keratinocytes needs to be elucidated. We used the 5-FU toxicity modulators uridine, thymidine and CF to discover the mechanism of 5-FU action in human keratinocyte cell line HaCaT. To measure the cellular viability, we used MTT test and RTCA test. CF did not augment 5-FU toxicity and 5-FU toxicity was weakened by uridine. Therefore, the primary mechanism of 5-FU toxicity in keratinocytes is 5-FU incorporation into RNA. The uridine protective effect cannot fully develop in the presence of CF. Thymidine addition to 5-FU and uridine treated cells not only prevents the toxicity-augmenting CF effect but it also prolongs the 5-FU treated cells survival in comparison to uridine only. Therefore, it can be assumed that in the presence of uridine the 5-FU toxicity mechanism is switched from RNA incorporation to TS inhibition. Although particular 5-FU toxicity mechanisms were previously described in various cell types, this is the first time when various combinations of pyrimidine nucleosides and CF were used for 5-FU toxicity mechanism elucidation in human keratinocytes. We suggest that for PPE treatment ointment containing uridine and thymidine should be further clinically tested.

  13. The toxicity of oxidised DWCNTs to the aquatic organisms, and related causing mechanisms

    CSIR Research Space (South Africa)

    Lukhele, LP

    2013-08-01

    Full Text Available earlier reported for the three aquatic organisms in earlier scientific reports. Finally, the paper discusses the linkage between the toxicity mechanisms and the physicochemical properties of DWCNTs, namely: agglomeration state, surface chemistry...

  14. New land disposal restrictions on contaminated soil and debris, and newly identified toxicity characteristic organics

    International Nuclear Information System (INIS)

    Fortune, William B.; Schumann, Jean C.; Fallon, William E.; Badden, Janet W.; Smith, Edward H.

    1992-01-01

    The applicability of the Resource Conservation and Recovery Act (RCRA) Land Disposal Restrictions (LDR) program to radioactive mixed wastes (RMW) has been clarified through U.S. Environmental Protection Agency (EPA) and U.S. Department of Energy (DOE) rulemakings and notices. However, a number of waste management concerns involving RMW and RMW-contaminated soil and debris continue to exist with respect to achieving compliance with LDR provisions and treatment standards. Consequently, DOE has become increasingly proactive in its participation in the LDR rulemaking process and in the identification of LDR compliance issues associated with its RMW inventories. Both data and recommendations from across the DOE complex were collected and transmitted to EPA in response to proposed requirements that would implement LDR for contaminated soil and debris, and certain newly identified toxicity characteristic (TC) organics. Much of this information focused on concerns related to the application of proposed regulatory approaches to RMW streams. Highlights from the information included in these DOE responses are presented. (author)

  15. Genome-wide association study to identify candidate loci and genes for Mn toxicity tolerance in rice.

    Directory of Open Access Journals (Sweden)

    Asis Shrestha

    Full Text Available Manganese (Mn is an essential micro-nutrient for plants, but flooded rice fields can accumulate high levels of Mn2+ leading to Mn toxicity. Here, we present a genome-wide association study (GWAS to identify candidate loci conferring Mn toxicity tolerance in rice (Oryza sativa L.. A diversity panel of 288 genotypes was grown in hydroponic solutions in a greenhouse under optimal and toxic Mn concentrations. We applied a Mn toxicity treatment (5 ppm Mn2+, 3 weeks at twelve days after transplanting. Mn toxicity caused moderate damage in rice in terms of biomass loss and symptom formation despite extremely high shoot Mn concentrations ranging from 2.4 to 17.4 mg g-1. The tropical japonica subpopulation was more sensitive to Mn toxicity than other subpopulations. Leaf damage symptoms were significantly correlated with Mn uptake into shoots. Association mapping was conducted for seven traits using 416741 single nucleotide polymorphism (SNP markers using a mixed linear model, and detected six significant associations for the traits shoot manganese concentration and relative shoot length. Candidate regions contained genes coding for a heavy metal transporter, peroxidase precursor and Mn2+ ion binding proteins. The significant marker SNP-2.22465867 caused an amino acid change in a gene (LOC_Os02g37170 with unknown function. This study demonstrated significant natural variation in rice for Mn toxicity tolerance and the possibility of using GWAS to unravel genetic factors responsible for such complex traits.

  16. Quantum Mechanics/Molecular Mechanics Simulations Identify the Ring-Opening Mechanism of Creatininase.

    Science.gov (United States)

    Jitonnom, Jitrayut; Mujika, Jon I; van der Kamp, Marc W; Mulholland, Adrian J

    2017-12-05

    Creatininase catalyzes the conversion of creatinine (a biosensor for kidney function) to creatine via a two-step mechanism: water addition followed by ring opening. Water addition is common to other known cyclic amidohydrolases, but the precise mechanism for ring opening is still under debate. The proton donor in this step is either His178 or a water molecule bound to one of the metal ions, and the roles of His178 and Glu122 are unclear. Here, the two possible reaction pathways have been fully examined by means of combined quantum mechanics/molecular mechanics simulations at the SCC-DFTB/CHARMM22 level of theory. The results indicate that His178 is the main catalytic residue for the whole reaction and explain its role as proton shuttle during the ring-opening step. In the first step, His178 provides electrostatic stabilization to the gem-diolate tetrahedral intermediate. In the second step, His178 abstracts the hydroxyl proton of the intermediate and delivers it to the cyclic amide nitrogen, leading to ring opening. The latter is the rate-limiting step with a free energy barrier of 18.5 kcal/mol, in agreement with the experiment. We find that Glu122 must be protonated during the enzyme reaction, so that it can form a stable hydrogen bond with its neighboring water molecule. Simulations of the E122Q mutant showed that this replacement disrupts the H-bond network formed by three conserved residues (Glu34, Ser78, and Glu122) and water, increasing the energy barrier. Our computational studies provide a comprehensive explanation for previous structural and kinetic observations, including why the H178A mutation causes a complete loss of activity but the E122Q mutation does not.

  17. A review of toxicity and mechanisms of individual and mixtures of heavy metals in the environment.

    Science.gov (United States)

    Wu, Xiangyang; Cobbina, Samuel J; Mao, Guanghua; Xu, Hai; Zhang, Zhen; Yang, Liuqing

    2016-05-01

    The rational for the study was to review the literature on the toxicity and corresponding mechanisms associated with lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As), individually and as mixtures, in the environment. Heavy metals are ubiquitous and generally persist in the environment, enabling them to biomagnify in the food chain. Living systems most often interact with a cocktail of heavy metals in the environment. Heavy metal exposure to biological systems may lead to oxidation stress which may induce DNA damage, protein modification, lipid peroxidation, and others. In this review, the major mechanism associated with toxicities of individual metals was the generation of reactive oxygen species (ROS). Additionally, toxicities were expressed through depletion of glutathione and bonding to sulfhydryl groups of proteins. Interestingly, a metal like Pb becomes toxic to organisms through the depletion of antioxidants while Cd indirectly generates ROS by its ability to replace iron and copper. ROS generated through exposure to arsenic were associated with many modes of action, and heavy metal mixtures were found to have varied effects on organisms. Many models based on concentration addition (CA) and independent action (IA) have been introduced to help predict toxicities and mechanisms associated with metal mixtures. An integrated model which combines CA and IA was further proposed for evaluating toxicities of non-interactive mixtures. In cases where there are molecular interactions, the toxicogenomic approach was used to predict toxicities. The high-throughput toxicogenomics combines studies in genetics, genome-scale expression, cell and tissue expression, metabolite profiling, and bioinformatics.

  18. Dynamics in microbial communities: Unraveling mechanisms to identify principles

    Energy Technology Data Exchange (ETDEWEB)

    Konopka, Allan; Lindemann, Stephen R.; Fredrickson, Jim K.

    2015-07-01

    Diversity begets higher order properties such as functional stability and robustness in microbial communities, but principles that inform conceptual (and eventually predictive) models of community dynamics are lacking. Recent work has shown that selection as well as dispersal and drift shape communities, but the mechanistic bases for assembly of communities and the forces that maintain their function in the face of environmental perturbation are not well understood. Conceptually, some interactions among community members could generate endogenous dynamics in composition, even in the absence of environmental changes. These endogenous dynamics are further perturbed by exogenous forcing factors to produce a richer network of community interactions, and it is this “system” that is the basis for higher order community properties. Elucidation of principles that follow from this conceptual model requires identifying the mechanisms that (a) optimize diversity within a community and (b) impart community stability. The network of interactions between organisms can be an important element by providing a buffer against disturbance beyond the effect of functional redundancy, as alternative pathways with different combinations of microbes can be recruited to fulfill specific functions.

  19. On the mechanism of nanoparticulate CeO{sub 2} toxicity to freshwater algae

    Energy Technology Data Exchange (ETDEWEB)

    Angel, Brad M., E-mail: Brad.Angel@csiro.au [Centre for Environmental Contaminants Research, CSIRO Land and Water Flagship, Locked Bag 2007, Kirrawee, NSW 2232 (Australia); Vallotton, Pascal [Digital Productivity Flagship, CSIRO, North Ryde, NSW 1670 (Australia); Apte, Simon C. [Centre for Environmental Contaminants Research, CSIRO Land and Water Flagship, Locked Bag 2007, Kirrawee, NSW 2232 (Australia)

    2015-11-15

    Highlights: • Nanoparticulate CeO{sub 2} less toxic than micron-sized CeO{sub 2}. • UV light filters prevented ROS generation by CeO{sub 2}. • ROS not toxic mechanism: CeO{sub 2} toxicity was similar in presence and absence of ROS. • Strong sorption of nanoparticulate CeO{sub 2} to Pseudokirchneriella subcapitata in synthetic fresh water. • CeO{sub 2} sorption to cells was prevented and toxicity mitigated in the presence of DOC. - Abstract: The factors affecting the chronic (72-h) toxicity of three nanoparticulate (10–34 nm) and one micron-sized form of CeO{sub 2} to the green alga, Pseudokirchneriella subcapitata were investigated. To characterise transformations in solution, hydrodynamic diameters (HDD) were measured by dynamic light scatter, zeta potential values by electrophoretic mobility, and dissolution by equilibrium dialysis. The protective effects of humic and fulvic dissolved organic carbon (DOC) on toxicity were also assessed. To investigate the mechanisms of algal toxicity, the CytoViva hyperspectral imaging system was used to visualise algal–CeO{sub 2} interactions in the presence and absence of DOC, and the role of reactive oxygen species (ROS) was investigated by ‘switching off’ ROS production using UV-filtered lighting conditions. The nanoparticulate CeO{sub 2} immediately aggregated in solution to HDDs measured in the range 113–193 nm, whereas the HDD and zeta potential values were significantly lower in the presence of DOC. Negligible CeO{sub 2} dissolution over the time course of the bioassay ruled out potential toxicity from dissolved cerium. The nanoparticulate CeO{sub 2} concentration that caused 50% inhibition of algal growth rate (IC50) was in the range 7.6–28 mg/L compared with 59 mg/L for micron-sized ceria, indicating that smaller particles were more toxic. The presence of DOC mitigated toxicity, with IC50s increasing to greater than 100 mg/L. Significant ROS were generated in the nanoparticulate CeO{sub 2

  20. A general mechanism for intracellular toxicity of metal-containing nanoparticles

    Science.gov (United States)

    Sabella, Stefania; Carney, Randy P.; Brunetti, Virgilio; Malvindi, Maria Ada; Al-Juffali, Noura; Vecchio, Giuseppe; Janes, Sam M.; Bakr, Osman M.; Cingolani, Roberto; Stellacci, Francesco; Pompa, Pier Paolo

    2014-05-01

    The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment - where particles are abundantly internalized - is responsible for the cascading events associated with nanoparticles-induced intracellular toxicity. We call this mechanism a ``lysosome-enhanced Trojan horse effect'' since, in the case of nanoparticles, the protective cellular machinery designed to degrade foreign objects is actually responsible for their toxicity. To test our hypothesis, we compare the toxicity of similar gold particles whose main difference is in the internalization pathways. We show that particles known to pass directly through cell membranes become more toxic when modified so as to be mostly internalized by endocytosis. Furthermore, using experiments with chelating and lysosomotropic agents, we found that the toxicity mechanism for different metal containing NPs (such as metallic, metal oxide, and semiconductor NPs) is mainly associated with the release of the corresponding toxic ions. Finally, we show that particles unable to release toxic ions (such as stably coated NPs, or diamond and silica NPs) are not harmful to intracellular environments.The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment - where

  1. Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Sarah L. Kerns

    2016-08-01

    Full Text Available Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity and single nucleotide polymorphism (SNP associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08–4.69, p-value 4.16 × 10−8 and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10−8. These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.

  2. Molecular mechanisms of toxicity of important food-borne phytotoxins

    NARCIS (Netherlands)

    Rietjens, I.M.C.M.; Martena, M.J.; Boersma, M.G.; Spiegelenberg, W.; Alink, G.M.

    2005-01-01

    At present, there is an increasing interest for plant ingredients and their use in drugs, for teas, or in food supplements. The present review describes the nature and mechanism of action of the phytochemicals presently receiving increased attention in the field of food toxicology. This relates to

  3. Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics.

    Science.gov (United States)

    Wilmes, Anja; Bielow, Chris; Ranninger, Christina; Bellwon, Patricia; Aschauer, Lydia; Limonciel, Alice; Chassaigne, Hubert; Kristl, Theresa; Aiche, Stephan; Huber, Christian G; Guillou, Claude; Hewitt, Philipp; Leonard, Martin O; Dekant, Wolfgang; Bois, Frederic; Jennings, Paul

    2015-12-25

    Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of solid tumours. The major dose-limiting factor is nephrotoxicity, in particular in the proximal tubule. Here, we use an integrated omics approach, including transcriptomics, proteomics and metabolomics coupled to biokinetics to identify cell stress response pathways induced by cisplatin. The human renal proximal tubular cell line RPTEC/TERT1 was treated with sub-cytotoxic concentrations of cisplatin (0.5 and 2 μM) in a daily repeat dose treating regime for up to 14 days. Biokinetic analysis showed that cisplatin was taken up from the basolateral compartment, transported to the apical compartment, and accumulated in cells over time. This is in line with basolateral uptake of cisplatin via organic cation transporter 2 and bioactivation via gamma-glutamyl transpeptidase located on the apical side of proximal tubular cells. Cisplatin affected several pathways including, p53 signalling, Nrf2 mediated oxidative stress response, mitochondrial processes, mTOR and AMPK signalling. In addition, we identified novel pathways changed by cisplatin, including eIF2 signalling, actin nucleation via the ARP/WASP complex and regulation of cell polarization. In conclusion, using an integrated omic approach together with biokinetics we have identified both novel and established mechanisms of cisplatin toxicity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. ToxiFly: Can Fruit Flies be Used to Identify Toxicity Pathways for Airborne Chemicals?

    Science.gov (United States)

    Current high-throughput and alternative screening assays for chemical toxicity are unable to test volatile organic compounds (VOCs), thus limiting their scope. Further, the data generated by these assays require mechanistic information to link effects at molecular targets to adve...

  5. Quinolinic Acid, an Endogenous Molecule Combining Excitotoxicity, Oxidative Stress and Other Toxic Mechanisms

    Directory of Open Access Journals (Sweden)

    Verónica Pérez-De La Cruz

    2012-01-01

    Full Text Available Quinolinic acid (QUIN, an endogenous metabolite of the kynurenine pathway, is involved in several neurological disorders, including Huntington's disease, Alzheimer's disease, schizophrenia, HIV associated dementia (HAD etc. QUIN toxicity involves several mechanisms which trigger various metabolic pathways and transcription factors. The primary mechanism exerted by this excitotoxin in the central nervous system (CNS has been largely related with the overactivation of N-methyl-D-aspartate receptors and increased cytosolic Ca 2+ concentrations, followed by mitochondrial dysfunction, cytochrome c release, ATP exhaustion, free radical formation and oxidative damage. As a result, this toxic pattern is responsible for selective loss of middle size striatal spiny GABAergic neurons and motor alterations in lesioned animals. This toxin has recently gained attention in biomedical research as, in addition to its proven excitotoxic profile, a considerable amount of evidence suggests that oxidative stress and energetic disturbances are major constituents of its toxic pattern in the CNS. Hence, this profile has changed our perception of how QUIN-related disorders combine different toxic mechanisms resulting in brain damage. This review will focus on the description and integration of recent evidence supporting old and suggesting new mechanisms to explain QUIN toxicity.

  6. Epigenetics as a mechanism linking developmental exposures to long-term toxicity.

    Science.gov (United States)

    Barouki, R; Melén, E; Herceg, Z; Beckers, J; Chen, J; Karagas, M; Puga, A; Xia, Y; Chadwick, L; Yan, W; Audouze, K; Slama, R; Heindel, J; Grandjean, P; Kawamoto, T; Nohara, K

    2018-05-01

    A variety of experimental and epidemiological studies lend support to the Developmental Origin of Health and Disease (DOHaD) concept. Yet, the actual mechanisms accounting for mid- and long-term effects of early-life exposures remain unclear. Epigenetic alterations such as changes in DNA methylation, histone modifications and the expression of certain RNAs have been suggested as possible mediators of long-term health effects of environmental stressors. This report captures discussions and conclusions debated during the last Prenatal Programming and Toxicity meeting held in Japan. Its first aim is to propose a number of criteria that are critical to support the primary contribution of epigenetics in DOHaD and intergenerational transmission of environmental stressors effects. The main criteria are the full characterization of the stressors, the actual window of exposure, the target tissue and function, the specificity of the epigenetic changes and the biological plausibility of the linkage between those changes and health outcomes. The second aim is to discuss long-term effects of a number of stressors such as smoking, air pollution and endocrine disruptors in order to identify the arguments supporting the involvement of an epigenetic mechanism. Based on the developed criteria, missing evidence and suggestions for future research will be identified. The third aim is to critically analyze the evidence supporting the involvement of epigenetic mechanisms in intergenerational and transgenerational effects of environmental exposure and to particularly discuss the role of placenta and sperm. While the article is not a systematic review and is not meant to be exhaustive, it critically assesses the contribution of epigenetics in the long-term effects of environmental exposures as well as provides insight for future research. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Different toxicity mechanisms between bare and polymer-coated copper oxide nanoparticles in Lemna gibba

    International Nuclear Information System (INIS)

    Perreault, François; Popovic, Radovan; Dewez, David

    2014-01-01

    In this report, we investigated how the presence of a polymer shell (poly(styrene-co-butyl acrylate) alters the toxicity of CuO NPs in Lemna gibba. Based on total Cu concentration, core–shell CuO NPs were 10 times more toxic than CuO NPs, inducing a 50% decrease of growth rate at 0.4 g l −1 after 48-h of exposure while a concentration of 4.5 g l −1 was required for CuO NPs for a similar effect. Toxicity of CuO NPs was mainly due to NPs solubilization in the media. Based on the accumulated copper content in the plants, core–shell CuO NPs induced 4 times more reactive oxygen species compared to CuO NPs and copper sulfate, indicating that the presence of the polymer shell changed the toxic effect induced in L. gibba. This effect could not be attributed to the polymer alone and reveals that surface modification may change the nature of NPs toxicity. -- Highlights: • Bare and polymer-coated CuO nanoparticles were toxic to Lemna gibba. • Toxicity of bare CuO was mainly due to solubilized soluble copper. • Coated CuO accumulated inside the plants four times more. • Formation of reactive oxygen species was increased by polymer coating. • Coating of nanomaterials modifies mechanisms of action at cellular level. -- Polymer coating increases oxidative stress effect by core–shell CuO nanoparticles

  8. Mechanism of chlorphentermine-induced lymphocyte toxicity: initial investigations

    International Nuclear Information System (INIS)

    Sauers, L.J.; Wierda, D.; Reasor, M.J.

    1986-01-01

    Chlorphentermine (CP) inhibits the blastogenic response of mouse splenic and human peripheral blood lymphocytes to the T-cell mitogens, phytohemagglutinin (PHA) and concanavalin A (Con A). The purpose of these studies was to examine in vitro the mechanism mediating this immunosuppression. If mouse or human lymphocytes are pretreated with CP for 30 minutes, then stimulated with PHA, their blastogenic response is inhibited 80% and 45%, respectively. However, if CP is not added until 10 minutes or later following PHA stimulation, the inhibitory effect of the drug is essentially eliminated. The authors also determined that CP can potentiate Con A-induced agglutination of human lymphocytes. Enhanced agglutination can result from changes in the integrity of membrane phospholipids. Because changes in membrane phospholipid biochemistry characteristically occur within 10 minutes after mitogen-induced lymphocyte activation, the authors examined whether CP altered the incorporation of choline into cellular phospholipids. They found that CP decreases overall incorporation of 14 C-choline into cellular phospholipids of mouse lymphocytes by 45% during the first 4 hours of activation. These data suggest that the immunotoxicity associated with CP may be mediated by drug-induced changes at the membrane level that appear to occur early during lymphocyte activation

  9. Homeostatic and toxic mechanisms regulating manganese uptake, retention, and elimination

    Directory of Open Access Journals (Sweden)

    JEROME A ROTH

    2006-01-01

    Full Text Available This review attempts to summarize and clarify our basic knowledge as to the various factors that potentially influence the risks imposed from chronic exposure to high atmospheric levels of manganese (Mn. The studies describe the interrelationship of the different systems in the body that regulate Mn homeostasis by characterizing specific, biological components involved in its systemic and cellular uptake and its elimination from the body. A syndrome known as manganism occurs when individuals are exposed chronically to high levels of Mn, consisting of reduced response speed, intellectual deficits, mood changes, and compulsive behaviors in the initial stages of the disorder to more prominent and irreversible extrapyramidal dysfunction resembling Parkinson's disease upon protracted exposure. Mn intoxication is most often associated with occupations in which abnormally high atmospheric concentrations prevail, such as in welding and mining. There are three potentially important routes by which Mn in inspired air can gain access the body to: 1 direct uptake into the CNS via uptake into the olfactory or trigeminal presynaptic nerve endings located in the nasal mucosa and the subsequent retrograde axonal transport directly into the CNS; 2 transport across the pulmonary epithelial lining and its subsequent deposition into lymph or blood; and/or 3 mucocilliary elevator clearance from the lung and the subsequent ingestion of the metal in the gastrointestinal tract. Each of these processes and their overall contribution to the uptake of Mn in the body is discussed in this review as well as a description of the various mechanisms that have been proposed for the transport of Mn across the blood-brain barrier which include both a transferrin-dependent and a transferrin-independent process that may involve store-operated Ca channels.

  10. TIC-Tox: A preliminary discussion on identifying the forcing agents of DBP-mediated toxicity of disinfected water.

    Science.gov (United States)

    Plewa, Michael J; Wagner, Elizabeth D; Richardson, Susan D

    2017-08-01

    The disinfection of drinking water is a major public health achievement; however, an unintended consequence of disinfection is the generation of disinfection by-products (DBPs). Many of the identified DBPs exhibit in vitro and in vivo toxicity, generate a diversity of adverse biological effects, and may be hazards to the public health and the environment. Only a few DBPs are regulated by several national and international agencies and it is not clear if these regulated DBPs are the forcing agents that drive the observed toxicity and their associated health effects. In this study, we combine analytical chemical and biological data to resolve the forcing agents associated with mammalian cell cytotoxicity of drinking water samples from three cities. These data suggest that the trihalomethanes (THMs) and haloacetic acids may be a small component of the overall cytotoxicity of the organic material isolated from disinfected drinking water. Chemical classes of nitrogen-containing DBPs, such as the haloacetonitriles and haloacetamides, appear to be the major forcing agents of toxicity in these samples. These findings may have important implications for the design of epidemiological studies that primarily rely on the levels of THMs to define DBP exposure among populations. The TIC-Tox approach constitutes a beginning step in the process of identifying the forcing agents of toxicity in disinfected water. Copyright © 2017. Published by Elsevier B.V.

  11. Metal uptake and acute toxicity in zebrafish: Common mechanisms across multiple metals

    Energy Technology Data Exchange (ETDEWEB)

    Alsop, Derek, E-mail: alsopde@mcmaster.ca [Department of Biology, McMaster University, 1280 Main St. W., Hamilton, ON L8S 4K1 (Canada); Wood, Chris M. [Department of Biology, McMaster University, 1280 Main St. W., Hamilton, ON L8S 4K1 (Canada)

    2011-10-15

    All metals tested reduced calcium uptake in zebrafish larvae. However, it was whole body sodium loss that was functionally related to toxicity. The zebrafish larvae acute toxicity assay save time, space and resources. - Abstract: Zebrafish larvae (Danio rerio) were used to examine the mechanisms of action and acute toxicities of metals. Larvae had similar physiological responses and sensitivities to waterborne metals as adults. While cadmium and zinc have previously been shown to reduce Ca{sup 2+} uptake, copper and nickel also decreased Ca{sup 2+} uptake, suggesting that the epithelial transport of all these metals is through Ca{sup 2+} pathways. However, exposure to cadmium, copper or nickel for up to 48 h had little or no effect on total whole body Ca{sup 2+} levels, indicating that the reduction of Ca{sup 2+} uptake is not the acute toxic mechanism of these metals. Instead, mortalities were effectively related to whole body Na{sup +}, which decreased up to 39% after 48 h exposures to different metals around their respective 96 h LC50s. Decreases in whole body K{sup +} were also observed, although they were not as pronounced or frequent as Na{sup +} losses. None of the metals tested inhibited Na{sup +} uptake in zebrafish (Na{sup +} uptake was in fact increased with exposure) and the observed losses of Na{sup +}, K{sup +}, Ca{sup 2+} and Mg{sup 2+} were proportional to the ionic gradients between the plasma and water, indicating diffusive ion loss with metal exposure. This study has shown that there is a common pathway for metal uptake and a common mechanism of acute toxicity across groups of metals in zebrafish. The disruption of ion uptake accompanying metal exposure does not appear to be responsible for the acute toxicity of metals, as has been previously suggested, but rather the toxicity is instead due to total ion loss (predominantly Na{sup +}).

  12. Differential protein expression of hepatic cells associated with MeHg exposure: deepening into the molecular mechanisms of toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Cuello, Susana; Madrid, Yolanda; Luque-Garcia, Jose L.; Camara, Carmen [Complutense University of Madrid, Department of Analytical Chemistry, Faculty of Chemistry, Madrid (Spain); Ramos, Sonia [Institute of Food Science, Technology and Nutrition, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid (Spain)

    2012-08-15

    Understanding the molecular mechanisms underlying MeHg toxicity and the way in which this molecule interacts with living organisms is a critical point since MeHg represents a well-known risk to ecosystems and human health. We used a quantitative proteomic approach based on stable isotopic labeling by amino acids in cell culture in combination with SDS-PAGE and nanoflow LC-ESI-LTQ for analyzing the differential protein expression of hepatic cells associated to MeHg exposure. Seventy-eight proteins were found de-regulated by more than 1.5-fold. We identified a number of proteins involved in different essential biological processes including apoptosis, mitochondrial dysfunction, cellular trafficking and energy production. Among these proteins, we found several molecules whose de-regulation has been already related to MeHg exposure, thus confirming the usefulness of our discovery approach, and new ones that helped to gain a deeper insight into the biomolecular mechanisms related to MeHg-induced toxicity. Overexpression of several HSPs and the proteasome 26S subunit itself showed the proteasome system as a molecular target of toxic MeHg. As for the interaction networks, the top ranked was the nucleic acid metabolism, where many of the identified de-regulated proteins are involved. (orig.)

  13. Essentially deadly: living with toxic elements: Humans and plants have evolved various mechanisms to deal with and even adopt toxic heavy metals

    OpenAIRE

    Hunter, Philip

    2015-01-01

    Organisms have evolved to deal with or make use of toxic metals. Understanding these mechanisms could help to protect the health of mine workers, tackle malnourishment, or improve ways to clean up polluted environments.

  14. Common Lung Microbiome Identified among Mechanically Ventilated Surgical Patients.

    Directory of Open Access Journals (Sweden)

    Ashley D Smith

    Full Text Available The examination of the pulmonary microbiome in patients with non-chronic disease states has not been extensively examined. Traditional culture based screening methods are often unable to identify bacteria from bronchoalveolar lavage samples. The advancement of next-generation sequencing technologies allows for a culture-independent molecular based analysis to determine the microbial composition in the lung of this patient population. For this study, the Ion Torrent PGM system was used to assess the microbial complexity of culture negative bronchoalveolar lavage samples. A group of samples were identified that all displayed high diversity and similar relative abundance of bacteria. This group consisted of Hydrogenophaga, unclassified Bacteroidetes, Pedobacter, Thauera, and Acinetobacter. These bacteria may be representative of a common non-pathogenic pulmonary microbiome associated within this population of patients.

  15. Seeking a Mechanism for the Toxicity of Oligomeric α-Synuclein

    Directory of Open Access Journals (Sweden)

    Hazel L. Roberts

    2015-03-01

    Full Text Available In a number of neurological diseases including Parkinson’s disease (PD, α‑synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of α-synuclein in vivo. The toxicity of α-synuclein is popularly attributed to the formation of “toxic oligomers”: a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of α-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between α-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of α-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described.

  16. Sediment tolerance mechanisms identified in sponges using advanced imaging techniques

    Directory of Open Access Journals (Sweden)

    Brian W. Strehlow

    2017-11-01

    Full Text Available Terrestrial runoff, resuspension events and dredging can affect filter-feeding sponges by elevating the concentration of suspended sediments, reducing light intensity, and smothering sponges with sediments. To investigate how sponges respond to pressures associated with increased sediment loads, the abundant and widely distributed Indo-Pacific species Ianthella basta was exposed to elevated suspended sediment concentrations, sediment deposition, and light attenuation for 48 h (acute exposure and 4 weeks (chronic exposure. In order to visualise the response mechanisms, sponge tissue was examined by 3D X-ray microscopy and scanning electron microscopy (SEM. Acute exposures resulted in sediment rapidly accumulating in the aquiferous system of I. basta, although this sediment was fully removed within three days. Sediment removal took longer (>2 weeks following chronic exposures, and I. basta also exhibited tissue regression and a smaller aquiferous system. The application of advanced imaging approaches revealed that I. basta employs a multilevel system for sediment rejection and elimination, containing both active and passive components. Sponges responded to sediment stress through (i mucus production, (ii exclusion of particles by incurrent pores, (iii closure of oscula and pumping cessation, (iv expulsion of particles from the aquiferous system, and (v tissue regression to reduce the volume of the aquiferous system, thereby entering a dormant state. These mechanisms would result in tolerance and resilience to exposure to variable and high sediment loads associated with both anthropogenic impacts like dredging programs and natural pressures like flood events.

  17. Air toxic emissions from the combustion of coal: Identifying and quantifying hazardous air pollutants from US coals

    Energy Technology Data Exchange (ETDEWEB)

    Szpunar, C.B.

    1992-09-01

    This report addresses the key air toxic emissions likely to emanate from continued and expanded use of domestic coal. It identifies and quantifies those trace elements specified in the US 1990 Clean Air Act Amendments, by tabulating selected characterization data on various source coals by region, state, and rank. On the basis of measurements by various researchers, this report also identifies those organic compounds likely to be derived from the coal combustion process (although their formation is highly dependent on specific boiler configurations and operating conditions).

  18. Air toxic emissions from the combustion of coal: Identifying and quantifying hazardous air pollutants from US coals

    International Nuclear Information System (INIS)

    Szpunar, C.B.

    1992-09-01

    This report addresses the key air toxic emissions likely to emanate from continued and expanded use of domestic coal. It identifies and quantifies those trace elements specified in the US 1990 Clean Air Act Amendments, by tabulating selected characterization data on various source coals by region, state, and rank. On the basis of measurements by various researchers, this report also identifies those organic compounds likely to be derived from the coal combustion process (although their formation is highly dependent on specific boiler configurations and operating conditions)

  19. Identifying mechanisms for superdiffusive dynamics in cell trajectories

    Science.gov (United States)

    Passucci, Giuseppe; Brasch, Megan; Henderson, James; Manning, M. Lisa

    Self-propelled particle (SPP) models have been used to explore features of active matter such as motility-induced phase separation, jamming, and flocking, and are often used to model biological cells. However, many cells exhibit super-diffusive trajectories, where displacements scale faster than t 1 / 2 in all directions, and these are not captured by traditional SPP models. We extract cell trajectories from image stacks of mouse fibroblast cells moving on 2D substrates and find super-diffusive mean-squared displacements in all directions across varying densities. Two SPP model modifications have been proposed to capture super-diffusive dynamics: Levy walks and heterogeneous motility parameters. In mouse fibroblast cells displacement probability distributions collapse when time is rescaled by a power greater than 1/2, which is consistent with Levy walks. We show that a simple SPP model with heterogeneous rotational noise can also generate a similar collapse. Furthermore, a close examination of statistics extracted directly from cell trajectories is consistent with a heterogeneous mobility SPP model and inconsistent with a Levy walk model. Our work demonstrates that a simple set of analyses can distinguish between mechanisms for anomalous diffusion in active matter.

  20. Lectin-based food poisoning: a new mechanism of protein toxicity.

    Science.gov (United States)

    Miyake, Katsuya; Tanaka, Toru; McNeil, Paul L

    2007-08-01

    Ingestion of the lectins present in certain improperly cooked vegetables can result in acute GI tract distress, but the mechanism of toxicity is unknown. In vivo, gut epithelial cells are constantly exposed to mechanical and other stresses and consequently individual cells frequently experience plasma membrane disruptions. Repair of these cell surface disruptions allows the wounded cell to survive: failure results in necrotic cell death. Plasma membrane repair is mediated, in part, by an exocytotic event that adds a patch of internal membrane to the defect site. Lectins are known to inhibit exocytosis. We therefore tested the novel hypothesis that lectin toxicity is due to an inhibitory effect on plasma membrane repair. Repair of plasma membrane disruptions and exocytosis of mucus was assessed after treatment of cultured cell models and excised segments of the GI tract with lectins. Plasma membrane disruptions were produced by focal irradiation of individual cells, using a microscope-based laser, or by mechanical abrasion of multiple cells, using a syringe needle. Repair was then assessed by monitoring the cytosolic penetration of dyes incapable of crossing the intact plasma membrane. We found that cell surface-bound lectins potently inhibited plasma membrane repair, and the exocytosis of mucus that normally accompanies the repair response. Lectins potently inhibit plasma membrane repair, and hence are toxic to wounded cells. This represents a novel form of protein-based toxicity, one that, we propose, is the basis of plant lectin food poisoning.

  1. Lectin-based food poisoning: a new mechanism of protein toxicity.

    Directory of Open Access Journals (Sweden)

    Katsuya Miyake

    Full Text Available BACKGROUND: Ingestion of the lectins present in certain improperly cooked vegetables can result in acute GI tract distress, but the mechanism of toxicity is unknown. In vivo, gut epithelial cells are constantly exposed to mechanical and other stresses and consequently individual cells frequently experience plasma membrane disruptions. Repair of these cell surface disruptions allows the wounded cell to survive: failure results in necrotic cell death. Plasma membrane repair is mediated, in part, by an exocytotic event that adds a patch of internal membrane to the defect site. Lectins are known to inhibit exocytosis. We therefore tested the novel hypothesis that lectin toxicity is due to an inhibitory effect on plasma membrane repair. METHODS AND FINDINGS: Repair of plasma membrane disruptions and exocytosis of mucus was assessed after treatment of cultured cell models and excised segments of the GI tract with lectins. Plasma membrane disruptions were produced by focal irradiation of individual cells, using a microscope-based laser, or by mechanical abrasion of multiple cells, using a syringe needle. Repair was then assessed by monitoring the cytosolic penetration of dyes incapable of crossing the intact plasma membrane. We found that cell surface-bound lectins potently inhibited plasma membrane repair, and the exocytosis of mucus that normally accompanies the repair response. CONCLUSIONS: Lectins potently inhibit plasma membrane repair, and hence are toxic to wounded cells. This represents a novel form of protein-based toxicity, one that, we propose, is the basis of plant lectin food poisoning.

  2. Identifying inequitable exposure to toxic air pollution in racialized and low-income neighbourhoods to support pollution prevention

    Directory of Open Access Journals (Sweden)

    Suzanne Kershaw

    2013-05-01

    Full Text Available Numerous environmental justice studies have confirmed a relationship between population characteristics such as low-income or minority status and the location of environmental health hazards. However, studies of the health risks from exposure to harmful substances often do not consider their toxicological characteristics. We used two different methods, the unit-hazard and the distance-based approach, to evaluate demographic and socio-economic characteristics of the population residing near industrial facilities in the City of Toronto, Canada. In addition to the mass of air emissions obtained from the national pollutant release inventory (NPRI, we also considered their toxicity using toxic equivalency potential (TEP scores. Results from the unit-hazard approach indicate no significant difference in the proportion of low-income individuals living in host versus non-host census tracts (t(107 = 0.3, P = 0.735. However, using the distance-based approach, the proportion of low-income individuals was significantly higher (+5.1%, t(522 = 6.0, P <0.001 in host tracts, while the indicator for “racialized” communities (“visible minority” was 16.1% greater (t(521 = 7.2, P <0.001 within 2 km of a NPRI facility. When the most toxic facilities by non-carcinogenic TEP score were selected, the rate of visible minorities living near the most toxic NPRI facilities was significantly higher (+12.9%, t(352 = 3.5, P = 0.001 than near all other NPRI facilities. TEP scores were also used to identify areas in Toronto that face a double burden of poverty and air toxics exposure in order to prioritise pollution prevention.

  3. DNA Repair Alterations in Children With Pediatric Malignancies: Novel Opportunities to Identify Patients at Risk for High-Grade Toxicities

    International Nuclear Information System (INIS)

    Ruebe, Claudia E.; Fricke, Andreas; Schneider, Ruth; Simon, Karin; Kuehne, Martin; Fleckenstein, Jochen; Graeber, Stefan; Graf, Norbert; Ruebe, Christian

    2010-01-01

    Purpose: To evaluate, in a pilot study, the phosphorylated H2AX (γH2AX) foci approach for identifying patients with double-strand break (DSB) repair deficiencies, who may overreact to DNA-damaging cancer therapy. Methods and Materials: The DSB repair capacity of children with solid cancers was analyzed compared with that of age-matched control children and correlated with treatment-related normal-tissue responses (n = 47). Double-strand break repair was investigated by counting γH2AX foci in blood lymphocytes at defined time points after irradiation of blood samples. Results: Whereas all healthy control children exhibited proficient DSB repair, 3 children with tumors revealed clearly impaired DSB repair capacities, and 2 of these repair-deficient children developed life-threatening or even lethal normal-tissue toxicities. The underlying mutations affecting regulatory factors involved in DNA repair pathways were identified. Moreover, significant differences in mean DSB repair capacity were observed between children with tumors and control children, suggesting that childhood cancer is based on genetic alterations affecting DSB repair function. Conclusions: Double-strand break repair alteration in children may predispose to cancer formation and may affect children's susceptibility to normal-tissue toxicities. Phosphorylated H2AX analysis of blood samples allows one to detect DSB repair deficiencies and thus enables identification of children at risk for high-grade toxicities.

  4. Target or barrier? The cell wall of early- and later- diverging plants vs cadmium toxicity: differences in the response mechanisms

    Directory of Open Access Journals (Sweden)

    Luigi eParrotta

    2015-03-01

    Full Text Available Increasing industrialization and urbanization result in emission of pollutants in the environment including toxic heavy metals, as cadmium and lead. Among the different heavy metals contaminating the environment, cadmium raises great concern, as it is ecotoxic and as such can heavily impact ecosystems. The cell wall is the first structure of plant cells to come in contact with heavy metals. Its composition, characterized by proteins, polysaccharides and in some instances lignin and other phenolic compounds, confers the ability to bind non-covalently and/or covalently heavy metals via functional groups. A strong body of evidence in the literature has shown the role of the cell wall in heavy metal response: it sequesters heavy metals, but at the same time its synthesis and composition can be severely affected. The present review analyzes the dual property of plant cell walls, i.e. barrier and target of heavy metals, by taking Cd toxicity as example. Following a summary of the known physiological and biochemical responses of plants to Cd, the review compares the wall-related mechanisms in early- and later-diverging land plants, by considering the diversity in cell wall composition. By doing so, common as well as unique response mechanisms to metal/cadmium toxicity are identified among plant phyla and discussed. After discussing the role of hyperaccumulators’ cell walls as a particular case, the review concludes by considering important aspects for plant engineering.

  5. Lead toxicity in rice: effects, mechanisms, and mitigation strategies--a mini review.

    Science.gov (United States)

    Ashraf, Umair; Kanu, Adam Sheka; Mo, Zhaowen; Hussain, Saddam; Anjum, Shakeel Ahmad; Khan, Imran; Abbas, Rana Nadeem; Tang, Xiangru

    2015-12-01

    Lead (Pb) is a major environmental pollutant that affects plant morpho-physiological and biochemical attributes. Its higher levels in the environment are not only toxic to human beings but also harmful for plants and soil microbes. We have reviewed the uptake, translocation, and accumulation mechanisms of Pb and its toxic effects on germination, growth, yield, nutrient relation, photosynthesis, respiration, oxidative damage, and antioxidant defense system of rice. Lead toxicity hampers rice germination, root/shoot length, growth, and final yield. It reduces nutrient uptake through roots, disrupts chloroplastic ultrastructure and cell membrane permeability, induces alterations in leaves respiratory activities, produces reactive oxygen species (ROS), and triggers some enzyme and non-enzymatic antioxidants (as defense to oxidative damage). In the end, biochar amendments and phytoremediation technologies have been proposed as soil remediation approaches for Pb tainted soils.

  6. Caddisflies as biomonitors identifying thresholds of toxic metal bioavailability that affect the stream benthos

    International Nuclear Information System (INIS)

    Rainbow, Philip S.; Hildrew, Alan G.; Smith, Brian D.; Geatches, Tim; Luoma, Samuel N.

    2012-01-01

    It has been proposed that bioaccumulated concentrations of toxic metals in tolerant biomonitors be used as indicators of metal bioavailability that could be calibrated against the ecological response to metals of sensitive biotic assemblages. Our hypothesis was that metal concentrations in caddisfly larvae Hydropsyche siltalai and Plectrocnemia conspersa, as tolerant biomonitors, indicate metal bioavailability in contaminated streams, and can be calibrated against metal-specific ecological responses of mayflies. Bioaccumulated concentrations of Cu, As, Zn and Pb in H. siltalai from SW English streams were related to the mayfly assemblage. Mayflies were always sparse where bioavailabilities were high and were abundant and diverse where bioavailabilities of all metals were low, a pattern particularly evident when the combined abundance of heptageniid and ephemerellid mayflies was the response variable. The results offer promise that bioaccumulated concentrations of metals in tolerant biomonitors can be used to diagnose ecological impacts on stream benthos from metal stressors. - Highlights: ► Metal concentrations in caddisfly larvae can be calibrated against mayfly ecological responses. ► Cu, As, Zn and Pb concentrations in Hydropsyche siltalai were related to stream mayfly assemblages. ► Mayflies were sparse in high metal bioavailabilities, and abundant in low bioavailabilities. ► Joint heptageniid and ephemerellid mayfly abundance was the most sensitive response variable. ► Copper, arsenic and, in one catchment, lead were the primary stressors limiting mayfly abundance. - Accumulated metal concentrations in tolerant biomonitors can be used to detect and diagnose ecological impacts on freshwater stream benthos from metal stressors.

  7. Intracellular uptake: a possible mechanism for silver engineered nanoparticle toxicity to a freshwater alga Ochromonas danica.

    Directory of Open Access Journals (Sweden)

    Ai-Jun Miao

    2010-12-01

    Full Text Available The behavior and toxicity of silver engineered nanoparticles (Ag-ENs to the mixotrophic freshwater alga Ochromonas danica were examined in the present study to determine whether any other mechanisms are involved in their algal toxicity besides Ag(+ liberation outside the cells. Despite their good dispersability, the Ag-ENs were found to continuously aggregate and dissolve rapidly. When the initial nanoparticle concentration was lower than 10 µM, the total dissolved Ag(+ concentration ([Ag(+](T in the suspending media reached its maximum after 1 d and then decreased suggesting that Ag(+ release might be limited by the nanoparticle surface area under these conditions. Furthermore, Ag-EN dissolution extent remarkably increased in the presence of glutathione. In the Ag-EN toxicity experiment, glutathione was also used to eliminate the indirect effects of Ag(+ that was released. However, remarkable toxicity was still observed although the free Ag(+ concentration in the media was orders of magnitude lower than the non-observed effect concentration of Ag(+ itself. Such inhibitive effects were mitigated when more glutathione was added, but could never be completely eliminated. Most importantly, we demonstrate, for the first time, that Ag-ENs can be taken in and accumulated inside the algal cells, where they exerted their toxic effects. Therefore, nanoparticle internalization may be an alternative pathway through which algal growth can be influenced.

  8. Metabolomics reveals the mechanisms for the cardiotoxicity of Pinelliae Rhizoma and the toxicity-reducing effect of processing

    Science.gov (United States)

    Su, Tao; Tan, Yong; Tsui, Man-Shan; Yi, Hua; Fu, Xiu-Qiong; Li, Ting; Chan, Chi Leung; Guo, Hui; Li, Ya-Xi; Zhu, Pei-Li; Tse, Anfernee Kai Wing; Cao, Hui; Lu, Ai-Ping; Yu, Zhi-Ling

    2016-10-01

    Pinelliae Rhizoma (PR) is a commonly used Chinese medicinal herb, but it has been frequently reported about its toxicity. According to the traditional Chinese medicine theory, processing can reduce the toxicity of the herbs. Here, we aim to determine if processing reduces the toxicity of raw PR, and to explore the underlying mechanisms of raw PR-induced toxicities and the toxicity-reducing effect of processing. Biochemical and histopathological approaches were used to evaluate the toxicities of raw and processed PR. Rat serum metabolites were analyzed by LC-TOF-MS. Ingenuity pathway analysis of the metabolomics data highlighted the biological pathways and network functions involved in raw PR-induced toxicities and the toxicity-reducing effect of processing, which were verified by molecular approaches. Results showed that raw PR caused cardiotoxicity, and processing reduced the toxicity. Inhibition of mTOR signaling and activation of the TGF-β pathway contributed to raw PR-induced cardiotoxicity, and free radical scavenging might be responsible for the toxicity-reducing effect of processing. Our data shed new light on the mechanisms of raw PR-induced cardiotoxicity and the toxicity-reducing effect of processing. This study provides scientific justifications for the traditional processing theory of PR, and should help in optimizing the processing protocol and clinical combinational application of PR.

  9. Lysosomal membrane permeabilization: Carbon nanohorn-induced reactive oxygen species generation and toxicity by this neglected mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Mei, E-mail: happy_deercn@163.com [Nanotube Research Center, National Institute of Advanced Industrial Science and Technology 5-2, 1-1-1 Higashi, Tsukuba 305-8565 (Japan); Zhang, Minfang; Tahara, Yoshio; Chechetka, Svetlana; Miyako, Eijiro [Nanotube Research Center, National Institute of Advanced Industrial Science and Technology 5-2, 1-1-1 Higashi, Tsukuba 305-8565 (Japan); Iijima, Sumio [Nanotube Research Center, National Institute of Advanced Industrial Science and Technology 5-2, 1-1-1 Higashi, Tsukuba 305-8565 (Japan); Faculty of Science and Technology, Meijo University, 1-501 Shiogamaguchi, Tenpaku, Nagoya 468-8502 (Japan); Yudasaka, Masako, E-mail: m-yudasaka@aist.go.jp [Nanotube Research Center, National Institute of Advanced Industrial Science and Technology 5-2, 1-1-1 Higashi, Tsukuba 305-8565 (Japan)

    2014-10-01

    Understanding the molecular mechanisms responsible for the cytotoxic effects of carbon nanomaterials is important for their future biomedical applications. Carbon nanotubular materials induce the generation of reactive oxygen species (ROS), which causes cell death; however, the exact details of this process are still unclear. Here, we identify a mechanism of ROS generation that is involved in the apoptosis of RAW264.7 macrophages caused by excess uptake of carbon nanohorns (CNHs), a typical type of carbon nanotubule. CNH accumulated in the lysosomes, where they induced lysosomal membrane permeabilization (LMP) and the subsequent release of lysosomal proteases, such as cathepsins, which in turn caused mitochondrial dysfunction and triggered the generation of ROS in the mitochondria. The nicotinamide adenine dinucleotide phosphate oxidase was not directly involved in CNH-related ROS production, and the ROS generation cannot be regulated by mitochondrial electron transport chain. ROS fed back to amplify the mitochondrial dysfunction, leading to the subsequent activation of caspases and cell apoptosis. Carbon nanotubules commonly accumulate in the lysosomes after internalization in cells; however, lysosomal dysfunction has not attracted much attention in toxicity studies of these materials. These results suggest that LMP, a neglected mechanism, may be the primary reason for carbon nanotubule toxicity. - Highlights: • We clarify an apoptotic mechanism of RAW264.7 cells caused by carbon nanohorns. • In the meantime, the mechanism of CNH-induced ROS generation is identified. • LMP is the initial factor of CNH-induced ROS generation and cell death. • Cathepsins work as mediators that connect LMP and mitochondrial dysfunction.

  10. Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

    Directory of Open Access Journals (Sweden)

    Brandon L Pierce

    Full Text Available Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8 for percentages of both monomethylarsonic acid (MMA and dimethylarsinic acid (DMA near the AS3MT gene (arsenite methyltransferase; 10q24.32, with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity and 1,794 controls, we show that one of these five variants (rs9527 is also associated with skin lesion risk (P = 0.0005. Using a subset of individuals with prospectively measured arsenic (n = 769, we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01. Expression quantitative trait locus (eQTL analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10(-12 and neighboring gene C10orf32 (P = 10(-44, which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical

  11. Ozonides: intermediates in ozone-induced toxicity : a study on their mechanism of toxic action and detoxification by antioxidants

    NARCIS (Netherlands)

    Hempenius, R.A.

    2000-01-01

    Ozone is a major constituent of photochemical smog. The toxicity of ozone is well documented and has been related to its strong oxidative potential. The principal target organ for ozone toxicity is the respiratory system. Unsaturated fatty acids, which are present in both the lipids of the

  12. Oxidative Stress and Mitochondrial Activation as the Main Mechanisms Underlying Graphene Toxicity against Human Cancer Cells

    Directory of Open Access Journals (Sweden)

    Anna Jarosz

    2016-01-01

    Full Text Available Due to the development of nanotechnology graphene and graphene-based nanomaterials have attracted the most attention owing to their unique physical, chemical, and mechanical properties. Graphene can be applied in many fields among which biomedical applications especially diagnostics, cancer therapy, and drug delivery have been arousing a lot of interest. Therefore it is essential to understand better the graphene-cell interactions, especially toxicity and underlying mechanisms for proper use and development. This review presents the recent knowledge concerning graphene cytotoxicity and influence on different cancer cell lines.

  13. The underlying toxicological mechanism of chemical mixtures: A case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Dayong [State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China); Department of Chemical and Environmental Engineering, Anyang Institute of Technology, Anyang 455000 (China); Lin, Zhifen, E-mail: lzhifen@tongji.edu.cn [State Key Laboratory of Pollution Control and Resource Reuse, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China); Zhou, Xianghong [Department of Public Management, Tongji University, Shanghai 200092 (China); Yin, Daqiang [Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092 (China)

    2013-10-15

    Intracellular chemical reaction of chemical mixtures is one of the main reasons that cause synergistic or antagonistic effects. However, it still remains unclear what the influencing factors on the intracellular chemical reaction are, and how they influence on the toxicological mechanism of chemical mixtures. To reveal this underlying toxicological mechanism of chemical mixtures, a case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum was employed, and both their joint effects and mixture toxicity were observed. Then series of two-step linear regressions were performed to describe the relationships between joint effects, the expected additive toxicities and descriptors of individual chemicals (including concentrations, binding affinity to receptors, octanol/water partition coefficients). Based on the quantitative relationships, the underlying joint toxicological mechanisms were revealed. The result shows that, for mixtures with their joint effects resulting from intracellular chemical reaction, their underlying toxicological mechanism depends on not only their interaction with target proteins, but also their transmembrane actions and their concentrations. In addition, two generic points of toxicological mechanism were proposed including the influencing factors on intracellular chemical reaction and the difference of the toxicological mechanism between single reactive chemicals and their mixtures. This study provided an insight into the understanding of the underlying toxicological mechanism for chemical mixtures with intracellular chemical reaction. - Highlights: • Joint effects of nitriles and aldehydes at non-equitoxic ratios were determined. • A novel descriptor, ligand–receptor interaction energy (E{sub binding}), was employed. • Quantitative relationships for mixtures were developed based on a novel descriptor. • The underlying toxic mechanism was revealed based on quantitative relationships. • Two

  14. The underlying toxicological mechanism of chemical mixtures: A case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum

    International Nuclear Information System (INIS)

    Tian, Dayong; Lin, Zhifen; Zhou, Xianghong; Yin, Daqiang

    2013-01-01

    Intracellular chemical reaction of chemical mixtures is one of the main reasons that cause synergistic or antagonistic effects. However, it still remains unclear what the influencing factors on the intracellular chemical reaction are, and how they influence on the toxicological mechanism of chemical mixtures. To reveal this underlying toxicological mechanism of chemical mixtures, a case study on mixture toxicity of cyanogenic toxicants and aldehydes to Photobacterium phosphoreum was employed, and both their joint effects and mixture toxicity were observed. Then series of two-step linear regressions were performed to describe the relationships between joint effects, the expected additive toxicities and descriptors of individual chemicals (including concentrations, binding affinity to receptors, octanol/water partition coefficients). Based on the quantitative relationships, the underlying joint toxicological mechanisms were revealed. The result shows that, for mixtures with their joint effects resulting from intracellular chemical reaction, their underlying toxicological mechanism depends on not only their interaction with target proteins, but also their transmembrane actions and their concentrations. In addition, two generic points of toxicological mechanism were proposed including the influencing factors on intracellular chemical reaction and the difference of the toxicological mechanism between single reactive chemicals and their mixtures. This study provided an insight into the understanding of the underlying toxicological mechanism for chemical mixtures with intracellular chemical reaction. - Highlights: • Joint effects of nitriles and aldehydes at non-equitoxic ratios were determined. • A novel descriptor, ligand–receptor interaction energy (E binding ), was employed. • Quantitative relationships for mixtures were developed based on a novel descriptor. • The underlying toxic mechanism was revealed based on quantitative relationships. • Two generic

  15. Mechanism of oxidative stress involved in the toxicity of ZnO nanoparticles against eukaryotic cells

    Directory of Open Access Journals (Sweden)

    M. Saliani

    2016-01-01

    Full Text Available ZnO NPs (zinc oxide nanoparticles has generated significant scientific interest as a novel antibacterial and anticancer agent. Since oxidative stress is a critical determinant of ZnO NPs-induced damage, it is necessary to characterize their underlying mode of action. Different structural and physicochemical properties of ZnO NPs such as particle surface, size, shape, crystal structure, chemical position, and presence of metals can lead to changes in biological activities including ROS (reactive oxygen species production. However, there are some inconsistencies in the literature on the relation between the physicochemical features of ZnO NPs and their plausible oxidative stress mechanism. Herein, the possible oxidative stress mechanism of ZnO NPs was reviewed. This is worthy of further detailed evaluations in order to improve our understanding of vital NPs characteristics governing their toxicity. Therefore, this study focuses on the different reported oxidative stress paradigms induced by ZnO NPs including ROS generated by NPs, oxidative stress due to the NPs-cell interaction, and role of the particle dissolution in the oxidative damage. Also, this study tries to characterize and understand the multiple pathways involved in oxidative stress induced by ZnO NPs. Knowledge about different cellular signaling cascades stimulated by ZnO NPs lead to the better interpretation of the toxic influences induced by the cellular and acellular parameters. Regarding the potential benefits of toxic effects of ZnO NPs, in-depth evaluation of their toxicity mechanism and various effects of these nanoparticles would facilitate their implementation for biomedical applications.

  16. Metal Oxide Nanomaterial QNAR Models: Available Structural Descriptors and Understanding of Toxicity Mechanisms

    Directory of Open Access Journals (Sweden)

    Jiali Ying

    2015-10-01

    Full Text Available Metal oxide nanomaterials are widely used in various areas; however, the divergent published toxicology data makes it difficult to determine whether there is a risk associated with exposure to metal oxide nanomaterials. The application of quantitative structure activity relationship (QSAR modeling in metal oxide nanomaterials toxicity studies can reduce the need for time-consuming and resource-intensive nanotoxicity tests. The nanostructure and inorganic composition of metal oxide nanomaterials makes this approach different from classical QSAR study; this review lists and classifies some structural descriptors, such as size, cation charge, and band gap energy, in recent metal oxide nanomaterials quantitative nanostructure activity relationship (QNAR studies and discusses the mechanism of metal oxide nanomaterials toxicity based on these descriptors and traditional nanotoxicity tests.

  17. Photolysis of polycyclic aromatic hydrocarbons (PAHs) on Fe3+-montmorillonite surface under visible light: Degradation kinetics, mechanism, and toxicity assessments.

    Science.gov (United States)

    Zhao, Song; Jia, Hanzhong; Nulaji, Gulimire; Gao, Hongwei; Wang, Fu; Wang, Chuanyi

    2017-10-01

    Photochemical behavior of various polycyclic aromatic hydrocarbons (PAHs) on Fe 3+ -modified montmorillonite was explored to determine their potential kinetics, pathways, and mechanism under visible light. Depending on the type of PAH molecules, the transformation rate follows the order of benzo[a]pyrene ≈ anthracene > benzo[a]anthracene > phenanthrene. Quantum simulation results confirm the crucial role of "cation-π" interaction between Fe 3+ and PAHs on their transformation kinetics. Primary intermediates, including quinones, ring-opening products and benzene derivatives, were identified by gas chromatography-mass spectrometer (GC-MS), and the possible photodegradation pathway of benzo[a]pyrene was proposed. Meanwhile, radical intermediates, such as reactive oxygen species (ROS) and free organic radicals, were detected by electron paramagnetic resonance (EPR) technique. The photolysis of selected PAHs, such as anthracene and benzo[a]pyrene, on clay surface firstly occurs by electron transfer from PAHs to Fe 3+ -montmorillonite, followed by degradation involving photo-induced ROS such as ·OH and ·O 2 - . To investigate the acute toxicity of photolysis products, the Microtox ® toxicity test was performed during the photodegradation processes of various PAHs. As a result, the photo-irradiation initially induces increased toxicity by generating reactive intermediates, such as free organic radicals, and then the toxicity gradually decreases with increasing of reaction time. Overall, the present study provides useful information to understand the fate and photo-transformation of PAHs in contaminated soils. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. A new mechanism of macrophyte mitigation: how submerged plants reduce malathion's acute toxicity to aquatic animals.

    Science.gov (United States)

    Brogan, William R; Relyea, Rick A

    2014-08-01

    A growing body of evidence suggests that aquatic plants can mitigate the toxicity of insecticides to sensitive aquatic animals. The current paradigm is that this ability is driven primarily by insecticide sorption to plant tissues, especially for hydrophobic compounds. However, recent work shows that submerged plants can strongly mitigate the toxicity of the relatively hydrophilic insecticide malathion, despite the fact that this compound exhibits a slow sorption rate to plants. To examine this disparity, we tested the hypothesis that the mitigating effect of submerged plants on malathion's toxicity is driven primarily by the increased water pH from plant photosynthesis causing the hydrolysis of malathion, rather than by sorption. To do this, we compared zooplankton (Daphnia magna) survival across five environmentally relevant malathion concentrations (0, 1, 4, 6, or 36 μg L(-1)) in test containers where we chemically manipulated water pH in the absence of plants or added the submerged plant (Elodea canadensis) but manipulated plant photosynthetic activity via shading or no shading. We discovered that malathion was equally lethal to Daphnia at all concentrations tested when photosynthetically inactive (i.e. shaded) plants were present (pH at time of dosing=7.8) or when pH was chemically decreased (pH=7.7). In contrast, when photosynthetically active (i.e. unshaded) plants were present (pH=9.8) or when pH was chemically increased (pH=9.5), the effects of 4 and 6 μg L(-1) of malathion on Daphnia were mitigated strongly and to an equal degree. These results demonstrate that the mitigating effect of submerged plants on malathion's toxicity can be explained entirely by a mechanism of photosynthesizing plants causing an increase in water pH, resulting in rapid malathion hydrolysis. Our findings suggest that current ecotoxicological models and phytoremediation strategies may be overlooking a critical mechanism for mitigating pesticides. Copyright © 2014 Elsevier Ltd

  19. Proteome Profiling Reveals Potential Toxicity and Detoxification Pathways Following Exposure of BEAS-2B Cells to Engineered Nanoparticle Titanium Dioxide

    Science.gov (United States)

    Identification of toxicity pathways linked to chemical -exposure is critical for a better understanding of biological effects of the exposure, toxic mechanisms, and for enhancement of the prediction of chemical toxicity and adverse health outcomes. To identify toxicity pathways a...

  20. Photocatalytic degradation of bisphenol A in the presence of Ce–ZnO: Evolution of kinetics, toxicity and photodegradation mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Bechambi, Olfa [Université de Tunis El Manar, Faculté des Sciences de Tunis, Laboratoire de Chimie des Matériaux et Catalyse, 2092, Tunis (Tunisia); Jlaiel, Lobna [Laboratoire de Bioprocédés Environnementaux, Centre de Biotechnologie de Sfax, B.P. 1177, 3018 Sfax (Tunisia); Najjar, Wahiba, E-mail: najjarwahiba2014@gmail.com [Université de Tunis El Manar, Faculté des Sciences de Tunis, Laboratoire de Chimie des Matériaux et Catalyse, 2092, Tunis (Tunisia); Sayadi, Sami [Laboratoire de Bioprocédés Environnementaux, Centre de Biotechnologie de Sfax, B.P. 1177, 3018 Sfax (Tunisia)

    2016-04-15

    Ce–ZnO (2 mol %) and undoped ZnO catalysts have been synthesized through hydrothermal method and characterized by X-ray diffraction (XRD), Nitrogen physisorption at 77 K; Fourier transformed infrared spectroscopy (FTIR), UV–Visible spectroscopy, Photoluminescence spectra (PL), and Raman spectroscopy. Ce-doping reduces the average crystallite size, increases the BET surface area, shifts the absorption edge, reduces the electron–hole recombination and consequently improves photodegradation efficiency of Bisphenol A (BPA) in the presence of UV irradiation and hydrogen peroxide. The photocatalytic optimum conditions were established by studying the influence of various operational parameters including catalyst concentration, initial BPA concentration, H{sub 2}O{sub 2} concentration and initial pH. Under optimum conditions, Ce–ZnO (2%) achieved 100% BPA degradation and 61% BPA mineralization after 24 h of UV irradiation. BPA degradation reaction followed pseudo first-order kinetics according to the Langmuir–Hinshelwood model. Based on the identified intermediate products, the possible mechanism for BPA photodegradation is proposed. Toxicity under the optimum condition was also evaluated. - Graphical abstract: Proposed photocatalytic degradation pathway of BPA in the presence of Ce– ZnO (2%)/UV/H{sub 2}O{sub 2} system. - Highlights: • Influence of different parameters on the degradation and mineralization of BPA. • Identification of possible degradation products. • Toxicity tests conducted with Vibrio fischeri. • Simple and direct photodegradation mechanism of BPA is proposed.

  1. Mechanisms behind pH changes by plant roots and shoots caused by elevated concentration of toxic elements

    OpenAIRE

    Javed, Muhammad Tariq

    2011-01-01

    Toxic elements are present in polluted water from mines, industrial outlets, storm water etc. Wetland plants take up toxic elements and increase the pH of the medium. In this thesis was investigated how the shoots of submerged plants and roots of emergent plants affected the pH of the surrounding water in the presence of free toxic ions. The aim was to clarify the mechanisms by which these plants change the surrounding water pH in the presence of toxic ions. The influence of Elodea canadensis...

  2. Elucidating mechanisms of toxic action of dissolved organic chemicals in oil sands process-affected water (OSPW).

    Science.gov (United States)

    Morandi, Garrett D; Wiseman, Steve B; Guan, Miao; Zhang, Xiaowei W; Martin, Jonathan W; Giesy, John P

    2017-11-01

    Oil sands process-affected water (OSPW) is generated during extraction of bitumen in the surface-mining oil sands industry in Alberta, Canada, and is acutely and chronically toxic to aquatic organisms. It is known that dissolved organic compounds in OSPW are responsible for most toxic effects, but knowledge of the specific mechanism(s) of toxicity, is limited. Using bioassay-based effects-directed analysis, the dissolved organic fraction of OSPW has previously been fractionated, ultimately producing refined samples of dissolved organic chemicals in OSPW, each with distinct chemical profiles. Using the Escherichia coli K-12 strain MG1655 gene reporter live cell array, the present study investigated relationships between toxic potencies of each fraction, expression of genes and characterization of chemicals in each of five acutely toxic and one non-toxic extract of OSPW derived by use of effects-directed analysis. Effects on expressions of genes related to response to oxidative stress, protein stress and DNA damage were indicative of exposure to acutely toxic extracts of OSPW. Additionally, six genes were uniquely responsive to acutely toxic extracts of OSPW. Evidence presented supports a role for sulphur- and nitrogen-containing chemical classes in the toxicity of extracts of OSPW. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Phenanthrene causes ocular developmental toxicity in zebrafish embryos and the possible mechanisms involved

    International Nuclear Information System (INIS)

    Huang, Lixing; Wang, Chonggang; Zhang, Youyu; Wu, Meifang; Zuo, Zhenghong

    2013-01-01

    Highlights: • Phe exposure caused obvious morphological changes in the retina. • Phe exposure caused apoptosis and reduction of cell proliferation in the retina. • Phe causes ocular toxicity might be via the AhR/Zeb1/Mitf/Pax6 signaling pathway. • AhR is a repressor of Zeb1. -- Abstract: Recent studies show that polycyclic aromatic hydrocarbons (PAHs) may be a candidate cause of developmental defects of the retina, but the mechanism is still unclear. We evaluated the mechanism(s) underlying PAH-induced retinal development defects due to exposure to environmental concentrations of Phenanthrene (Phe) in zebrafish. We found that exposure to environmental concentrations of Phe caused obvious morphological changes, developmental retardation, apoptosis, and reduction of cell proliferation in the retina. Our results indicated that Phe could cause visual system developmental defects. Phe exposure up-regulated aryl hydrocarbon receptor (AhR) and microphthalmia-associated transcription factor (Mtif) expression, and down-regulated zinc finger E-box binding homeobox 1 (Zeb1) and paired box 6 (Pax6). Moreover, we demonstrated that AhR was a repressor of Zeb1. We propose that Phe's ocular toxicity is mediated by up-regulating AhR, which then down-regulates Zeb1, in turn inducing Mitf expression while inhibiting Pax6 expression

  4. Salinity-dependent mechanisms of copper toxicity in the galaxiid fish, Galaxias maculatus.

    Science.gov (United States)

    Glover, Chris N; Urbina, Mauricio A; Harley, Rachel A; Lee, Jacqueline A

    2016-05-01

    The euryhaline galaxiid fish, inanga (Galaxias maculatus) is widely spread throughout the Southern hemisphere occupying near-coastal streams that may be elevated in trace elements such as copper (Cu). Despite this, nothing is known regarding their sensitivity to Cu contamination. The mechanisms of Cu toxicity in inanga, and the ameliorating role of salinity, were investigated by acclimating fish to freshwater (FW), 50% seawater (SW), or 100% SW and exposing them to a graded series of Cu concentrations (0-200μgL(-1)) for 48h. Mortality, whole body Cu accumulation, measures of ionoregulatory disturbance (whole body ions, sodium (Na) influx, sodium/potassium ATPase activity) and ammonia excretion were monitored. Toxicity of Cu was greatest in FW, with mortality likely resulting from impaired Na influx. In both FW and 100% SW, ammonia excretion was significantly elevated, an effect opposite to that observed in previous studies, suggesting fundamental differences in the effect of Cu in this species relative to other studied fish. Salinity was protective against Cu toxicity, and physiology seemed to play a more important role than water chemistry in this protection. Inanga are sensitive to waterborne Cu through a conserved impairment of Na ion homeostasis, but some effects of Cu exposure in this species are distinct. Based on effect concentrations, current regulatory tools and limits are likely protective of this species in New Zealand waters. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Cyanotoxins: producing organisms, occurrence, toxicity, mechanism of action and human health toxicological risk evaluation.

    Science.gov (United States)

    Buratti, Franca M; Manganelli, Maura; Vichi, Susanna; Stefanelli, Mara; Scardala, Simona; Testai, Emanuela; Funari, Enzo

    2017-03-01

    Cyanobacteria were present on the earth 3.5 billion years ago; since then they have colonized almost all terrestrial and aquatic ecosystems. They produce a high number of bioactive molecules, among which some are cyanotoxins. Cyanobacterial growth at high densities, forming blooms, is increasing in extension and frequency, following anthropogenic activities and climate changes, giving rise to some concern for human health and animal life exposed to cyanotoxins. Numerous cases of lethal poisonings have been associated with cyanotoxins ingestion in wild animal and livestock. In humans few episodes of lethal or severe human poisonings have been recorded after acute or short-term exposure, but the repeated/chronic exposure to low cyanotoxin levels remains a critical issue. The properties of the most frequently detected cyanotoxins (namely, microcystins, nodularins, cylindrospermopsin and neurotoxins) are here critically reviewed, describing for each toxin the available information on producing organisms, biosynthesis/genetic and occurrence, with a focus on the toxicological profile (including kinetics, acute systemic toxicity, mechanism and mode of action, local effects, repeated toxicity, genotoxicity, carcinogenicity, reproductive toxicity; human health effects and epidemiological studies; animal poisoning) with the derivation of health-based values and considerations on the risks for human health.

  6. Nanoscale copper in the soil–plant system – toxicity and underlying potential mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Anjum, Naser A., E-mail: anjum@ua.pt [CESAM-Centre for Environmental and Marine Studies & Department of Chemistry, University of Aveiro, 3810-193 Aveiro (Portugal); Adam, Vojtech [Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno (Czech Republic); Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno (Czech Republic); Kizek, Rene [Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno (Czech Republic); Duarte, Armando C.; Pereira, Eduarda [CESAM-Centre for Environmental and Marine Studies & Department of Chemistry, University of Aveiro, 3810-193 Aveiro (Portugal); Iqbal, Muhammad [Department of Botany, Faculty of Science, Hamdard University, New Delhi 110062 (India); Lukatkin, Alexander S. [Department of Botany, Plant Physiology and Ecology, N.P. Ogarev Mordovia State University, Bolshevistskaja Str., 68. Saransk 430005 (Russian Federation); Ahmad, Iqbal, E-mail: ahmadr@ua.pt [CESAM-Centre for Environmental and Marine Studies & Department of Chemistry, University of Aveiro, 3810-193 Aveiro (Portugal); CESAM-Centre for Environmental and Marine Studies & Department of Biology, University of Aveiro, 3810-193 Aveiro (Portugal)

    2015-04-15

    Nanoscale copper particles (nano-Cu) are used in many antimicrobial formulations and products for their antimicrobial activity. They may enter deliberately and/or accidentally into terrestrial environments including soils. Being the major ‘eco-receptors’ of nanoscale particles in the terrestrial ecosystem, soil–microbiota and plants (the soil–plant system) have been used as a model to dissect the potential impact of these particles on the environmental and human health. In the soil–plant system, the plant can be an indirect non-target organism of the soil-associated nano-Cu that may in turn affect plant-based products and their consumers. By all accounts, information pertaining to nano-Cu toxicity and the underlying potential mechanisms in the soil–plant system remains scanty, deficient and little discussed. Therefore, based on some recent reports from (bio)chemical, molecular and genetic studies of nano-Cu versus soil–plant system, this article: (i) overviews the status, chemistry and toxicity of nano-Cu in soil and plants, (ii) discusses critically the poorly understood potential mechanisms of nano-Cu toxicity and tolerance both in soil–microbiota and plants, and (iii) proposes future research directions. It appears from studies hitherto made that the uncontrolled generation and inefficient metabolism of reactive oxygen species through different reactions are the major factors underpinning the overall nano-Cu consequences in both the systems. However, it is not clear whether the nano-Cu or the ion released from it is the cause of the toxicity. We advocate to intensify the multi-approach studies focused at a complete characterization of the nano-Cu, its toxicity (during life cycles of the least-explored soil–microbiota and plants), and behavior in an environmentally relevant terrestrial exposure setting. Such studies may help to obtain a deeper insight into nano-Cu actions and address adequately the nano-Cu-associated safety concerns in the

  7. Nanoscale copper in the soil–plant system – toxicity and underlying potential mechanisms

    International Nuclear Information System (INIS)

    Anjum, Naser A.; Adam, Vojtech; Kizek, Rene; Duarte, Armando C.; Pereira, Eduarda; Iqbal, Muhammad; Lukatkin, Alexander S.; Ahmad, Iqbal

    2015-01-01

    Nanoscale copper particles (nano-Cu) are used in many antimicrobial formulations and products for their antimicrobial activity. They may enter deliberately and/or accidentally into terrestrial environments including soils. Being the major ‘eco-receptors’ of nanoscale particles in the terrestrial ecosystem, soil–microbiota and plants (the soil–plant system) have been used as a model to dissect the potential impact of these particles on the environmental and human health. In the soil–plant system, the plant can be an indirect non-target organism of the soil-associated nano-Cu that may in turn affect plant-based products and their consumers. By all accounts, information pertaining to nano-Cu toxicity and the underlying potential mechanisms in the soil–plant system remains scanty, deficient and little discussed. Therefore, based on some recent reports from (bio)chemical, molecular and genetic studies of nano-Cu versus soil–plant system, this article: (i) overviews the status, chemistry and toxicity of nano-Cu in soil and plants, (ii) discusses critically the poorly understood potential mechanisms of nano-Cu toxicity and tolerance both in soil–microbiota and plants, and (iii) proposes future research directions. It appears from studies hitherto made that the uncontrolled generation and inefficient metabolism of reactive oxygen species through different reactions are the major factors underpinning the overall nano-Cu consequences in both the systems. However, it is not clear whether the nano-Cu or the ion released from it is the cause of the toxicity. We advocate to intensify the multi-approach studies focused at a complete characterization of the nano-Cu, its toxicity (during life cycles of the least-explored soil–microbiota and plants), and behavior in an environmentally relevant terrestrial exposure setting. Such studies may help to obtain a deeper insight into nano-Cu actions and address adequately the nano-Cu-associated safety concerns in the

  8. Possible mechanism for species difference on the toxicity of pivalic acid between dogs and rats

    International Nuclear Information System (INIS)

    Yamaguchi, Toshiro; Nakajima, Yoshitsugu; Nakamura, Yutaka

    2006-01-01

    In a high dose toxicity study of pivalic acid (PA), PA caused skeletal muscle disorder in dog, and a significant increase of pivaloyl carnitine (PC) was observed in canine muscle, but not in rat muscle. In order to understand species difference of the toxicity of PA, we compared the in vitro metabolism of PA among dog, rat and rabbit, especially focussing on the carnitine conjugate. Canine muscle showed low, but significant carnitine conjugating activity, while that of rat was negligible. Canine kidney mitochondria had significant activity in the pivaloyl CoA synthesis (7 nmol/mg protein/h), but muscle mitochondria showed only trace activity. Both kidney and muscle mitochondria displayed similar carnitine acyltransferase activity (2-3 nmol/mg protein/h) towards pivaloyl CoA. On the other hand, with respect to the activity of carnitine acyltransferase in the reverse direction using PC as substrate, canine muscle mitochondria showed higher activity than that of kidney mitochondria. This means that PC is not the final stable metabolite, but is converted easily to pivaloyl CoA in canine muscle. These results suggest one of the possible mechanisms for canine selective muscle disorder to be as follows. Only canine muscle can metabolize PA to its carnitine conjugate slowly, but significantly. In canine muscle, PC is not the final stable metabolite; it is easily converted to pivaloyl CoA. As carnitine conjugation is thought to be the only detoxification metabolic route in canine muscle, under certain circumstances such as carnitine deficiency, the risk of exposure with toxic pivaloyl CoA might increase and the CoASH pool in canine muscle might be exhausted, resulting in toxicity in canine muscle

  9. Absence of a Universal Mechanism of Mitochondrial Toxicity by Nucleoside Analogs▿

    Science.gov (United States)

    Lund, Kaleb C.; Peterson, LaRae L.; Wallace, Kendall B.

    2007-01-01

    Nucleoside analogs are associated with various mitochondrial toxicities, and it is becoming increasingly difficult to accommodate these differences solely in the context of DNA polymerase gamma inhibition. Therefore, we examined the toxicities of zidovudine (AZT) (10 and 50 μM; 2.7 and 13.4 μg/ml), didanosine (ddI) (10 and 50 μM; 2.4 and 11.8 μg/ml), and zalcitabine (ddC) (1 and 5 μM; 0.21 and 1.1 μg/ml) in HepG2 and H9c2 cells without the presumption of mitochondrial DNA (mtDNA) depletion. Ethidium bromide (EtBr) (0.5 μg/ml; 1.3 μM) was used as a positive control. AZT treatment resulted in metabolic disruption (increased lactate and superoxide) and increased cell mortality with decreased proliferation, while mtDNA remained unchanged or increased (HepG2 cells; 50 μM AZT). ddC caused pronounced mtDNA depletion in HepG2 cells but not in H9c2 cells and increased mortality in HepG2 cells, but no significant metabolic disruption in either cell type. ddI caused a moderate depletion of mtDNA in both cell types but showed no other effects. EtBr exposure resulted in metabolic disruption, increased cell mortality with decreased cell proliferation, and mtDNA depletion in both cell types. We conclude that nucleoside analogs display unique toxicities within and between culture models, and therefore, care should be taken when generalizing about the mechanisms of nucleoside reverse transcriptase inhibitor toxicity. Additionally, mtDNA abundance does not necessarily correlate with metabolic disruption, especially in cell culture; careful discernment is recommended in this regard. PMID:17470651

  10. Absence of a universal mechanism of mitochondrial toxicity by nucleoside analogs.

    Science.gov (United States)

    Lund, Kaleb C; Peterson, LaRae L; Wallace, Kendall B

    2007-07-01

    Nucleoside analogs are associated with various mitochondrial toxicities, and it is becoming increasingly difficult to accommodate these differences solely in the context of DNA polymerase gamma inhibition. Therefore, we examined the toxicities of zidovudine (AZT) (10 and 50 microM; 2.7 and 13.4 microg/ml), didanosine (ddI) (10 and 50 microM; 2.4 and 11.8 microg/ml), and zalcitabine (ddC) (1 and 5 microM; 0.21 and 1.1 microg/ml) in HepG2 and H9c2 cells without the presumption of mitochondrial DNA (mtDNA) depletion. Ethidium bromide (EtBr) (0.5 microg/ml; 1.3 microM) was used as a positive control. AZT treatment resulted in metabolic disruption (increased lactate and superoxide) and increased cell mortality with decreased proliferation, while mtDNA remained unchanged or increased (HepG2 cells; 50 microM AZT). ddC caused pronounced mtDNA depletion in HepG2 cells but not in H9c2 cells and increased mortality in HepG2 cells, but no significant metabolic disruption in either cell type. ddI caused a moderate depletion of mtDNA in both cell types but showed no other effects. EtBr exposure resulted in metabolic disruption, increased cell mortality with decreased cell proliferation, and mtDNA depletion in both cell types. We conclude that nucleoside analogs display unique toxicities within and between culture models, and therefore, care should be taken when generalizing about the mechanisms of nucleoside reverse transcriptase inhibitor toxicity. Additionally, mtDNA abundance does not necessarily correlate with metabolic disruption, especially in cell culture; careful discernment is recommended in this regard.

  11. Cytotoxicity of polycations: Relationship of molecular weight and the hydrolytic theory of the mechanism of toxicity.

    Science.gov (United States)

    Monnery, Bryn D; Wright, Michael; Cavill, Rachel; Hoogenboom, Richard; Shaunak, Sunil; Steinke, Joachim H G; Thanou, Maya

    2017-04-15

    The mechanism of polycation cytotoxicity and the relationship to polymer molecular weight is poorly understood. To gain an insight into this important phenomenon a range of newly synthesised uniform (near monodisperse) linear polyethylenimines, commercially available poly(l-lysine)s and two commonly used PEI-based transfectants (broad 22kDa linear and 25kDa branched) were tested for their cytotoxicity against the A549 human lung carcinoma cell line. Cell membrane damage assays (LDH release) and cell viability assays (MTT) showed a strong relationship to dose and polymer molecular weight, and increasing incubation times revealed that even supposedly "non-toxic" low molecular weight polymers still damage cell membranes. The newly proposed mechanism of cell membrane damage is acid catalysed hydrolysis of lipidic phosphoester bonds, which was supported by observations of the hydrolysis of DOPC liposomes. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  12. Heterocyclic Schiff bases as non toxic antioxidants: Solvent effect, structure activity relationship and mechanism of action

    Science.gov (United States)

    Shanty, Angamaly Antony; Mohanan, Puzhavoorparambil Velayudhan

    2018-03-01

    Phenolic heterocyclic imine based Schiff bases from Thiophene-2-carboxaldehyde and Pyrrole-2-carboxaldehyde were synthesized and characterized as novel antioxidants. The solvent effects of these Schiff bases were determined and compared with standard antioxidants, BHA employing DPPH assay and ABTS assay. Fixed reaction time and Steady state measurement were used for study. IC50 and EC50 were calculated. Structure-activity relationship revealed that the electron donating group in the phenolic ring increases the activity where as the electron withdrawing moiety decreases the activity. The Schiff base derivatives showed antioxidant property by two different pathways namely SPLET and HAT mechanisms in DPPH assay. While in ABTS method, the reaction between ABTS radical and Schiff bases involves electron transfer followed by proton transfer (ET-PT) mechanism. The cytotoxicity of these compounds has been evaluated by MTT assay. The results showed that all these compounds are non toxic in nature.

  13. Variation in shoot tolerance mechanisms not related to ion toxicity in barley

    KAUST Repository

    Tilbrook, Joanne

    2017-09-27

    Soil salinity can severely reduce crop growth and yield. Many studies have investigated salinity tolerance mechanisms in cereals using phenotypes that are relatively easy to measure. The majority of these studies measured the accumulation of shoot Na+ and the effect this has on plant growth. However, plant growth is reduced immediately after exposure to NaCl before Na+ accumulates to toxic concentrations in the shoot. In this study, nondestructive and destructive measurements are used to evaluate the responses of 24 predominately Australian barley (Hordeum vulgare L.) lines at 0, 150 and 250mMNaCl. Considerable variation for shoot tolerance mechanisms not related to ion toxicity (shoot ion-independent tolerance) was found, withsome lines being able to maintain substantial growth rates under salt stress, whereas others stopped growing. Hordeum vulgare spp. spontaneum accessions and barley landraces predominantly had the best shoot ion independent tolerance, although two commercial cultivars, Fathom and Skiff, also had high tolerance. The tolerance of cv. Fathom may be caused by a recent introgression from H. vulgare L. spp. spontaneum. This study shows that the most salt-tolerant barley lines are those that contain both shoot ion-independent tolerance and the ability to exclude Na+ from the shoot (and thus maintain high K+: Na+ ratios).

  14. Variation in shoot tolerance mechanisms not related to ion toxicity in barley

    KAUST Repository

    Tilbrook, Joanne; Schilling, Rhiannon K.; Berger, Bettina; Garcia, Alexandre F.; Trittermann, Christine; Coventry, Stewart; Rabie, Huwaida; Brien, Chris; Nguyen, Martin; Tester, Mark A.; Roy, Stuart J.

    2017-01-01

    Soil salinity can severely reduce crop growth and yield. Many studies have investigated salinity tolerance mechanisms in cereals using phenotypes that are relatively easy to measure. The majority of these studies measured the accumulation of shoot Na+ and the effect this has on plant growth. However, plant growth is reduced immediately after exposure to NaCl before Na+ accumulates to toxic concentrations in the shoot. In this study, nondestructive and destructive measurements are used to evaluate the responses of 24 predominately Australian barley (Hordeum vulgare L.) lines at 0, 150 and 250mMNaCl. Considerable variation for shoot tolerance mechanisms not related to ion toxicity (shoot ion-independent tolerance) was found, withsome lines being able to maintain substantial growth rates under salt stress, whereas others stopped growing. Hordeum vulgare spp. spontaneum accessions and barley landraces predominantly had the best shoot ion independent tolerance, although two commercial cultivars, Fathom and Skiff, also had high tolerance. The tolerance of cv. Fathom may be caused by a recent introgression from H. vulgare L. spp. spontaneum. This study shows that the most salt-tolerant barley lines are those that contain both shoot ion-independent tolerance and the ability to exclude Na+ from the shoot (and thus maintain high K+: Na+ ratios).

  15. Photodegradation of gemfibrozil in aqueous solution under UV irradiation: kinetics, mechanism, toxicity, and degradation pathways.

    Science.gov (United States)

    Ma, Jingshuai; Lv, Wenying; Chen, Ping; Lu, Yida; Wang, Fengliang; Li, Fuhua; Yao, Kun; Liu, Guoguang

    2016-07-01

    The lipid regulator gemfibrozil (GEM) has been reported to be persistent in conventional wastewater treatment plants. This study investigated the photolytic behavior, toxicity of intermediate products, and degradation pathways of GEM in aqueous solutions under UV irradiation. The results demonstrated that the photodegradation of GEM followed pseudo-first-order kinetics, and the pseudo-first-order rate constant was decreased markedly with increasing initial concentrations of GEM and initial pH. The photodegradation of GEM included direct photolysis via (3)GEM(*) and self-sensitization via ROS, where the contribution rates of degradation were 0.52, 90.05, and 8.38 % for ·OH, (1)O2, and (3)GEM(*), respectively. Singlet oxygen ((1)O2) was evidenced by the molecular probe compound, furfuryl alcohol (FFA), and was identified as the primary reactive species in the photolytic process. The steady-state concentrations of (1)O2 increased from (0.324 ± 0.014) × 10(-12) to (1.021 ± 0.040) × 10(-12) mol L(-1), as the initial concentrations of GEM were increased from 5 to 20 mg L(-1). The second-order rate constant for the reaction of GEM with (1)O2 was calculated to be 2.55 × 10(6) M(-1) s(-1). The primary transformation products were identified using HPLC-MS/MS, and possible photodegradation pathways were proposed by hydroxylation, aldehydes reactions, as well as the cleavage of ether side chains. The toxicity of phototransformation product evaluation revealed that photolysis potentially provides a critical pathway for GEM toxicity reduction in potable water and wastewater treatment facilities.

  16. Disentangling the effects of polymer coatings on silver nanoparticle agglomeration, dissolution, and toxicity to determine mechanisms of nanotoxicity

    International Nuclear Information System (INIS)

    Zook, Justin M.; Halter, Melissa D.; Cleveland, Danielle; Long, Stephen E.

    2012-01-01

    Silver nanoparticles (AgNPs) are frequently coated with a variety of polymers, which may affect various interdependent mechanisms of toxicity or antimicrobial action, including agglomeration and dissolution rates. Here, we systematically measure how citrate, dextran, 5 and 20 kDa poly(ethylene glycol) (PEG), and poly(vinyl pyrrolidone) coatings affect AgNP agglomeration, dissolution, and toxicity. In addition, to disentangle the coatings’ effects on agglomeration from their other effects, we produce multiple stable agglomerate sizes of several of the coated ∼23 nm AgNPs ranging from singly-dispersed to mean agglomerate sizes of several hundred nanometers. These dispersions allow us to independently study the effects of agglomeration and polymer coating on dissolution rate and hemolytic toxicity. We find that both hemolytic toxicity and dissolution rate are highest for the 5 kDa PEG coating, and toxicity and dissolution rate decrease significantly with increasing agglomerate size independent of coating. This correlation between toxicity and dissolution rate suggests that both polymer coating and agglomeration may affect hemolytic toxicity largely through their effects on dissolution. Because both the AgNP dissolution rate and hemolysis decrease only moderately compared to the large increases in agglomerate size, AgNPs’ hemolytic toxicity may be caused by their large surface area and consequently high dissolution rate, rather than from other size-specific effects. At the silver concentrations used in this work, silver dissolved from AgNPs is expected to be primarily in the form of AgCl NPs, which are therefore more likely than Ag + ions to be the primary drivers of hemolytic toxicity. In addition, all AgNPs we tested are much more toxic to horse red blood cells than sheep red blood cells, highlighting the complexity of toxic responses and the need to test toxicity in multiple biological systems.

  17. Disentangling the effects of polymer coatings on silver nanoparticle agglomeration, dissolution, and toxicity to determine mechanisms of nanotoxicity

    Science.gov (United States)

    Zook, Justin M.; Halter, Melissa D.; Cleveland, Danielle; Long, Stephen E.

    2012-10-01

    Silver nanoparticles (AgNPs) are frequently coated with a variety of polymers, which may affect various interdependent mechanisms of toxicity or antimicrobial action, including agglomeration and dissolution rates. Here, we systematically measure how citrate, dextran, 5 and 20 kDa poly(ethylene glycol) (PEG), and poly(vinyl pyrrolidone) coatings affect AgNP agglomeration, dissolution, and toxicity. In addition, to disentangle the coatings' effects on agglomeration from their other effects, we produce multiple stable agglomerate sizes of several of the coated 23 nm AgNPs ranging from singly-dispersed to mean agglomerate sizes of several hundred nanometers. These dispersions allow us to independently study the effects of agglomeration and polymer coating on dissolution rate and hemolytic toxicity. We find that both hemolytic toxicity and dissolution rate are highest for the 5 kDa PEG coating, and toxicity and dissolution rate decrease significantly with increasing agglomerate size independent of coating. This correlation between toxicity and dissolution rate suggests that both polymer coating and agglomeration may affect hemolytic toxicity largely through their effects on dissolution. Because both the AgNP dissolution rate and hemolysis decrease only moderately compared to the large increases in agglomerate size, AgNPs' hemolytic toxicity may be caused by their large surface area and consequently high dissolution rate, rather than from other size-specific effects. At the silver concentrations used in this work, silver dissolved from AgNPs is expected to be primarily in the form of AgCl NPs, which are therefore more likely than Ag+ ions to be the primary drivers of hemolytic toxicity. In addition, all AgNPs we tested are much more toxic to horse red blood cells than sheep red blood cells, highlighting the complexity of toxic responses and the need to test toxicity in multiple biological systems.

  18. Disentangling the effects of polymer coatings on silver nanoparticle agglomeration, dissolution, and toxicity to determine mechanisms of nanotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Zook, Justin M., E-mail: jzook@nist.gov; Halter, Melissa D.; Cleveland, Danielle; Long, Stephen E. [National Institute of Standards and Technology, Material Measurement Laboratory (United States)

    2012-10-15

    Silver nanoparticles (AgNPs) are frequently coated with a variety of polymers, which may affect various interdependent mechanisms of toxicity or antimicrobial action, including agglomeration and dissolution rates. Here, we systematically measure how citrate, dextran, 5 and 20 kDa poly(ethylene glycol) (PEG), and poly(vinyl pyrrolidone) coatings affect AgNP agglomeration, dissolution, and toxicity. In addition, to disentangle the coatings' effects on agglomeration from their other effects, we produce multiple stable agglomerate sizes of several of the coated {approx}23 nm AgNPs ranging from singly-dispersed to mean agglomerate sizes of several hundred nanometers. These dispersions allow us to independently study the effects of agglomeration and polymer coating on dissolution rate and hemolytic toxicity. We find that both hemolytic toxicity and dissolution rate are highest for the 5 kDa PEG coating, and toxicity and dissolution rate decrease significantly with increasing agglomerate size independent of coating. This correlation between toxicity and dissolution rate suggests that both polymer coating and agglomeration may affect hemolytic toxicity largely through their effects on dissolution. Because both the AgNP dissolution rate and hemolysis decrease only moderately compared to the large increases in agglomerate size, AgNPs' hemolytic toxicity may be caused by their large surface area and consequently high dissolution rate, rather than from other size-specific effects. At the silver concentrations used in this work, silver dissolved from AgNPs is expected to be primarily in the form of AgCl NPs, which are therefore more likely than Ag{sup +} ions to be the primary drivers of hemolytic toxicity. In addition, all AgNPs we tested are much more toxic to horse red blood cells than sheep red blood cells, highlighting the complexity of toxic responses and the need to test toxicity in multiple biological systems.

  19. Mechanisms of carbon nanotube-induced toxicity: Focus on oxidative stress

    Energy Technology Data Exchange (ETDEWEB)

    Shvedova, Anna A., E-mail: ats1@cdc.gov [Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, University of Rome “Tor Vergata”, Rome (Italy); Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, University of Rome “Tor Vergata”, Rome (Italy); Pietroiusti, Antonio [Department of Biopathology, University of Rome “Tor Vergata”, Rome (Italy); Fadeel, Bengt [Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden); Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA (United States); Kagan, Valerian E. [Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA (United States)

    2012-06-01

    Nanotechnologies are emerging as highly promising technologies in many sectors in the society. However, the increasing use of engineered nanomaterials also raises concerns about inadvertent exposure to these materials and the potential for adverse effects on human health and the environment. Despite several years of intensive investigations, a common paradigm for the understanding of nanoparticle-induced toxicity remains to be firmly established. Here, the so-called oxidative stress paradigm is scrutinized. Does oxidative stress represent a secondary event resulting inevitably from disruption of biochemical processes and the demise of the cell, or a specific, non-random event that plays a role in the induction of cellular damage e.g. apoptosis? The answer to this question will have important ramifications for the development of strategies for mitigation of adverse effects of nanoparticles. Recent examples of global lipidomics studies of nanoparticle-induced tissue damage are discussed along with proteomics and transcriptomics approaches to achieve a comprehensive understanding of the complex and interrelated molecular changes in cells and tissues exposed to nanoparticles. We also discuss instances of non-oxidative stress-mediated cellular damage resulting from direct physical interference of nanomaterials with cellular structures. -- Highlights: ► CNT induced non-random oxidative stress associated with apoptosis. ► Non-oxidative mechanisms for cellular toxicity of carbon nanotubes. ► Biodegradation of CNT by cells of innate immune system. ► “Omics”-based biomarkers of CNT exposures.

  20. Silver nanoparticles: mechanism of antimicrobial action, synthesis, medical applications, and toxicity effects

    Science.gov (United States)

    Prabhu, Sukumaran; Poulose, Eldho K.

    2012-10-01

    Silver nanoparticles are nanoparticles of silver which are in the range of 1 and 100 nm in size. Silver nanoparticles have unique properties which help in molecular diagnostics, in therapies, as well as in devices that are used in several medical procedures. The major methods used for silver nanoparticle synthesis are the physical and chemical methods. The problem with the chemical and physical methods is that the synthesis is expensive and can also have toxic substances absorbed onto them. To overcome this, the biological method provides a feasible alternative. The major biological systems involved in this are bacteria, fungi, and plant extracts. The major applications of silver nanoparticles in the medical field include diagnostic applications and therapeutic applications. In most of the therapeutic applications, it is the antimicrobial property that is being majorly explored, though the anti-inflammatory property has its fair share of applications. Though silver nanoparticles are rampantly used in many medical procedures and devices as well as in various biological fields, they have their drawbacks due to nanotoxicity. This review provides a comprehensive view on the mechanism of action, production, applications in the medical field, and the health and environmental concerns that are allegedly caused due to these nanoparticles. The focus is on effective and efficient synthesis of silver nanoparticles while exploring their various prospective applications besides trying to understand the current scenario in the debates on the toxicity concerns these nanoparticles pose.

  1. Mechanisms of carbon nanotube-induced toxicity: Focus on oxidative stress

    International Nuclear Information System (INIS)

    Shvedova, Anna A.; Pietroiusti, Antonio; Fadeel, Bengt; Kagan, Valerian E.

    2012-01-01

    Nanotechnologies are emerging as highly promising technologies in many sectors in the society. However, the increasing use of engineered nanomaterials also raises concerns about inadvertent exposure to these materials and the potential for adverse effects on human health and the environment. Despite several years of intensive investigations, a common paradigm for the understanding of nanoparticle-induced toxicity remains to be firmly established. Here, the so-called oxidative stress paradigm is scrutinized. Does oxidative stress represent a secondary event resulting inevitably from disruption of biochemical processes and the demise of the cell, or a specific, non-random event that plays a role in the induction of cellular damage e.g. apoptosis? The answer to this question will have important ramifications for the development of strategies for mitigation of adverse effects of nanoparticles. Recent examples of global lipidomics studies of nanoparticle-induced tissue damage are discussed along with proteomics and transcriptomics approaches to achieve a comprehensive understanding of the complex and interrelated molecular changes in cells and tissues exposed to nanoparticles. We also discuss instances of non-oxidative stress-mediated cellular damage resulting from direct physical interference of nanomaterials with cellular structures. -- Highlights: ► CNT induced non-random oxidative stress associated with apoptosis. ► Non-oxidative mechanisms for cellular toxicity of carbon nanotubes. ► Biodegradation of CNT by cells of innate immune system. ► “Omics”-based biomarkers of CNT exposures.

  2. Combined toxicity and underlying mechanisms of a mixture of eight heavy metals.

    Science.gov (United States)

    Zhou, Qi; Gu, Yuanliang; Yue, Xia; Mao, Guochuan; Wang, Yafei; Su, Hong; Xu, Jin; Shi, Hongbo; Zou, Baobo; Zhao, Jinshun; Wang, Renyuan

    2017-02-01

    With the rapid development of modernization and industrialization in China, a large quantity of heavy metals, including zinc, copper, lead, cadmium and mercury, have been entering the atmosphere, soil and water, the latter being the primary route of pollution. In the present study, in vitro experiments were performed to examine the joint toxicity and the underlying mechanisms of the eight most common heavy metals contaminating offshore waters on the eastern coast of Ningbo region. Using a cell cycle assay, cell apoptosis and reactive oxygen species (ROS) detection methods, the present study demonstrated that the heavy metal mixture arrested JB6 cells at the S phase, induced the generation of ROS and cell apoptosis. A luciferase assay indicated that the levels of activator protein‑1 and nuclear factor‑κB transcription factors were upregulated. Upregulation of the protein levels of C‑jun and p65 were detected in the JB6 cells by western blot analysis; these two genes have important roles in cell carcinogenesis. These results provide a useful reference for further investigations on the combined toxicity of the exposure to multiple heavy metals.

  3. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms.

    Science.gov (United States)

    Rogosnitzky, Moshe; Branch, Stacy

    2016-06-01

    Gadolinium chelates are widely used as contrast media for magnetic resonance imaging. The approved gadolinium-based contrast agents (GBCAs) have historically been considered safe and well tolerated when used at recommended dosing levels. However, for nearly a decade, an association between GBCA administration and the development of nephrogenic systemic fibrosis (NSF) has been recognized in patients with severe renal impairment. This has led to modifications in clinical practices aimed at reducing the potential and incidence of NSF development. Newer reports have emerged regarding the accumulation of gadolinium in various tissues of patients who do not have renal impairment, including bone, brain, and kidneys. Despite the observations of gadolinium accumulation in tissues regardless of renal function, very limited clinical data regarding the potential for and mechanisms of toxicity is available. This significant gap in knowledge warrants retrospective cohort study efforts, as well as prospective studies that involve gadolinium ion (Gd(3+)) testing in patients exposed to GBCA. This review examines the potential biochemical and molecular basis of gadolinium toxicity, possible clinical significance of gadolinium tissue retention and accumulation, and methods that can limit gadolinium body burden.

  4. From basic physics to mechanisms of toxicity: the ``liquid drop'' approach applied to develop predictive classification models for toxicity of metal oxide nanoparticles

    Science.gov (United States)

    Sizochenko, Natalia; Rasulev, Bakhtiyor; Gajewicz, Agnieszka; Kuz'min, Victor; Puzyn, Tomasz; Leszczynski, Jerzy

    2014-10-01

    Many metal oxide nanoparticles are able to cause persistent stress to live organisms, including humans, when discharged to the environment. To understand the mechanism of metal oxide nanoparticles' toxicity and reduce the number of experiments, the development of predictive toxicity models is important. In this study, performed on a series of nanoparticles, the comparative quantitative-structure activity relationship (nano-QSAR) analyses of their toxicity towards E. coli and HaCaT cells were established. A new approach for representation of nanoparticles' structure is presented. For description of the supramolecular structure of nanoparticles the ``liquid drop'' model was applied. It is expected that a novel, proposed approach could be of general use for predictions related to nanomaterials. In addition, in our study fragmental simplex descriptors and several ligand-metal binding characteristics were calculated. The developed nano-QSAR models were validated and reliably predict the toxicity of all studied metal oxide nanoparticles. Based on the comparative analysis of contributed properties in both models the LDM-based descriptors were revealed to have an almost similar level of contribution to toxicity in both cases, while other parameters (van der Waals interactions, electronegativity and metal-ligand binding characteristics) have unequal contribution levels. In addition, the models developed here suggest different mechanisms of nanotoxicity for these two types of cells.Many metal oxide nanoparticles are able to cause persistent stress to live organisms, including humans, when discharged to the environment. To understand the mechanism of metal oxide nanoparticles' toxicity and reduce the number of experiments, the development of predictive toxicity models is important. In this study, performed on a series of nanoparticles, the comparative quantitative-structure activity relationship (nano-QSAR) analyses of their toxicity towards E. coli and HaCaT cells were

  5. An integrative view of cisplatin-induced renal and cardiac toxicities: molecular mechanisms, current treatment challenges and potential protective measures

    Science.gov (United States)

    Dugbartey, George J.; Peppone, Luke J.; de Graaf, Inge A.M.

    2017-01-01

    Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies show cisplatin generates reactive oxygen species, which impair the cell’s antioxidant defense system, causing oxidative stress and potentiating injury, thereby culminating in kidney and heart failure. Understanding the molecular mechanisms of cisplatin-induced renal and cardiac toxicities may allow clinicians to prevent or treat this problem better and may also provide a model for investigating drug-induced organ toxicity in general. This review discusses some of the major molecular mechanisms of cisplatin-induced renal and cardiac toxicities including disruption of ionic homeostasis and energy status of the cell leading to cell injury and cell death. We highlight clinical manifestations of both toxicities as well as (novel)biomarkers such as kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also present some current treatment challenges and propose potential protective strategies with novel pharmacological compounds that might mitigate or prevent these toxicities, which include the use of hydrogen sulfide. PMID:27717837

  6. Reactions of clofibric acid with oxidative and reductive radicals—Products, mechanisms, efficiency and toxic effects

    International Nuclear Information System (INIS)

    Csay, Tamás; Rácz, Gergely; Salik, Ádám; Takács, Erzsébet; Wojnárovits, László

    2014-01-01

    The degradation of clofibric acid induced by hydroxyl radical, hydrated electron and O 2 −∙ /HO 2 ∙ reactive species was studied in aqueous solutions. Clofibric acid was decomposed more effectively by hydroxyl radical than by hydrated electron or O 2 −∙ /HO 2 ∙ . Various hydroxylated, dechlorinated and fragmentation products have been identified and quantified. A new LC–MS method was developed based on 18 O isotope labeling to follow the formation of hydroxylated derivatives of clofibric acid. Possible degradation pathways have been proposed. The overall degradation was monitored by determination of sum parameters like COD, TOC and AOX. It was found that the organic chlorine degrades very effectively prior to complete mineralization. After the treatment no toxic effect was found according to Vibrio fischeri tests. However, at early stages some of the reaction products were more harmful than clofibric acid. - Highlights: • Clofibric acid is effectively degraded by OH radical. • Main primary and secondary products are hydroxylated and dihydroxylated phenyl type derivatives of clofibric acid. • In air saturated aqueous solutions O 2 plays an important role in decomposition of the aromatic structure. • A new LC–MS method with 18 O-labeling was developed. • Early stage reaction products are more toxic to bacteria Vibrio fischeri than clofibric acid

  7. Sertraline-induced reproductive toxicity in male rats: evaluation of possible underlying mechanisms

    Directory of Open Access Journals (Sweden)

    Ozlem Atli

    2017-01-01

    Full Text Available This study was conducted to clarify the toxic effects of sertraline (SRT on the reproductive system of male rats and to elucidate the underlying mechanisms. Rats were treated orally with SRT at doses of 5, 10, and 20 mg kg−1 for 28 consecutive days. At the end of the treatment period, sperm concentration, sperm motility, and sperm morphology were investigated by computer-assisted sperm analysis system whereas sperm DNA damage was detected by comet assay. The oxidative status of the testes was investigated, and a histopathological examination was conducted. Serum testosterone, follicle-stimulating hormone (FSH, and luteinizing hormone (LH levels were measured to determine the effects of SRT on the spermatogenesis process. One-way ANOVA, post-hoc Dunnett′s T3 test for the sperm comet assay, and post-hoc Tukey′s test for the others were performed for statistical analysis. The results showed that SRT caused an increase in sperm DNA damage and induced histopathological lesions in all groups treated with SRT. There was abnormal sperm morphology and increased malondialdehyde (MDA in the 10 mg kg−1 treatment group. More dramatic changes were observed in the 20 mg kg−1 treatment group. Decreased sperm count was accompanied by a significant increase in abnormal sperm morphology, DNA damage, and degeneration in cellular-tubular structures. Serum LH and testosterone levels were elevated in the 20 mg kg−1 treatment group. Decreased glutathione (GSH and increased MDA were signs of enhanced oxidative stress (OS. In conclusion, SRT induced testicular toxicity in a dose-dependent manner and OS is suggested as a crucial mechanism.

  8. Ionoregulatory disruption as the acute toxic mechanism for lead in the rainbow trout (Oncorhynchus mykiss)

    International Nuclear Information System (INIS)

    Rogers, J.T.; Richards, J.G.; Wood, C.M.

    2003-01-01

    The mechanism for acute toxicity of lead (Pb) in rainbow trout (Oncorhynchus mykiss) was investigated at Pb concentrations close to the 96 h LC50 of 1.0 mg dissolved Pb l -1 (0.8-1.4, 95% C.I.) determined in dechlorinated Hamilton city tap water (from Lake Ontario, hardness=140 mg l -1 CaCO 3 ). Tissue Pb accumulation associated with death was highest in the gill, followed by kidney and liver. Significant ionoregulatory impacts were observed in adult rainbow trout (200-300 g) fitted with indwelling dorsal aortic catheters and exposed to 1.1±0.04 mg dissolved Pb l -1 . Decreased plasma [Ca 2+ ], [Na + ] and [Cl - ] occurred after 48 h of exposure through to 120 h, with increases in plasma [Mg 2+ ], ammonia, and cortisol. No marked changes in PaO 2 , PaCO 2 , pH, glucose, or hematological parameters were evident. Branchial Na + /K + ATPase activity in juvenile trout exposed to concentrations close to the 96 h LC50 was inhibited by approximately 40% after 48 h of Pb exposure. Calcium ion flux measurements using 45 Ca as a radiotracer showed 65% inhibition of Ca 2+ influx after 0, 12, 24 or 48 h exposure to the 96 h LC50 concentration of Pb. There was also significant inhibition (40-50%) of both Na + and Cl - uptake, measured with 22 Na and 36 Cl simultaneously. We conclude that the mechanism of acute toxicity for Pb in rainbow trout occurs by ionoregulatory disruption rather than respiratory or acid/base distress at Pb concentrations close to the 96 h LC50 in moderately hard water

  9. Ionoregulatory disruption as the acute toxic mechanism for lead in the rainbow trout (Oncorhynchus mykiss)

    Energy Technology Data Exchange (ETDEWEB)

    Rogers, J.T.; Richards, J.G.; Wood, C.M

    2003-07-16

    The mechanism for acute toxicity of lead (Pb) in rainbow trout (Oncorhynchus mykiss) was investigated at Pb concentrations close to the 96 h LC50 of 1.0 mg dissolved Pb l{sup -1} (0.8-1.4, 95% C.I.) determined in dechlorinated Hamilton city tap water (from Lake Ontario, hardness=140 mg l{sup -1} CaCO{sub 3}). Tissue Pb accumulation associated with death was highest in the gill, followed by kidney and liver. Significant ionoregulatory impacts were observed in adult rainbow trout (200-300 g) fitted with indwelling dorsal aortic catheters and exposed to 1.1{+-}0.04 mg dissolved Pb l{sup -1}. Decreased plasma [Ca{sup 2+}], [Na{sup +}] and [Cl{sup -}] occurred after 48 h of exposure through to 120 h, with increases in plasma [Mg{sup 2+}], ammonia, and cortisol. No marked changes in PaO{sub 2}, PaCO{sub 2}, pH, glucose, or hematological parameters were evident. Branchial Na{sup +}/K{sup +} ATPase activity in juvenile trout exposed to concentrations close to the 96 h LC50 was inhibited by approximately 40% after 48 h of Pb exposure. Calcium ion flux measurements using {sup 45}Ca as a radiotracer showed 65% inhibition of Ca{sup 2+} influx after 0, 12, 24 or 48 h exposure to the 96 h LC50 concentration of Pb. There was also significant inhibition (40-50%) of both Na{sup +} and Cl{sup -} uptake, measured with {sup 22}Na and {sup 36}Cl simultaneously. We conclude that the mechanism of acute toxicity for Pb in rainbow trout occurs by ionoregulatory disruption rather than respiratory or acid/base distress at Pb concentrations close to the 96 h LC50 in moderately hard water.

  10. Cerebrovascular Acute Radiation Syndrome : Radiation Neurotoxins, Mechanisms of Toxicity, Neuroimmune Interactions.

    Science.gov (United States)

    Popov, Dmitri; Maliev, Slava

    . Radiation Toxins (SRD-1)had been isolated from Central Lymph of irradiated animals (cows, sheep, pigs). Experiments to study toxicity of Radiation Neurotoxins had been performed. Intravenous (IV) and intramuscular (IM) administration of RT SRD-1 to radiation naive animals had induced acute toxicity which referred to the harmful effects generated by high doses of radiation. In-jection of toxic doses of RT SRD-1 (Toxic doses: 0,1 mg/kg, 0,5mg/kg, 1 mg/kg, 10mg/kg,30 mg/kg, 50mg/kg,70 mg/kg,100 mg/kg, 110mg/kg)were compared to the similar effects caused by high doses of radiation. Results: Injection of SRD-1 ( Neurotoxin Cv ARS)of all ten tested toxic doses had caused a death of radiation naive animals within the first hours after admin-istration of toxins. For all animals in all experiments, a short period of extreme agitation was replaced by deep coma, and suppression of blood circulation and breathing. The results of postmortem section had showed characteristics of intra-cortical hemorrhage. Conclusions: Acute radiation injury induces a disorder of blood supply of the Central Nervous System (CNS). However, administration of SRD-1 Radiation Toxins to radiation naive animals produces crit-ically important inflammatory reactions with hemorrhagic stroke development. Neurotoxicity and Excitotoxicity are two stages of the pathological processes resulted in damaging and killing nerve cells thorough apoptotic necrosis. Excitotoxicity is well known as a pathological process that occurs when important excitatory neurotransmitters (glutamate, serotonin) over-activate the receptors -NMDA, AMPA, 5HT1, 5HT2, 5H3. Radiation Neurotoxins possibly act on the same receptors and activate the cell death mechanisms through direct or indirect excessive activation of same receptors.

  11. The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome.

    Science.gov (United States)

    Harlow, Philippa H; Perry, Simon J; Widdison, Stephanie; Daniels, Shannon; Bondo, Eddie; Lamberth, Clemens; Currie, Richard A; Flemming, Anthony J

    2016-03-18

    To determine whether a C. elegans bioassay could predict mammalian developmental activity, we selected diverse compounds known and known not to elicit such activity and measured their effect on C. elegans egg viability. 89% of compounds that reduced C. elegans egg viability also had mammalian developmental activity. Conversely only 25% of compounds found not to reduce egg viability in C. elegans were also inactive in mammals. We conclude that the C. elegans egg viability assay is an accurate positive predictor, but an inaccurate negative predictor, of mammalian developmental activity. We then evaluated C. elegans as a tool to identify mechanisms affecting toxicological outcomes among related compounds. The difference in developmental activity of structurally related fungicides in C. elegans correlated with their rate of metabolism. Knockdown of the cytochrome P450s cyp-35A3 and cyp-35A4 increased the toxicity to C. elegans of the least developmentally active compounds to the level of the most developmentally active. This indicated that these P450s were involved in the greater rate of metabolism of the less toxic of these compounds. We conclude that C. elegans based approaches can predict mammalian developmental activity and can yield plausible hypotheses for factors affecting the biological potency of compounds in mammals.

  12. INTER-SPECIES MODELS FOR ACUTE AQUATIC TOXICITY BASED ON MECHANISM OF ACTION

    Science.gov (United States)

    This presentation will provide interspecies QSARs for acute toxicity to 17 aquatic species, such as fish, snail, tadpole, hydrozoan, crustacean, insect larvae, and bacteria developed using 5,000 toxic effect results for approximately 2400 chemicals.

  13. Reactions of clofibric acid with oxidative and reductive radicals-Products, mechanisms, efficiency and toxic effects

    Science.gov (United States)

    Csay, Tamás; Rácz, Gergely; Salik, Ádám; Takács, Erzsébet; Wojnárovits, László

    2014-09-01

    The degradation of clofibric acid induced by hydroxyl radical, hydrated electron and O2-•/HO2• reactive species was studied in aqueous solutions. Clofibric acid was decomposed more effectively by hydroxyl radical than by hydrated electron or O2-•/HO2•. Various hydroxylated, dechlorinated and fragmentation products have been identified and quantified. A new LC-MS method was developed based on 18O isotope labeling to follow the formation of hydroxylated derivatives of clofibric acid. Possible degradation pathways have been proposed. The overall degradation was monitored by determination of sum parameters like COD, TOC and AOX. It was found that the organic chlorine degrades very effectively prior to complete mineralization. After the treatment no toxic effect was found according to Vibrio fischeri tests. However, at early stages some of the reaction products were more harmful than clofibric acid.

  14. Hematopoietic Acute Radiation Syndrome (Bone marrow syndrome, Aplastic Anemia): Molecular Mechanisms of Radiation Toxicity.

    Science.gov (United States)

    Popov, Dmitri

    Key Words: Aplastic Anemia (AA), Pluripotential Stem Cells (PSC) Introduction: Aplastic Anemia (AA) is a disorder of the pluripotential stem cells involve a decrease in the number of cells of myeloid, erythroid and megakaryotic lineage [Segel et al. 2000 ]. The etiology of AA include idiopathic cases and secondary aplastic anemia after exposure to drugs, toxins, chemicals, viral infections, lympho-proliferative diseases, radiation, genetic causes, myelodisplastic syndromes and hypoplastic anemias, thymomas, lymphomas. [Brodskyet al. 2005.,Modan et al. 1975., Szklo et al. 1975]. Hematopoietic Acute Radiation Syndrome (or Bone marrow syndrome, or Radiation-Acquired Aplastic Anemia) is the acute toxic syndrome which usually occurs with a dose of irradiation between 0.7 and 10 Gy (70- 1000 rads), depending on the species irradiated. [Waselenko et al., 2004]. The etiology of bone morrow damage from high-level radiation exposure results depends on the radiosensitivity of certain bone marrow cell lines. [Waselenko et al. 2004] Aplastic anemia after radiation exposure is a clinical syndrome that results from a marked disorder of bone marrow blood cell production. [Waselenko et al. 2004] Radiation hematotoxicity is mediated via genotoxic and other specific toxic mechanisms, leading to aplasia, cell apoptosis or necrosis, initiation via genetic mechanisms of clonal disorders, in cases such as the acute radiation-acquired form of AA. AA results from radiation injury to pluripotential and multipotential stem cells in the bone marrow. The clinical signs displayed in reticulocytopenia, anemia, granulocytopenia, monocytopenia, and thrombocytopenia. The number of marrow CD34+ cells (multipotential hematopoietic progenitors) and their derivative colony-forming unit{granulocyte-macrophage (CFU-GM) and burst forming unit {erythroid (BFU{E) are reduced markedly in patients with AA. [Guinan 2011, Brodski et al. 2005, Beutler et al.,2000] Cells expressing CD34 (CD34+ cell) are normally

  15. Identifying the cause of sediment toxicity in agricultural sediments: the role of pyrethroids and nine seldom-measured hydrophobic pesticides.

    Science.gov (United States)

    Weston, Donald P; Ding, Yuping; Zhang, Minghua; Lydy, Michael J

    2013-01-01

    Few currently used agricultural pesticides are routinely monitored for in the environment. Even if concentrations are known, sediment LC(50) values are often lacking for common sediment toxicity testing species. To help fill this data gap, sediments in California's Central Valley were tested for nine hydrophobic pesticides seldom analyzed: abamectin, diazinon, dicofol, fenpropathrin, indoxacarb, methyl parathion, oxyfluorfen, propargite, and pyraclostrobin. Most were detected, but rarely at concentrations acutely toxic to Hyalella azteca or Chironomus dilutus. Only abamectin, fenpropathrin, and methyl parathion were found at concentrations of potential concern, and only in one or two samples. One-quarter of over 100 samples from agriculture-affected waterways exhibited toxicity, and in three-fourths of the toxic samples, pyrethroids exceeded concentrations expected to cause toxicity. The pyrethroid Bi-fen-thrin in particular, as well as lambda-cyhalothrin, cypermethrin, esfenvalerate, permethrin, and the organophosphate chlorpyrifos, were primarily responsible for the observed toxicity, rather than the more novel analytes, despite the fact that much of the sampling targeted areas of greatest use of the novel pesticides. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Identifying mechanisms in the control of quantum dynamics through Hamiltonian encoding

    International Nuclear Information System (INIS)

    Mitra, Abhra; Rabitz, Herschel

    2003-01-01

    A variety of means are now available to design control fields for manipulating the evolution of quantum systems. However, the underlying physical mechanisms often remain obscure, especially in the cases of strong fields and high quantum state congestion. This paper proposes a method to quantitatively determine the various pathways taken by a quantum system in going from the initial state to the final target. The mechanism is revealed by encoding a signal in the system Hamiltonian and decoding the resultant nonlinear distortion of the signal in the system time-evolution operator. The relevant interfering pathways determined by this analysis give insight into the physical mechanisms operative during the evolution of the quantum system. A hierarchy of mechanism identification algorithms with increasing ability to extract more detailed pathway information is presented. The mechanism identification concept is presented in the context of analyzing computer simulations of controlled dynamics. As illustrations of the concept, mechanisms are identified in the control of several simple, discrete-state quantum systems. The mechanism analysis tools reveal the roles of multiple interacting quantum pathways to maximally take advantage of constructive and destructive interference. Similar procedures may be applied directly in the laboratory to identify control mechanisms without resort to computer modeling, although this extension is not addressed in this paper

  17. Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jae Ho; Jenrow, Kenneth A.; Brown, Stephen L. [Dept.of Radiation Oncology, Henry Ford Health System, Detroit (United States)

    2014-09-15

    To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs.

  18. Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials

    International Nuclear Information System (INIS)

    Kim, Jae Ho; Jenrow, Kenneth A.; Brown, Stephen L.

    2014-01-01

    To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs.

  19. Mechanism of toxicity of MPTP: A cause of Parkinsonism in human beings

    International Nuclear Information System (INIS)

    Denton, T.L.

    1988-01-01

    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was found in 1983 to cause a syndrome virtually identical to Parkinson's Disease in humans and other primates. The symptoms, as in idiopathic Parkinson's syndrome, are due to destruction of dopaminergic neurons in the pars compacta of the substantia nigra resulting in depletion of dopamine in the basal ganglia. The mechanism of toxicity was investigated with a dopamine containing cell line, PC12, a MPTP resistant variant (MPTP r ), and synaptosomes from the striate cortex of mice, rats, guinea pigs and a monkey. The mechanism of acute effects was studied with membrane preparations from human and rat striate cortex. MPTP displaced [ 3 H]haloperidol from binding sites in human and rat striate cortex, but could not displace [ 3 H]flupenthixol, suggesting that MPTP is a D2 receptor ligand of equivalent potency in both species. MPTP was a competitive inhibitor of uptake of [ 3 H]dopamine in PC12 but did not accumulate in PC12 or in synaptosomes of rat, guinea pig, mouse or monkey striate cortex. 100 uM MPTP depleted catecholamine levels in PC12 cells by about 50%, without killing

  20. Cobalt chloride speciation, mechanisms of cytotoxicity on human pulmonary cells, and synergistic toxicity with zinc

    International Nuclear Information System (INIS)

    Bresson, Carole; Darolles, Carine; Sage, Nicole; Malard, Veronique; Carmona, Asuncion; Roudeau, Stephane; Ortega, Richard; Gautier, Celine; Ansoborlo, Eric

    2013-01-01

    Cobalt is used in numerous industrial sectors, leading to occupational diseases, particularly by inhalation. Cobalt-associated mechanisms of toxicity are far from being understood and information that could improve knowledge in this area is required. We investigated the impact of a soluble cobalt compound, CoCl 2 .6H 2 O, on the BEAS-2B lung epithelial cell line, as well as its impact on metal homeostasis. Cobalt speciation in different culture media, in particular soluble and precipitated cobalt species, was investigated via theoretical and analytical approaches. The cytotoxic effects of cobalt on the cells were assessed. Upon exposure of BEAS-2B cells to cobalt, intracellular accumulation of cobalt and zinc was demonstrated using direct in situ microchemical analysis based on ion micro-beam techniques and analysis after cell lysis by inductively coupled plasma mass spectrometry (ICP-MS). Microchemical imaging revealed that cobalt was rather homogeneously distributed in the nucleus and in the cytoplasm whereas zinc was more abundant in the nucleus. The modulation of zinc homeostasis led to the evaluation of the effect of combined cobalt and zinc exposure. In this case, a clear synergistic increase in toxicity was observed as well as a substantial increase in zinc content within cells. Western blots performed under the same co-exposure conditions revealed a decrease in ZnT1 expression, suggesting that cobalt could inhibit zinc release through the modulation of ZnT1. Overall, this study highlights the potential hazard to lung function, of combined exposure to cobalt and zinc. (authors)

  1. Cobalt chloride speciation, mechanisms of cytotoxicity on human pulmonary cells, and synergistic toxicity with zinc

    International Nuclear Information System (INIS)

    Bresson, Carole; Darolles, Carine; Sage, Nicole; Malard, Veronique; Carmona, Asuncion; Roudeau, Stephane; Ortega, Richard; Gautier, Celine; Ansoborlo, Eric

    2013-01-01

    Complete text of publication follows: Cobalt is used in numerous industrial sectors, leading to occupational diseases, particularly by inhalation. Cobalt-associated mechanisms of toxicity are far from being understood and information that could improve knowledge in this area is required. We investigated the impact of a soluble cobalt compound, CoCl 2 , on the BEAS-2B lung epithelial cell line, as well as its impact on metal homeostasis. Cobalt speciation in different culture media, in particular soluble and precipitated cobalt species, was investigated via theoretical and analytical approaches. The cytotoxic effects of cobalt on the cells were assessed. Upon exposure of BEAS-2B cells to cobalt, intracellular accumulation of cobalt and zinc was demonstrated using direct in situ microchemical analysis based on ion micro-beam techniques and analysis after cell lysis by inductively coupled plasma mass spectrometry (ICP-MS). Microchemical imaging revealed that cobalt was rather homogeneously distributed in the nucleus and in the cytoplasm whereas zinc was more abundant in the nucleus. The modulation of zinc homeostasis led to the evaluation of the effect of combined cobalt and zinc exposure. In this case, a clear synergistic increase in toxicity was observed as well as a substantial increase in zinc content within cells. Western blots performed under the same co-exposure conditions revealed a decrease in ZnT1 expression, suggesting that cobalt could inhibit zinc release through the modulation of ZnT1. Overall, this study highlights the potential hazard to lung function, of combined exposure to cobalt and zinc

  2. Investigation of gamma-ray fingerprint identifying mechanism for the types of radiation sources

    CERN Document Server

    Liu Su Ping; Gu Dang Chang; Gong-Jian; Hao Fan Hua; Hu Guang Chun

    2002-01-01

    Radiation fingerprints sometimes can be used to label and identify the radiation resources. For instance, in a future nuclear reduction treaty that requires verification of irreversible dismantling of reduced nuclear warheads, the radiation fingerprints of nuclear warheads are expected to play a key role in labelling and identifying the reduced warheads. It would promote the development of nuclear warheads deep-cuts verification technologies if authors start right now some investigations on the issues related to the radiation fingerprints. The author dedicated to the investigation of gamma-ray fingerprint identifying mechanism for the types of radiation resources. The purpose of the identifying mechanism investigation is to find a credible way to tell whether any two gamma-ray spectral fingerprints that are under comparison are radiated from the same resource. The authors created the spectrum pattern comparison (SPC) to study the comparability of the two radiation fingerprints. Guided by the principle of SPC,...

  3. Protective effects and mechanisms of curcumin on podophyllotoxin toxicity in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Li, Juan; Dai, Cai-Xia; Sun, Hua [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China); Jin, Lu [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China); State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203 (China); Guo, Chong-Yi; Cao, Wei; Wu, Jie; Tian, Hai-Yan [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China); Luo, Cheng [State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203 (China); Ye, Wen-Cai [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China); Jiang, Ren-Wang, E-mail: trwjiang@jnu.edu.cn [Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632 (China)

    2012-12-01

    Podophyllotoxin (POD) is a naturally occurring lignan with pronounced antineoplastic and antiviral properties. POD binds to tubulin and prevents the formation of mitotic spindle. Although cases of overdose or accidental ingestion are quite often, no specific therapy is currently available to treat the POD intoxication. In the current investigation, the protective effects and mechanisms of curcumin (CUR) on podophyllotoxin toxicity were evaluated in vitro and in vivo. The results showed that CUR could protect POD-induced cytotoxicity by recovering the G2/M arrest and decrease the changes of membrane potential and microtubule structure in Vero cells. A significant decrease of mortality rates was observed in Swiss mice treated by intragastrical administration of POD + CUR as compared with POD alone. The POD + CUR group also exhibited decreases in plasma transaminases, alkaline phosphatase, lactate dehydrogenase, plasma urea, creatinine and malondialdehyde level but elevated superoxide dismutase and glutathione levels as compared to the POD group. Histological examination of the liver and kidney demonstrated less morphological changes in the treatment of POD + CUR as compared with POD alone. The mechanism of the protective effects might be due to the competitive binding of CUR with POD in the same colchicines binding site as revealed by the tubulin polymerization assay and the molecular docking analysis, and the antioxidant activity against the oxidative stress induced by POD. In summary, both in vitro and in vivo data indicated the promising role of CUR as a protective agent against the POD poisoning. Highlights: ► A potential antidote to treat the podophyllotoxin (POD) intoxication is found. ► Curcumin showed promising effects against POD poisoning in vitro and in vivo. ► The mechanisms lie in the antioxidant activity and competitive binding with tubulin.

  4. Identifying and Investigating Difficult Concepts in Engineering Mechanics and Electric Circuits. Research Brief

    Science.gov (United States)

    Streveler, Ruth; Geist, Monica; Ammerman, Ravel; Sulzbach, Candace; Miller, Ronald; Olds, Barbara; Nelson, Mary

    2007-01-01

    This study extends ongoing work to identify difficult concepts in thermal and transport science and measure students' understanding of those concepts via a concept inventory. Two research questions provided the focal point: "What important concepts in electric circuits and engineering mechanics do students find difficult to learn?" and…

  5. Identifying serotonergic mechanisms underlying the corticolimbic response to threat in humans

    DEFF Research Database (Denmark)

    Fisher, Patrick M; Hariri, Ahmad R

    2013-01-01

    . Integrating these methodological approaches offers novel opportunities to identify mechanisms through which serotonin signalling contributes to differences in brain function and behaviour, which in turn can illuminate factors that confer risk for illness and inform the development of more effective treatment...

  6. Uncovering the exposure mechanisms of sunken heavy oil that makes it chronically toxic to early life stages of fish

    International Nuclear Information System (INIS)

    Martin, J.; Young, G.; Lemire, B.; Hodson, P.

    2010-01-01

    A train derailment in 2005 caused the release of 150,000 litres of No. 6 heavy fuel oil into a lake in Alberta. The oil is a residue of the crude oil refinement process and contains 3-4 ringed alkylated forms of polycyclic aromatic hydrocarbons (PAH) that are known to cause sub-lethal toxic responses during the early life stages of rainbow trout. Because the oil does not disperse well, oil patches still persist in near-shore sediments of the lake where fish spawn. This study assessed how the behaviour of heavy oil in water interacts with exposure and toxicity to the early life stages of fish. Daily renewal tests with heavy fuel oil coated on glass plate demonstrated higher levels of toxicity to trout embryos than oil that was mechanically or chemically dispersed. A flow-through oil gravel column was used to assess whether the toxic constituents of the heavy oil are transferred quickly enough to cause toxicity. The aim of the study was to develop exposure and toxicity test methods that accurately reflect the behaviour of heavy oil after a spill.

  7. Investigation of gamma-ray fingerprint identifying mechanism for the types of radiation sources

    International Nuclear Information System (INIS)

    Liu Suping; Wu Huailong; Gu Dangchang; Gong Jian; Hao Fanhua; Hu Guangchun

    2002-01-01

    Radiation fingerprints sometimes can be used to label and identify the radiation resources. For instance, in a future nuclear reduction treaty that requires verification of irreversible dismantling of reduced nuclear warheads, the radiation fingerprints of nuclear warheads are expected to play a key role in labelling and identifying the reduced warheads. It would promote the development of nuclear warheads deep-cuts verification technologies if authors start right now some investigations on the issues related to the radiation fingerprints. The author dedicated to the investigation of gamma-ray fingerprint identifying mechanism for the types of radiation resources. The purpose of the identifying mechanism investigation is to find a credible way to tell whether any two gamma-ray spectral fingerprints that are under comparison are radiated from the same resource. The authors created the spectrum pattern comparison (SPC) to study the comparability of the two radiation fingerprints. Guided by the principle of SPC, the authors programmed a software dedicated to identify the types of radiation resources. The efficiency of the software was tested by a series of experiments with some laboratory gamma-ray resources. The experiments were designed to look into the relations between comparability and radioactive statistics, and the relations between comparability and some measurement conditions such as real time, resource activity and background etc. Two main results can be drawn from the investigation: 1) it is quite feasible to use the concept of spectral comparability to answer the question whether any two gamma-ray fingerprints are identity or not; 2) the identifying mechanism can only identify the types of radiation resources, and cannot identify the individuals with the same type and small differences

  8. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    International Nuclear Information System (INIS)

    Kleinstreuer, N.C.; Smith, A.M.; West, P.R.; Conard, K.R.; Fontaine, B.R.; Weir-Hauptman, A.M.; Palmer, J.A.; Knudsen, T.B.; Dix, D.J.; Donley, E.L.R.; Cezar, G.G.

    2011-01-01

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox® model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: ► We tested 11 environmental compounds in a hESC metabolomics platform. ► Significant changes in secreted small molecule metabolites were observed. ► Perturbed mass features map to pathways critical for normal development and pregnancy. ► Arginine, proline, nicotinate, nicotinamide and glutathione pathways were affected.

  9. Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

    Energy Technology Data Exchange (ETDEWEB)

    Kleinstreuer, N.C., E-mail: kleinstreuer.nicole@epa.gov [NCCT, US EPA, RTP, NC 27711 (United States); Smith, A.M.; West, P.R.; Conard, K.R.; Fontaine, B.R. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Weir-Hauptman, A.M. [Covance, Inc., Madison, WI 53704 (United States); Palmer, J.A. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Knudsen, T.B.; Dix, D.J. [NCCT, US EPA, RTP, NC 27711 (United States); Donley, E.L.R. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Cezar, G.G. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); University of Wisconsin-Madison, Madison, WI 53706 (United States)

    2011-11-15

    Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast Trade-Mark-Sign chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox Registered-Sign model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: Black-Right-Pointing-Pointer We tested 11 environmental compounds in a hESC metabolomics platform. Black-Right-Pointing-Pointer Significant changes in secreted small molecule metabolites were observed. Black-Right-Pointing-Pointer Perturbed mass features map to pathways critical for normal

  10. The Toxicity Mechanisms of Action of Aβ25–35 in Isolated Rat Cardiac Myocytes

    Directory of Open Access Journals (Sweden)

    Beiru Zhang

    2014-08-01

    Full Text Available β-Amyloid (Aβ is deposited in neurons and vascular cells of the brain and is characterized as a pathologic feature of Alzheimer’s disease (AD. Recently studies have reported that there is an association between cardiovascular risk factors and AD, however the mechanism of this association is still uncertain. In this study we observed Aβ had an effect on cardiovascular cells. We represent as a major discovery that Aβ25–35 had toxicity on isolated rat cardiac myocytes by impacting the cytoskeleton assembly and causing ER stress, ultimately contributing to the apoptosis of the myocytes. Importantly, the activation of ER stress and subsequent cellular dysfunction and apoptosis by Aβ25–35 was regulated by the MAPK pathway, which could be prevented by inhibition of p38 via pharmacological inhibitors. It was noteworthy that Aβ25–35 played a critical role in cardiac myocytes, suggesting that Alzheimer’s disease (AD had a relation with the heart and understanding of these associations in future will help search for effective treatment strategies.

  11. The toxic mechanism of high lethality of herbicide butachlor in marine flatfish flounder, Paralichthys olivaceus

    Science.gov (United States)

    Guo, Huarong; Yin, Licheng; Zhang, Shicui; Feng, Wenrong

    2010-09-01

    The toxic mechanism of herbicide butachlor to induce extremely high lethality in marine flatfish flounder, Paralichthys Olivaceus, was analyzed by histopathological examination, antioxidant enzymes activities and ATP content assay. Histopathological examination of gill, liver and kidney of exposed fishes showed that gill was a target organ of butachlor. The butachlor seriously impaired the respiration of gills by a series of lesions such as edema, lifting and detachment of lamellar epithelium, breakdown of pillar cells, and blood congestion. The dysfunction of gill respiration caused suffocation to the exposed flounder with extremely high acute lethality. Antioxidant enzyme activity assay of the in vitro cultured flounder gill (FG) cells exposed to butachlor indicated that butachlor markedly inhibited the antioxidant enzyme activities of Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX). Furthermore, along with the decline of antioxidant enzyme activities, ATP content in the exposed FG cells decreased, too. This infers that the oxidative stress induced by butachlor can inhibit the production of cellular ATP. Similar decrease of ATP content was also observed in the exposed flounder gill tissues. Taken together, as in FG cells, butachlor possibly induced a short supply of ATP in pillar cells by inhibiting the antioxidant enzyme activities and then affecting the contractibility of the pillar cells, which in turn resulted in the blood congestion and suffocation of exposed flounder.

  12. Rs895819 in MIR27A improves the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity.

    Science.gov (United States)

    Meulendijks, Didier; Henricks, Linda M; Amstutz, Ursula; Froehlich, Tanja K; Largiadèr, Carlo R; Beijnen, Jos H; de Boer, Anthonius; Deenen, Maarten J; Cats, Annemieke; Schellens, Jan H M

    2016-06-01

    The objective of this study was to determine whether genotyping of MIR27A polymorphisms rs895819A>G and rs11671784C>T can be used to improve the predictive value of DPYD variants to identify patients at risk of severe fluoropyrimidine-associated toxicity (FP-toxicity). Patients treated previously in a prospective study with fluoropyrimidine-based chemotherapy were genotyped for rs895819 and rs11671784, and DPYD c.2846A>T, c.1679T>G, c.1129-5923C>G and c.1601G>A. The predictive value of MIR27A variants for early-onset grade ≥3 FP-toxicity, alone or in combination with DPYD variants, was tested in multivariable logistic regression models. Random-effects meta-analysis was performed, including previously published data. A total of 1,592 patients were included. Allele frequencies of rs895819 and rs11671784 were 0.331 and 0.020, respectively. In DPYD wild-type patients, MIR27A variants did not affect risk of FP-toxicity (OR 1.3 for ≥1 variant MIR27A allele vs. none, 95% CI: 0.87-1.82, p = 0.228). In contrast, in patients carrying DPYD variants, the presence of ≥1 rs895819 variant allele was associated with increased risk of FP-toxicity (OR 4.9, 95% CI: 1.24-19.7, p = 0.023). Rs11671784 was not associated with FP-toxicity (OR 2.9, 95% CI: 0.47-18.0, p = 0.253). Patients carrying a DPYD variant and rs895819 were at increased risk of FP-toxicity compared to patients wild type for rs895819 and DPYD (OR 2.4, 95% CI: 1.27-4.37, p = 0.007), while patients with a DPYD variant but without a MIR27A variant were not (OR 0.3 95% CI: 0.06-1.17, p = 0.081). In meta-analysis, rs895819 remained significantly associated with FP-toxicity in DPYD variant allele carriers, OR 5.4 (95% CI: 1.83-15.7, p = 0.002). This study demonstrates the clinical validity of combined MIR27A/DPYD screening to identify patients at risk of severe FP-toxicity. © 2016 UICC.

  13. Mechanism of ad5 vaccine immunity and toxicity: fiber shaft targeting of dendritic cells.

    Directory of Open Access Journals (Sweden)

    Cheng Cheng

    2007-02-01

    Full Text Available Recombinant adenoviral (rAd vectors elicit potent cellular and humoral immune responses and show promise as vaccines for HIV-1, Ebola virus, tuberculosis, malaria, and other infections. These vectors are now widely used and have been generally well tolerated in vaccine and gene therapy clinical trials, with many thousands of people exposed. At the same time, dose-limiting adverse responses have been observed, including transient low-grade fevers and a prior human gene therapy fatality, after systemic high-dose recombinant adenovirus serotype 5 (rAd5 vector administration in a human gene therapy trial. The mechanism responsible for these effects is poorly understood. Here, we define the mechanism by which Ad5 targets immune cells that stimulate adaptive immunity. rAd5 tropism for dendritic cells (DCs was independent of the coxsackievirus and adenovirus receptor (CAR, its primary receptor or the secondary integrin RGD receptor, and was mediated instead by a heparin-sensitive receptor recognized by a distinct segment of the Ad5 fiber, the shaft. rAd vectors with CAR and RGD mutations did not infect a variety of epithelial and fibroblast cell types but retained their ability to transfect several DC types and stimulated adaptive immune responses in mice. Notably, the pyrogenic response to the administration of rAd5 also localized to the shaft region, suggesting that this interaction elicits both protective immunity and vector-induced fevers. The ability of replication-defective rAd5 viruses to elicit potent immune responses is mediated by a heparin-sensitive receptor that interacts with the Ad5 fiber shaft. Mutant CAR and RGD rAd vectors target several DC and mononuclear subsets and induce both adaptive immunity and toxicity. Understanding of these interactions facilitates the development of vectors that target DCs through alternative receptors that can improve safety while retaining the immunogenicity of rAd vaccines.

  14. Molecular mechanisms of toxic effects of fotemustine in rat hepatocytes and subcellular rat liver fractions.

    NARCIS (Netherlands)

    Brakenhoff, J.P.G.; Commandeur, J.N.M.; Wormhoudt, L.W.; Groot, E.J.; Vermeulen, N.P.E.

    1996-01-01

    Fotemustine is a clinically used DNA-alkylating 2-chloroethyl-substituted N-nitrosourea, which sometimes shows signs of haematotoxicity and reversible liver and renal toxicity as toxic side-effects. Mechanistic data on these side-effects are scarce and incomplete. In this study, firstly the

  15. Examining mechanism of toxicity of copper oxide nanoparticles to Saccharomyces cerevisiae and Caenorhabditis elegans

    Science.gov (United States)

    Mashock, Michael J.

    Copper oxide nanoparticles (CuO NPs) are an up and coming technology increasingly being used in industrial and consumer applications and thus may pose risk to humans and the environment. In the present study, the toxic effects of CuO NPs were studied with two model organisms Saccharomyces cerevisiae and Caenorhabditis elegans. The role of released Cu ions during dissolution of CuO NPs in growth media were studied with freshly suspended, aged NPs, and the released Cu 2+ fraction. Exposures to the different Cu treatments showed significant inhibition of S. cerevisiae cellular metabolic activity. Inhibition from the NPs was inversely proportional to size and was not fully explained by the released Cu ions. S. cerevisiae cultures grown under respiring conditions demonstrated greater metabolic sensitivity when exposed to CuO NPs compared to cultures undergoing fermentation. The cellular response to both CuO NPs and released Cu ions on gene expression was analyzed via microarray analysis after an acute exposure. It was observed that both copper exposures resulted in an increase in carbohydrate storage, a decrease in protein production, protein misfolding, increased membrane permeability, and cell cycle arrest. Cells exposed to NPs up-regulated genes related to oxidative phosphorylation but also may be inducing cell cycle arrest by a different mechanism than that observed with released Cu ions. The effect of CuO NPs on C. elegans was examined by using several toxicological endpoints. The CuO NPs displayed a more inhibitory effect, compared to copper sulfate, on nematode reproduction, feeding, and development. We investigated the effects of copper oxide nanoparticles and copper sulfate on neuronal health, a known tissue vulnerable to heavy metal toxicity. In transgenic C. eleganswith neurons expressing a green fluorescent protein reporter, neuronal degeneration was observed in up to 10% of the population after copper oxide nanoparticle exposure. Additionally, nematode

  16. Targeting Destructive Narcissism: A New Approach for Identifying and Eliminating Toxic Senior Leaders in the U.S. Air Force

    Science.gov (United States)

    2014-02-13

    aspects of this phenomenon. Constructive narcissists are well-balanced, possess positive self - esteem , display empathy, have an aptitude for...toxicity, Schmidt developed five descriptive dimensions: 1) abusive supervision, 2) authoritative leadership, 3) narcissism, 4) self - promotion and...three core values of Integrity First, Service before Self , and Excellence in All We Do. While a majority of senior Air Force officers enforce the

  17. Identifying the receptor subtype selectivity of retinoid X and retinoic acid receptors via quantum mechanics.

    Science.gov (United States)

    Tsuji, Motonori; Shudo, Koichi; Kagechika, Hiroyuki

    2017-03-01

    Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands.

  18. The different response mechanisms of Wolffia globosa: Light-induced silver nanoparticle toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Zou, Xiaoyan; Li, Penghui [Key Laboratory of Urban Pollutant Conversion, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen (China); Huang, Qing [Key Laboratory of Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen (China); Zhang, Hongwu, E-mail: hwzhang@iue.ac.cn [Key Laboratory of Urban Pollutant Conversion, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen (China); Ningbo Research Center for Urban Environment, Chinese Academy of Sciences, Ningbo (China)

    2016-07-15

    Highlights: • The different physiological responses of AgNPs in Wolffia golbosa were studied. • Effects of AgNPs on W. golbosa relied on the illumination conditions. • Different phytotoxic mechanisms of AgNPs for different light schemes were proposed. - Abstract: Silver nanoparticles (AgNPs) have emerged as a promising bactericide. Plants are a major point of entry of contaminants into trophic chains. Here, the physiological responses of Wolffia globosa to AgNPs have been probed using different light schemes, and these data may reveal new insights into the toxic mechanism of AgNPs. W. globosa was grown in culture medium and treated with different concentrations of AgNPs for 24 h under pre- and post-illuminated conditions. However, fluorescence quenching, the accumulation of sugar and the reduction of Hill reaction activity were found in response to the AgNP-stresses. In the pre-illuminated condition, oxidative damage was obvious, as indicated by the higher malondialdehyde (MDA) content and an up-regulation of superoxide dismutase (SOD) activity. The maximum increases of MDA content and SOD activity were 1.14 and 2.52 times the respective controls when exposed to 10 mg/L AgNPs. In contrast, in the post-illuminated condition, the alterations in photosynthetic pigment and soluble proteins content were more significant than the alterations in oxidative stress. The contents of chlorophyll a, carotenoids and soluble protein decreased to 77.7%, 66.2% and 72.9% of the controls after treatment with the highest concentration of AgNPs (10 mg/L). Based on the different physiological responses, we speculated that in the pre-illuminated condition, oxidative stress was responsible for the decline in the oxygen evolution rate, while in the post-illuminated condition, the decrease in the Hill reaction activity could be attributed to the blocking of electron transfer and an insufficient proton supply. Our findings demonstrate that environmental factors regulate the

  19. The different response mechanisms of Wolffia globosa: Light-induced silver nanoparticle toxicity

    International Nuclear Information System (INIS)

    Zou, Xiaoyan; Li, Penghui; Huang, Qing; Zhang, Hongwu

    2016-01-01

    Highlights: • The different physiological responses of AgNPs in Wolffia golbosa were studied. • Effects of AgNPs on W. golbosa relied on the illumination conditions. • Different phytotoxic mechanisms of AgNPs for different light schemes were proposed. - Abstract: Silver nanoparticles (AgNPs) have emerged as a promising bactericide. Plants are a major point of entry of contaminants into trophic chains. Here, the physiological responses of Wolffia globosa to AgNPs have been probed using different light schemes, and these data may reveal new insights into the toxic mechanism of AgNPs. W. globosa was grown in culture medium and treated with different concentrations of AgNPs for 24 h under pre- and post-illuminated conditions. However, fluorescence quenching, the accumulation of sugar and the reduction of Hill reaction activity were found in response to the AgNP-stresses. In the pre-illuminated condition, oxidative damage was obvious, as indicated by the higher malondialdehyde (MDA) content and an up-regulation of superoxide dismutase (SOD) activity. The maximum increases of MDA content and SOD activity were 1.14 and 2.52 times the respective controls when exposed to 10 mg/L AgNPs. In contrast, in the post-illuminated condition, the alterations in photosynthetic pigment and soluble proteins content were more significant than the alterations in oxidative stress. The contents of chlorophyll a, carotenoids and soluble protein decreased to 77.7%, 66.2% and 72.9% of the controls after treatment with the highest concentration of AgNPs (10 mg/L). Based on the different physiological responses, we speculated that in the pre-illuminated condition, oxidative stress was responsible for the decline in the oxygen evolution rate, while in the post-illuminated condition, the decrease in the Hill reaction activity could be attributed to the blocking of electron transfer and an insufficient proton supply. Our findings demonstrate that environmental factors regulate the

  20. The skeletal developmental toxicity of chlormequat chloride and its underlying mechanisms

    International Nuclear Information System (INIS)

    Huang, Dan; Wu, Shuang; Hou, Xiaohong; Jia, Lixia; Meng, Qinghe; Chu, Hongqian; Jiang, Jianjun; Shang, Lanqin; Hao, Weidong

    2017-01-01

    Chlormequat Chloride (CCC), a widely used plant growth regulator, could decrease body weight in animals; however, the mechanism has not been well studied. This study was designed to evaluate the skeletal development toxicity of CCC on pubertal male Sprague-Dawley (SD) rats and to investigate whether CCC impacts the development of chondrocyte, osteoblast and osteoclast through growth hormone (GH) and insulin like growth factor 1 (IGF-I). Rats from 23 to 70 on postnatal days were exposed to CCC daily by gavage at doses of 0, 75, 150, and 300 mg/kg bw/d. The results showed that the size of femurs and tibias, bone mineral density and biomechanical parameters were significantly decreased in the 300 mg/kg bw/d group compared with the control group. The concentration of osteocalcin (OCN) and C-terminal telopeptide of type I collagen (CTX-I) in blood in the 150 mg/kg bw/d group was also changed. The mRNA expression ratio of the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in 150 and 300 mg/kg bw/d group was increased. Histological analysis of proximal and distal epiphyseal plates of the right femurs showed that both the proliferative zone and hypertrophic zone narrowed in CCC-treated groups. The concentration of IGF-I in blood was reduced with an increase in exposure doses of CCC. The mRNA expression of growth hormone receptor (GHR) in tibia was decreased in the CCC-treated group. The results indicated that CCC might indirectly impact the formation and activation of chondrocytes, osteoblasts and osteoclasts because of the decline of GHR and IGF-I, leading to skeletal development damage.

  1. Mechanical and assembly units of viral capsids identified via quasi-rigid domain decomposition.

    Directory of Open Access Journals (Sweden)

    Guido Polles

    Full Text Available Key steps in a viral life-cycle, such as self-assembly of a protective protein container or in some cases also subsequent maturation events, are governed by the interplay of physico-chemical mechanisms involving various spatial and temporal scales. These salient aspects of a viral life cycle are hence well described and rationalised from a mesoscopic perspective. Accordingly, various experimental and computational efforts have been directed towards identifying the fundamental building blocks that are instrumental for the mechanical response, or constitute the assembly units, of a few specific viral shells. Motivated by these earlier studies we introduce and apply a general and efficient computational scheme for identifying the stable domains of a given viral capsid. The method is based on elastic network models and quasi-rigid domain decomposition. It is first applied to a heterogeneous set of well-characterized viruses (CCMV, MS2, STNV, STMV for which the known mechanical or assembly domains are correctly identified. The validated method is next applied to other viral particles such as L-A, Pariacoto and polyoma viruses, whose fundamental functional domains are still unknown or debated and for which we formulate verifiable predictions. The numerical code implementing the domain decomposition strategy is made freely available.

  2. Identifying mechanisms that structure ecological communities by snapping model parameters to empirically observed tradeoffs.

    Science.gov (United States)

    Thomas Clark, Adam; Lehman, Clarence; Tilman, David

    2018-04-01

    Theory predicts that interspecific tradeoffs are primary determinants of coexistence and community composition. Using information from empirically observed tradeoffs to augment the parametrisation of mechanism-based models should therefore improve model predictions, provided that tradeoffs and mechanisms are chosen correctly. We developed and tested such a model for 35 grassland plant species using monoculture measurements of three species characteristics related to nitrogen uptake and retention, which previous experiments indicate as important at our site. Matching classical theoretical expectations, these characteristics defined a distinct tradeoff surface, and models parameterised with these characteristics closely matched observations from experimental multi-species mixtures. Importantly, predictions improved significantly when we incorporated information from tradeoffs by 'snapping' characteristics to the nearest location on the tradeoff surface, suggesting that the tradeoffs and mechanisms we identify are important determinants of local community structure. This 'snapping' method could therefore constitute a broadly applicable test for identifying influential tradeoffs and mechanisms. © 2018 The Authors. Ecology Letters published by CNRS and John Wiley & Sons Ltd.

  3. Role of annexin A5 in cisplatin-induced toxicity in renal cells: molecular mechanism of apoptosis.

    Science.gov (United States)

    Jeong, Jin-Joo; Park, Nahee; Kwon, Yeo-Jung; Ye, Dong-Jin; Moon, Aree; Chun, Young-Jin

    2014-01-24

    Annexin A5 belongs to a large family of calcium-binding and phospholipid-binding proteins and may act as an endogenous regulator of various pathophysiological processes. There is increasing evidence that annexin A5 is related to cytotoxicity, but the precise function of this protein has yet to be elucidated. In this study, we aimed to verify the function of annexin A5 in the apoptosis of renal epithelial cells. Real-time PCR and Western blot analysis, together with immunofluorescence analysis, showed that the expression of annexin A5 significantly increased in the presence of cisplatin in both human and rat renal epithelial cells. With regard to the mechanism of cisplatin-induced apoptosis, apoptosis-inducing factor (AIF) release into the cytosol was observed, and the underlying mechanism was identified as voltage-dependent anion channel (VDAC) oligomerization. Mitochondrial membrane potential (Δψm) was found to be greatly disrupted in cisplatin-treated cells. Moreover, cisplatin strongly induced translocation of annexin A5 into mitochondria. To understand the functional significance of annexin A5 in renal cell death, we used a siRNA-mediated approach to knock down annexin A5. Annexin A5 depletion by siRNA led to decreased annexin A5 translocation into mitochondria and significantly reduced VDAC oligomerization and AIF release. Annexin A5 siRNA also increased cell viability compared with the control. Moreover, expression of annexin A5 was induced by other nephrotoxicants such as CdCl2 and bacitracin. Taken together, our data suggest that annexin A5 may play a crucial role in cisplatin-induced toxicity by mediating the mitochondrial apoptotic pathway via the induction and oligomerization of VDAC.

  4. Chronic Toxic Metal Exposure and Cardiovascular Disease: Mechanisms of Risk and Emerging Role of Chelation Therapy.

    Science.gov (United States)

    Aneni, Ehimen C; Escolar, Esteban; Lamas, Gervasio A

    2016-12-01

    Over the last few decades, there has been a growing body of epidemiologic evidence linking chronic toxic metal exposure to cardiovascular disease-related morbidity and mortality. The recent and unexpectedly positive findings from a randomized, double-blind, multicenter trial of metal chelation for the secondary prevention of atherosclerotic cardiovascular disease (Trial to Assess Chelation Therapy (TACT)) have focused the discussion on the role of chronic exposure to toxic metals in the development and propagation of cardiovascular disease and the role of toxic metal chelation therapy in the secondary prevention of cardiovascular disease. This review summarizes the most recent evidence linking chronic toxic metal exposure to cardiovascular disease and examines the findings of TACT.

  5. Impacts of triclosan exposure on zebrafish early-life stage: Toxicity and acclimation mechanisms.

    Science.gov (United States)

    Falisse, Elodie; Voisin, Anne-Sophie; Silvestre, Frédéric

    2017-08-01

    the acclimation process of larvae exposed to 100μg/L of TCS. Our integrative analysis revealed complex non-monotonic concentration-related effects on zebrafish early-life stages with increased resistance between 50 and 100μg/L exposures. This research highlighted oxidative stress and neurotoxicity as major toxicity mechanisms of TCS during development. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Mechanisms and manifestations of toxic actions at the bone tissue level

    International Nuclear Information System (INIS)

    1998-01-01

    The principal abnormalities determined by toxic at the bone level are: osteoporosis, osteomalacia, osteosclerosis or osteopetrosis. The principal toxics having a noxiousness at the bone level are: the fluorine, the phosphorus, the lead, the bismuth, the cadmium and the strontium. The strontium 90 has an important radioactivity that gives at the bone level osteosarcomas or at low doses, leukemoid reactions and marrow angiosarcoma. (N.C.)

  7. Protective influence of healthful nutrition on mechanisms of environmental pollutant toxicity and disease risks.

    Science.gov (United States)

    Hoffman, Jessie B; Hennig, Bernhard

    2017-06-01

    Human exposures to environmental contaminants around the world contribute to the global burden of disease and thus require urgent attention. Exploring preventive measures against environmental exposure and disease risk is essential. While a sedentary lifestyle and/or poor dietary habits can exacerbate the deleterious effects resulting from exposure to toxic chemicals, much emerging evidence suggests that positive lifestyle changes (e.g., healthful nutrition) can modulate and/or reduce the toxicity of environmental pollutants. Our work has shown that diets high in anti-inflammatory bioactive food components (e.g., phytochemicals or polyphenols) are possible strategies for modulating and reducing the disease risks associated with exposure to toxic pollutants in the environment. Thus, consuming healthy diets rich in plant-derived bioactive nutrients may reduce the vulnerability to diseases linked to environmental toxic insults. This nutritional paradigm in environmental toxicology requires further study in order to improve our understanding of the relationships between nutrition and other lifestyle modifications and toxicant-induced diseases. © 2017 New York Academy of Sciences.

  8. Molecular mechanisms of action of styrene toxicity in blood plasma and liver.

    Science.gov (United States)

    Niaz, Kamal; Mabqool, Faheem; Khan, Fazlullah; Ismail Hassan, Fatima; Baeeri, Maryam; Navaei-Nigjeh, Mona; Hassani, Shokoufeh; Gholami, Mahdi; Abdollahi, Mohammad

    2017-10-01

    Styrene is an aromatic colorless hydrocarbon available in liquid form and highly volatile. In its pure form, it gives a sweet smell. The primary source of exposure in the environment is from plastic materials, rubber industries, packaging materials, insulations, and fiber glass and carpet industry. Natural sources of styrene include: few metabolites in plants which are transferred through food chain. The current study was designed to evaluate styrene toxicity, including: superoxide dismutase (SOD) and protein carbonyl, oxidative stress, glucose-6-phosphatase (G6Pase), glycogen phosphorylase (GP), and phosphoenolpyruvate carboxykinase (PEPCK) activities, adenosine triphosphate (ATP) to adenosine diphosphate (ADP) ratio, and changes in gene expressions such as glutamate dehydrogenase 1 (GLUD1), glucose transporter 2 (GLUT2), and glucokinase (GCK) in the rat liver tissue. For this purpose, styrene was dissolved in corn oil and was administered via gavage, at doses 250, 500, 1000, 1500, 2000, mg/kg/day per mL and control (corn oil) to each rat with one day off in a week, for 42 days. Plasma SOD and protein carbonyl of plasma were significantly up-regulated in 1000, 1500, and 2000 mg/kg/day styrene administrated groups (P < .001). In addition, styrene caused an increase in lipid peroxidation (LPO) and reactive oxygen species (ROS) in the dose-dependent manners in liver tissue (P < .001). Furthermore, the ferrous reducing antioxidant power (FRAP) and total thiol molecules (TTM) in styrene-treated groups were significantly decreased in liver tissue (P < .001) with increasing doses. In treated rats, styrene significantly increased G6Pase activity (P < .001) and down-regulated GP activity (P < .001) as compared to the control group. The PEPCK activity was significantly raised in a dose-dependent manner (P < .001). The ATP/ADP ratio of live cells was significantly raised by increasing the dose (P < .001). There was significantly an up

  9. Congenital amusics use a secondary pitch mechanism to identify lexical tones.

    Science.gov (United States)

    Bones, Oliver; Wong, Patrick C M

    2017-09-01

    Amusia is a pitch perception disorder associated with deficits in processing and production of both musical and lexical tones, which previous reports have suggested may be constrained to fine-grained pitch judgements. In the present study speakers of tone-languages, in which lexical tones are used to convey meaning, identified words present in chimera stimuli containing conflicting pitch-cues in the temporal fine-structure and temporal envelope, and which therefore conveyed two distinct utterances. Amusics were found to be more likely than controls to judge the word according to the envelope pitch-cues. This demonstrates that amusia is not associated with fine-grained pitch judgements alone, and is consistent with there being two distinct pitch mechanisms and with amusics having an atypical reliance on a secondary mechanism based upon envelope cues. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. Carbon-dependent alleviation of ammonia toxicity for algae cultivation and associated mechanisms exploration.

    Science.gov (United States)

    Lu, Qian; Chen, Paul; Addy, Min; Zhang, Renchuan; Deng, Xiangyuan; Ma, Yiwei; Cheng, Yanling; Hussain, Fida; Chen, Chi; Liu, Yuhuan; Ruan, Roger

    2018-02-01

    Ammonia toxicity in wastewater is one of the factors that limit the application of algae technology in wastewater treatment. This work explored the correlation between carbon sources and ammonia assimilation and applied a glucose-assisted nitrogen starvation method to alleviate ammonia toxicity. In this study, ammonia toxicity to Chlorella sp. was observed when NH 3 -N concentration reached 28.03mM in artificial wastewater. Addition of alpha-ketoglutarate in wastewater promoted ammonia assimilation, but low utilization efficiency and high cost of alpha-ketoglutarate limits its application in wastewater treatment. Comparison of three common carbon sources, glucose, citric acid, and sodium bicarbonate, indicates that in terms of ammonia assimilation, glucose is the best carbon source. Experimental results suggest that organic carbon with good ability of generating energy and hydride donor may be critical to ammonia assimilation. Nitrogen starvation treatment assisted by glucose increased ammonia removal efficiencies and algal viabilities. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Mechanisms of the Testis Toxicity Induced by Chronic Exposure to Mequindox

    Directory of Open Access Journals (Sweden)

    Qianying Liu

    2017-09-01

    Full Text Available Mequindox (MEQ is a synthetic antimicrobial agent widely used in China since the 1980s. Although the toxicity of MEQ is well recognized, its testis toxicity has not been adequately investigated. In the present study, we provide evidence that MEQ triggers oxidative stress, mitochondrion dysfunction and spermatogenesis deficiency in mice after exposure to MEQ (0, 25, 55, and 110 mg/kg in the diet for up to 18 months. The genotoxicity and adrenal toxicity may contribute to sperm abnormalities caused by MEQ. Moreover, using LC/MS-IT-TOF analysis, two metabolites, 3-methyl-2-(1-hydroxyethyl quinoxaline-N4-monoxide (M4 and 3-methyl-2-(1-hydroxyethyl quinoxaline-N1-monoxide (M8, were detected in the serum of mice, which directly confirms the relationship between the N→O group reduction metabolism of MEQ and oxidative stress. Interestingly, only M4 was detected in the testes, suggesting that the higher reproductive toxicity of M4 than M8 might be due to the increased stability of M4-radical (M4-R compared to M8-radical (M8-R. Furthermore, the expression of the blood-testis barrier (BTB-associated junctions such as tight junctions, gap junctions and basal ectoplasmic specializations were also examined. The present study demonstrated for the first time the role of the M4 in testis toxicity, and illustrated that the oxidative stress, mitochondrion dysfunction and interference in spermatogenesis, as well as the altered expression of BTB related junctions, were involved in the reproductive toxicity mediated by MEQ in vivo.

  12. Identifying the nonlinear mechanical behaviour of micro-speakers from their quasi-linear electrical response

    Science.gov (United States)

    Zilletti, Michele; Marker, Arthur; Elliott, Stephen John; Holland, Keith

    2017-05-01

    In this study model identification of the nonlinear dynamics of a micro-speaker is carried out by purely electrical measurements, avoiding any explicit vibration measurements. It is shown that a dynamic model of the micro-speaker, which takes into account the nonlinear damping characteristic of the device, can be identified by measuring the response between the voltage input and the current flowing into the coil. An analytical formulation of the quasi-linear model of the micro-speaker is first derived and an optimisation method is then used to identify a polynomial function which describes the mechanical damping behaviour of the micro-speaker. The analytical results of the quasi-linear model are compared with numerical results. This study potentially opens up the possibility of efficiently implementing nonlinear echo cancellers.

  13. Identifying partial topology of complex dynamical networks via a pinning mechanism

    Science.gov (United States)

    Zhu, Shuaibing; Zhou, Jin; Lu, Jun-an

    2018-04-01

    In this paper, we study the problem of identifying the partial topology of complex dynamical networks via a pinning mechanism. By using the network synchronization theory and the adaptive feedback controlling method, we propose a method which can greatly reduce the number of nodes and observers in the response network. Particularly, this method can also identify the whole topology of complex networks. A theorem is established rigorously, from which some corollaries are also derived in order to make our method more cost-effective. Several numerical examples are provided to verify the effectiveness of the proposed method. In the simulation, an approach is also given to avoid possible identification failure caused by inner synchronization of the drive network.

  14. Cyclophosphamide-induced pulmonary toxicity

    International Nuclear Information System (INIS)

    Siemann, D.W.; Macler, L.; Penney, D.P.

    1986-01-01

    Unlike radiation effects, pulmonary toxicity following drug treatments may develop soon after exposure. The dose-response relationship between Cyclophosphamide and lung toxicity was investigated using increased breathing frequency assays used successfully for radiation induced injury. The data indicate that release of protein into the alveolus may play a significant role in Cy induced pulmonary toxicity. Although the mechanism responsible for the increased alveolar protein is as yet not identified, the present findings suggest that therapeutic intervention to inhibit protein release may be an approach to protect the lungs from toxic effects. (UK)

  15. Cluster analysis of spontaneous preterm birth phenotypes identifies potential associations among preterm birth mechanisms.

    Science.gov (United States)

    Esplin, M Sean; Manuck, Tracy A; Varner, Michael W; Christensen, Bryce; Biggio, Joseph; Bukowski, Radek; Parry, Samuel; Zhang, Heping; Huang, Hao; Andrews, William; Saade, George; Sadovsky, Yoel; Reddy, Uma M; Ilekis, John

    2015-09-01

    We sought to use an innovative tool that is based on common biologic pathways to identify specific phenotypes among women with spontaneous preterm birth (SPTB) to enhance investigators' ability to identify and to highlight common mechanisms and underlying genetic factors that are responsible for SPTB. We performed a secondary analysis of a prospective case-control multicenter study of SPTB. All cases delivered a preterm singleton at SPTB ≤34.0 weeks' gestation. Each woman was assessed for the presence of underlying SPTB causes. A hierarchic cluster analysis was used to identify groups of women with homogeneous phenotypic profiles. One of the phenotypic clusters was selected for candidate gene association analysis with the use of VEGAS software. One thousand twenty-eight women with SPTB were assigned phenotypes. Hierarchic clustering of the phenotypes revealed 5 major clusters. Cluster 1 (n = 445) was characterized by maternal stress; cluster 2 (n = 294) was characterized by premature membrane rupture; cluster 3 (n = 120) was characterized by familial factors, and cluster 4 (n = 63) was characterized by maternal comorbidities. Cluster 5 (n = 106) was multifactorial and characterized by infection (INF), decidual hemorrhage (DH), and placental dysfunction (PD). These 3 phenotypes were correlated highly by χ(2) analysis (PD and DH, P cluster 3 of SPTB. We identified 5 major clusters of SPTB based on a phenotype tool and hierarch clustering. There was significant correlation between several of the phenotypes. The INS gene was associated with familial factors that were underlying SPTB. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Identifying the causes of differences in ozone production from the CB05 and CBMIV chemical mechanisms

    Directory of Open Access Journals (Sweden)

    R. D. Saylor

    2012-02-01

    Full Text Available An investigation was conducted to identify the mechanistic differences between two versions of the carbon bond gas-phase chemical mechanism (CB05 and CBMIV which consistently lead to larger ground-level ozone concentrations being produced in the CB05 version of the National Air Quality Forecasting Capability (NAQFC modeling system even though the two parallel forecast systems utilize the same meteorology and base emissions and similar initial and boundary conditions. Box models of each of the mechanisms as they are implemented in the NAQFC were created and a set of 12 sensitivity simulations was designed. The sensitivity simulations independently probed the conceptual mechanistic differences between CB05 and CBMIV and were exercised over a 45-scenario simulation suite designed to emulate the wide range of chemical regimes encountered in a continental-scale atmospheric chemistry model. Results of the sensitivity simulations indicate that two sets of reactions that were included in the CB05 mechanism, but which were absent from the CBMIV mechanism, are the primary causes of the greater ozone production in the CB05 version of the NAQFC. One set of reactions recycles the higher organic peroxide species of CB05 (ROOH, resulting in additional photochemically reactive products that act to produce additional ozone in some chemical regimes. The other set of reactions recycles reactive nitrogen from less reactive forms back to NO2, increasing the effective NOx concentration of the system. In particular, the organic nitrate species (NTR, which was a terminal product for reactive nitrogen in the CBMIV mechanism, acts as a reservoir species in CB05 to redistribute NOx from major source areas to potentially NOx-sensitive areas where additional ozone may be produced in areas remote from direct NOx sources.

  17. Rapid, computer vision-enabled murine screening system identifies neuropharmacological potential of two new mechanisms

    Directory of Open Access Journals (Sweden)

    Steven L Roberds

    2011-09-01

    Full Text Available The lack of predictive in vitro models for behavioral phenotypes impedes rapid advancement in neuropharmacology and psychopharmacology. In vivo behavioral assays are more predictive of activity in human disorders, but such assays are often highly resource-intensive. Here we describe the successful application of a computer vision-enabled system to identify potential neuropharmacological activity of two new mechanisms. The analytical system was trained using multiple drugs that are used clinically to treat depression, schizophrenia, anxiety, and other psychiatric or behavioral disorders. During blinded testing the PDE10 inhibitor TP-10 produced a signature of activity suggesting potential antipsychotic activity. This finding is consistent with TP-10’s activity in multiple rodent models that is similar to that of clinically used antipsychotic drugs. The CK1ε inhibitor PF-670462 produced a signature consistent with anxiolytic activity and, at the highest dose tested, behavioral effects similar to that of opiate analgesics. Neither TP-10 nor PF-670462 was included in the training set. Thus, computer vision-based behavioral analysis can facilitate drug discovery by identifying neuropharmacological effects of compounds acting through new mechanisms.

  18. Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers

    NARCIS (Netherlands)

    Mannini, Benedetta; Cascella, Roberta; Zampagni, Mariagioia; Van Waarde-Verhagen, Maria; Meehan, Sarah; Roodveldt, Cintia; Campioni, Silvia; Boninsegna, Matilde; Penco, Amanda; Relini, Annalisa; Kampinga, Harm H.; Dobson, Christopher M.; Wilson, Mark R.; Cecchi, Cristina; Chiti, Fabrizio

    2012-01-01

    Chaperones are the primary regulators of the proteostasis network and are known to facilitate protein folding, inhibit protein aggregation, and promote disaggregation and clearance of misfolded aggregates inside cells. We have tested the effects of five chaperones on the toxicity of misfolded

  19. Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode

    Science.gov (United States)

    Kotb, Magd A.

    2012-01-01

    Ursodeoxycholic acid (UDCA) is a steroid bile acid approved for primary biliary cirrhosis (PBC). UDCA is reported to have “hepato-protective properties”. Yet, UDCA has “unanticipated” toxicity, pronounced by more than double number of deaths, and eligibility for liver transplantation compared to the control group in 28 mg/kg/day in primary sclerosing cholangitis, necessitating trial halt in North America. UDCA is associated with increase in hepatocellular carcinoma in PBC especially when it fails to achieve biochemical response (10 and 15 years incidence of 9% and 20% respectively). “Unanticipated” UDCA toxicity includes hepatitis, pruritus, cholangitis, ascites, vanishing bile duct syndrome, liver cell failure, death, severe watery diarrhea, pneumonia, dysuria, immune-suppression, mutagenic effects and withdrawal syndrome upon sudden halt. UDCA inhibits DNA repair, co-enzyme A, cyclic AMP, p53, phagocytosis, and inhibits induction of nitric oxide synthatase. It is genotoxic, exerts aneugenic activity, and arrests apoptosis even after cellular phosphatidylserine externalization. UDCA toxicity is related to its interference with drug detoxification, being hydrophilic and anti-apoptotic, has a long half-life, has transcriptional mutational abilities, down-regulates cellular functions, has a very narrow difference between the recommended (13 mg/kg/day) and toxic dose (28 mg/kg/day), and it typically transforms into lithocholic acid that induces DNA strand breakage, it is uniquely co-mutagenic, and promotes cell transformation. UDCA beyond PBC is unjustified. PMID:22942741

  20. Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects: Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode

    Directory of Open Access Journals (Sweden)

    Magd A. Kotb

    2012-07-01

    Full Text Available Ursodeoxycholic acid (UDCA is a steroid bile acid approved for primary biliary cirrhosis (PBC. UDCA is reported to have “hepato-protective properties”. Yet, UDCA has “unanticipated” toxicity, pronounced by more than double number of deaths, and eligibility for liver transplantation compared to the control group in 28 mg/kg/day in primary sclerosing cholangitis, necessitating trial halt in North America. UDCA is associated with increase in hepatocellular carcinoma in PBC especially when it fails to achieve biochemical response (10 and 15 years incidence of 9% and 20% respectively. “Unanticipated” UDCA toxicity includes hepatitis, pruritus, cholangitis, ascites, vanishing bile duct syndrome, liver cell failure, death, severe watery diarrhea, pneumonia, dysuria, immune-suppression, mutagenic effects and withdrawal syndrome upon sudden halt. UDCA inhibits DNA repair, co-enzyme A, cyclic AMP, p53, phagocytosis, and inhibits induction of nitric oxide synthatase. It is genotoxic, exerts aneugenic activity, and arrests apoptosis even after cellular phosphatidylserine externalization. UDCA toxicity is related to its interference with drug detoxification, being hydrophilic and anti-apoptotic, has a long half-life, has transcriptional mutational abilities, down-regulates cellular functions, has a very narrow difference between the recommended (13 mg/kg/day and toxic dose (28 mg/kg/day, and it typically transforms into lithocholic acid that induces DNA strand breakage, it is uniquely co-mutagenic, and promotes cell transformation. UDCA beyond PBC is unjustified.

  1. Identification of the mechanisms that drive the toxicity of TiO2 particulates: the contribution of physicochemical characteristics

    Directory of Open Access Journals (Sweden)

    Peters Sheona

    2009-12-01

    Full Text Available Abstract This review focuses on outlining the toxicity of titanium dioxide (TiO2 particulates in vitro and in vivo, in order to understand their ability to detrimentally impact on human health. Evaluating the hazards associated with TiO2 particles is vital as it enables risk assessments to be conducted, by combining this information with knowledge on the likely exposure levels of humans. This review has concentrated on the toxicity of TiO2, due to the fact that the greatest number of studies by far have evaluated the toxicity of TiO2, in comparison to other metal oxide particulates. This derives from historical reasons (whereby the size dependency of particulate toxicity was first realised for TiO2 and due to its widespread application within consumer products (such as sunscreens. The pulmonary and dermal hazards of TiO2 have been a particular focus of the available studies, due to the past use of TiO2 as a (negative control when assessing the pulmonary toxicity of particulates, and due to its incorporation within consumer products such as sunscreens. Mechanistic processes that are critical to TiO2 particulate toxicity will also be discussed and it is apparent that, in the main, the oxidant driven inflammatory, genotoxic and cytotoxic consequences associated with TiO2 exposure, are inherently linked, and are evident both in vivo and in vitro. The attributes of TiO2 that have been identified as being most likely to drive the observed toxicity include particle size (and therefore surface area, crystallinity (and photocatalytic activity, surface chemistry, and particle aggregation/agglomeration tendency. The experimental set up also influences toxicological outcomes, so that the species (or model used, route of exposure, experiment duration, particle concentration and light conditions are all able to influence the findings of investigations. In addition, the applicability of the observed findings for particular TiO2 forms, to TiO2 particulates in

  2. Mechanistic phenotypes: an aggregative phenotyping strategy to identify disease mechanisms using GWAS data.

    Directory of Open Access Journals (Sweden)

    Jonathan D Mosley

    Full Text Available A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1 non-synonymous SNPs (nsSNPs associated with "mechanistic phenotypes", comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1 thrombosis, evaluated in a population of 1,655 African Americans; and (2 four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs, and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03, driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10-5, FDR p = 0.03 (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L while the additive model showed enrichment related to chromatid segregation (p = 4×10-6, FDR p = 0.005 (KIF25, PINX1. We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.

  3. Towards identifying the mechanisms underlying field-aligned edge-loss of HHFW power on NSTX

    Energy Technology Data Exchange (ETDEWEB)

    Perkins, R. J.; Bell, R. E.; Bertelli, N.; Diallo, A.; Gerhardt, S.; Hosea, J. C.; Jaworski, M. A.; LeBlanc, B. P.; Kramer, G. J.; Maingi, R.; Phillips, C. K.; Podestà, M.; Roquemore, L.; Scotti, F.; Taylor, G.; Wilson, J. R. [Princeton Plasma Physics Laboratory, Princeton, NJ (United States); Ahn, J-W.; Gray, T. K.; Green, D. L.; McLean, A. [Oak Ridge National Laboratory, Oak Ridge, TN (United States); and others

    2014-02-12

    Fast-wave heating will be a major heating scheme on ITER, as it can heat ions directly and is relatively unaffected by the large machine size unlike neutral beams. However, fast-wave interactions with the plasma edge can lead to deleterious effects such as, in the case of the high-harmonic fast-wave (HHFW) system on NSTX, large losses of fast-wave power in the scrape off layer (SOL) under certain conditions. In such scenarios, a large fraction of the lost HHFW power is deposited on the upper and lower divertors in bright spiral shapes. The responsible mechanism(s) has not yet been identified but may include fast-wave propagation in the scrape off layer, parametric decay instability, and RF currents driven by the antenna reactive fields. Understanding and mitigating these losses is important not only for improving the heating and current-drive on NSTX-Upgrade but also for understanding fast-wave propagation across the SOL in any fast-wave system. This talk summarizes experimental results demonstrating that the flow of lost HHFW power to the divertor regions largely follows the open SOL magnetic field lines. This lost power flux is relatively large close to both the antenna and the last closed flux surface with a reduced level in between, so the loss mechanism cannot be localized to the antenna. At the same time, significant losses also occur along field lines connected to the inboard edge of the bottom antenna plate. The power lost within the spirals is roughly estimated, showing that these field-aligned losses to the divertor are significant but may not account for the total HHFW loss. To elucidate the role of the onset layer for perpendicular fast-wave propagation with regards to fast-wave propagation in the SOL, a cylindrical cold-plasma model is being developed. This model, in addition to advanced RF codes such as TORIC and AORSA, is aimed at identifying the underlying mechanism(s) behind these SOL losses, to minimize their effects in NSTX-U, and to predict

  4. Towards identifying the mechanisms underlying field-aligned edge-loss of HHFW power on NSTX

    International Nuclear Information System (INIS)

    Perkins, R. J.; Bell, R. E.; Bertelli, N.; Diallo, A.; Gerhardt, S.; Hosea, J. C.; Jaworski, M. A.; LeBlanc, B. P.; Kramer, G. J.; Maingi, R.; Phillips, C. K.; Podestà, M.; Roquemore, L.; Scotti, F.; Taylor, G.; Wilson, J. R.; Ahn, J-W.; Gray, T. K.; Green, D. L.; McLean, A.

    2014-01-01

    Fast-wave heating will be a major heating scheme on ITER, as it can heat ions directly and is relatively unaffected by the large machine size unlike neutral beams. However, fast-wave interactions with the plasma edge can lead to deleterious effects such as, in the case of the high-harmonic fast-wave (HHFW) system on NSTX, large losses of fast-wave power in the scrape off layer (SOL) under certain conditions. In such scenarios, a large fraction of the lost HHFW power is deposited on the upper and lower divertors in bright spiral shapes. The responsible mechanism(s) has not yet been identified but may include fast-wave propagation in the scrape off layer, parametric decay instability, and RF currents driven by the antenna reactive fields. Understanding and mitigating these losses is important not only for improving the heating and current-drive on NSTX-Upgrade but also for understanding fast-wave propagation across the SOL in any fast-wave system. This talk summarizes experimental results demonstrating that the flow of lost HHFW power to the divertor regions largely follows the open SOL magnetic field lines. This lost power flux is relatively large close to both the antenna and the last closed flux surface with a reduced level in between, so the loss mechanism cannot be localized to the antenna. At the same time, significant losses also occur along field lines connected to the inboard edge of the bottom antenna plate. The power lost within the spirals is roughly estimated, showing that these field-aligned losses to the divertor are significant but may not account for the total HHFW loss. To elucidate the role of the onset layer for perpendicular fast-wave propagation with regards to fast-wave propagation in the SOL, a cylindrical cold-plasma model is being developed. This model, in addition to advanced RF codes such as TORIC and AORSA, is aimed at identifying the underlying mechanism(s) behind these SOL losses, to minimize their effects in NSTX-U, and to predict

  5. The synthesis, structure-toxicity relationship of cisplatin derivatives for the mechanism research of cisplatin-induced nephrotoxicity.

    Science.gov (United States)

    Hu, Jing; Wu, Tian-Ming; Li, Hong-Ze; Zuo, Ze-Ping; Zhao, Ying-Lan; Yang, Li

    2017-08-01

    Cisplatin is a widely used antineoplastic drug, while its nephrotoxicity limits the clinical application. Although several mechanisms contributing to nephrotoxicity have been reported, the direct protein targets are unclear. Herein we reported the synthesis of 29 cisplatin derivatives and the structure-toxicity relationship (STR) of these compounds with MTT assay in human renal proximal tubule cells (HK-2) and pig kidney epithelial cells (LLC-PK1). To the best of our knowledge, this study represented the first report regarding the structure-toxicity relationship (STR) of cisplatin derivatives. The potency of biotin-pyridine conjugated derivative 3 met the requirement for target identification, and the preliminary chemical proteomics results suggested that it is a promising tool for further target identification of cisplatin-induced nephrotoxicity. Copyright © 2017. Published by Elsevier Ltd.

  6. An investigation of endocrine disrupting effects and toxic mechanisms modulated by benzo[a]pyrene in female scallop Chlamys farreri

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Shuangmei; Pan, Luqing, E-mail: panlq@ouc.edu.cn; Sun, Xiaohua

    2013-11-15

    Highlights: •B[a]P disturbed progesterone, 17β-estradiol and testosterone production in scallop. •B[a]P inhibited 3β-HSD, CYP17 and 17β-HSD expression after a 10-day exposure. •B[a]P of lower dose elevated AHR-CYP1A expression but high dose B[a]P inhibited them. •ER and vitellogenin transcription was consistent with AHR after B[a]P exposure. •B[a]P exposure induced relatively developmental delay and impairment of ovary. -- Abstract: The purpose of this study was to investigate the endocrine disrupting effects induced by benzo[a]pyrene (B[a]P) and explore the underlying mechanisms in mollusks. In this study, sexually mature female Chlamys farreri were exposed to benzo[a]pyrene for 10 days at four different concentrations as 0, 0.025, 0.5 and 10 μg/L. Sex steroids were identified and quantified by electrochemiluminescence immunoassay (ECLIA) method and results showed that exposure to B[a]P exerts great suppression on 17β-estradiol, testosterone production and disrupts progesterone levels in ovary. Transcription of genes were detected and measured by real-time RT-PCR. It showed that at day 10 B[a]P inhibited 3β-HSD, CYP17 and 17β-HSD mRNA expression in a dose-dependent manner, which suggests that they could be potential targets of B[a]P that disrupt steroidogenic machinery. Moreover, 0.025 μg/L B[a]P activated transcription of aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), CYP1A1 and estrogen receptor (ER), while 10 μg/L B[a]P suppressed all of them. The consistency of their responses to B[a]P exposure implies that AHR action may be involved in invertebrate CYP regulation and ER transcription despite of unknown mechanisms. Additionally, B[a]P exposure could induce ovarian impairment and developmental delay in C. farreri. Overall, sensitivity of C. farreri to endocrine disruption and toxicity suggests that C. farreri is a suitable species for study of endocrine-disrupting effects in marine invertebrates. This study will form a

  7. An investigation of endocrine disrupting effects and toxic mechanisms modulated by benzo[a]pyrene in female scallop Chlamys farreri

    International Nuclear Information System (INIS)

    Tian, Shuangmei; Pan, Luqing; Sun, Xiaohua

    2013-01-01

    Highlights: •B[a]P disturbed progesterone, 17β-estradiol and testosterone production in scallop. •B[a]P inhibited 3β-HSD, CYP17 and 17β-HSD expression after a 10-day exposure. •B[a]P of lower dose elevated AHR-CYP1A expression but high dose B[a]P inhibited them. •ER and vitellogenin transcription was consistent with AHR after B[a]P exposure. •B[a]P exposure induced relatively developmental delay and impairment of ovary. -- Abstract: The purpose of this study was to investigate the endocrine disrupting effects induced by benzo[a]pyrene (B[a]P) and explore the underlying mechanisms in mollusks. In this study, sexually mature female Chlamys farreri were exposed to benzo[a]pyrene for 10 days at four different concentrations as 0, 0.025, 0.5 and 10 μg/L. Sex steroids were identified and quantified by electrochemiluminescence immunoassay (ECLIA) method and results showed that exposure to B[a]P exerts great suppression on 17β-estradiol, testosterone production and disrupts progesterone levels in ovary. Transcription of genes were detected and measured by real-time RT-PCR. It showed that at day 10 B[a]P inhibited 3β-HSD, CYP17 and 17β-HSD mRNA expression in a dose-dependent manner, which suggests that they could be potential targets of B[a]P that disrupt steroidogenic machinery. Moreover, 0.025 μg/L B[a]P activated transcription of aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), CYP1A1 and estrogen receptor (ER), while 10 μg/L B[a]P suppressed all of them. The consistency of their responses to B[a]P exposure implies that AHR action may be involved in invertebrate CYP regulation and ER transcription despite of unknown mechanisms. Additionally, B[a]P exposure could induce ovarian impairment and developmental delay in C. farreri. Overall, sensitivity of C. farreri to endocrine disruption and toxicity suggests that C. farreri is a suitable species for study of endocrine-disrupting effects in marine invertebrates. This study will form a

  8. Absence of a Universal Mechanism of Mitochondrial Toxicity by Nucleoside Analogs▿

    OpenAIRE

    Lund, Kaleb C.; Peterson, LaRae L.; Wallace, Kendall B.

    2007-01-01

    Nucleoside analogs are associated with various mitochondrial toxicities, and it is becoming increasingly difficult to accommodate these differences solely in the context of DNA polymerase gamma inhibition. Therefore, we examined the toxicities of zidovudine (AZT) (10 and 50 μM; 2.7 and 13.4 μg/ml), didanosine (ddI) (10 and 50 μM; 2.4 and 11.8 μg/ml), and zalcitabine (ddC) (1 and 5 μM; 0.21 and 1.1 μg/ml) in HepG2 and H9c2 cells without the presumption of mitochondrial DNA (mtDNA) depletion. E...

  9. Mechanism of action and selective toxicity of ascamycin, a nucleoside antibiotic.

    OpenAIRE

    Osada, H; Isono, K

    1985-01-01

    An unidentified Streptomyces sp. produces two nucleoside antibiotics, ascamycin and its dealanyl derivative. In contrast to the broad antibacterial activity of dealanylascamycin against various gram-negative and gram-positive bacteria, ascamycin showed selective toxicity against Xanthomonas citri and X. oryzae. Both ascamycin and dealanylascamycin inhibited the protein synthesis of X. citri, but only dealanylascamycin inhibited that of Escherichia coli. In cell-free systems from E. coli and X...

  10. Influence of Leaf Tolerance Mechanisms and Rain on Boron Toxicity in Barley and Wheat1[C

    Science.gov (United States)

    Reid, Rob; Fitzpatrick, Kate

    2009-01-01

    Boron (B) toxicity is common in many areas of the world. Plant tolerance to high B varies widely and has previously been attributed to reduced uptake of B, most commonly as a result of B efflux from roots. In this study, it is shown that the expression of genes encoding B efflux transporters in leaves of wheat (Triticum aestivum) and barley (Hordeum vulgare) is associated with an ability of leaf tissues to withstand higher concentrations of B. In tolerant cultivars, necrosis in leaves occurred at B concentrations more than 2-fold higher than in sensitive cultivars. It is hypothesized that this leaf tolerance is achieved via redistribution of B by efflux transporters from sensitive symplastic compartments into the leaf apoplast. Measurements of B concentrations in leaf protoplasts, and of B released following infiltration of leaves, support this hypothesis. It was also shown that under B-toxic conditions, leaching of B from leaves by rain had a strong positive effect on growth of both roots and shoots. Measurements of rates of guttation and the concentration of B in guttation droplets indicated that the impact of guttation on the alleviation of B toxicity would be small. PMID:19625636

  11. A multicriteria approach to identify investment opportunities for the exploitation of the clean development mechanism

    International Nuclear Information System (INIS)

    Diakoulaki, D.; Georgiou, P.; Tourkolias, C.; Georgopoulou, E.; Lalas, D.; Mirasgedis, S.; Sarafidis, Y.

    2007-01-01

    The aim of the present paper is to investigate the prospects for the exploitation of the Kyoto Protocol's Clean Development Mechanism (CDM) in Greece. The paper is addressing 3 questions: in which country, what kind of investment, with which economic and environmental return? The proposed approach is based on a multicriteria analysis for identifying priority countries and interesting investment opportunities in each priority country. These opportunities are then evaluated through a conventional financial analysis in order to assess their economic and environmental attractiveness. To this purpose, the IRR of a typical project in each investment category is calculated by taking into account country-specific parameters, such as baseline emission factors, load factors, costs, energy prices etc. The results reveal substantial differences in the economic and environmental return of different types of projects in different host-countries and show that for the full exploitation of the CDM a multifaceted approach to decision-making is necessary

  12. Effect of natural uranium on the UMR-106 osteoblastic cell line: impairment of the autophagic process as an underlying mechanism of uranium toxicity.

    Science.gov (United States)

    Pierrefite-Carle, Valérie; Santucci-Darmanin, Sabine; Breuil, Véronique; Gritsaenko, Tatiana; Vidaud, Claude; Creff, Gaelle; Solari, Pier Lorenzo; Pagnotta, Sophie; Al-Sahlanee, Rasha; Auwer, Christophe Den; Carle, Georges F

    2017-04-01

    Natural uranium (U), which is present in our environment, exerts a chemical toxicity, particularly in bone where it accumulates. Generally, U is found at oxidation state +VI in its oxocationic form [Formula: see text] in aqueous media. Although U(VI) has been reported to induce cell death in osteoblasts, the cells in charge of bone formation, the molecular mechanism for U(VI) effects in these cells remains poorly understood. The objective of our study was to explore U(VI) effect at doses ranging from 5 to 600 µM, on mineralization and autophagy induction in the UMR-106 model osteoblastic cell line and to determine U(VI) speciation after cellular uptake. Our results indicate that U(VI) affects mineralization function, even at subtoxic concentrations (metal exposure. We observed that U(VI) was able to rapidly activate autophagy but an inhibition of the autophagic flux was observed after 24 h. Thus, our results indicate that U(VI) perturbs osteoblastic functions by reducing mineralization capacity. Our study identifies for the first time U(VI) in the form of meta-autunite in mammalian cells. In addition, U(VI)-mediated inhibition of the autophagic flux may be one of the underlying mechanisms leading to the decreased mineralization and the toxicity observed in osteoblasts.

  13. Assessment of mechanisms of metal-induced reproductive toxicity in aquatic species as a biomarker of exposure

    International Nuclear Information System (INIS)

    Anderson, M.; George, W.; Sikka, S.; Kamath, B.; Preslan, J.; Agrawal, K.; Rege, A.

    1993-01-01

    This project is designed to identify heavy metals and organic contaminants of concern which could impact on the biota in the Louisiana wetlands by assessment of uptake and bioaccumulation of contaminants and their effects on reproductive processes as biomarkers of exposure. Heavy metals (lead, cadmium, cobalt, and mercury) have been demonstrated to have toxic effects on reproduction in mammals and several aquatic species. Hexachlorobenzene (HCB) is an persistent environmental contaminant which has been measured in human serum, fat, semen, and follicular fluid. HCB has been shown to be a reproductive toxin in rats and primates. Polychlorinated biphenyls (PCBs) are prevalent chlorinated hydrocarbons currently contaminating our environment. PCBs resist degradation and are insoluble in water; however, they bioaccumulate in aquatic species. Disturbances of the reproductive systems are not only sensitive indicators of toxicity but threatens the propagation of a species

  14. Identifying social mechanisms for the prevention of adolescent drinking and driving.

    Science.gov (United States)

    Chen, Meng-Jinn; Grube, Joel W; Nygaard, Peter; Miller, Brenda A

    2008-03-01

    This study identifies social mechanisms that might help prevent youth from being involved in driving under the influence of alcohol (DUI) and riding with drinking drivers (RWDD). Data collected through telephone surveys with 1534 adolescents and young adults aged 15-20 years (mean=17.6, S.D.=1.6) in California, USA, were analyzed. Structural equation modeling analyses showed that DUI and RWDD were strongly related to drinking in unstructured situations, modeling of DUI by peers and parents, and perceived peer approval or disapproval of DUI. DUI outcome expectancies were indirectly related to DUI and RWDD through situational drinking. Parental monitoring and DUI law enforcement were also indirectly related to DUI and RWDD through DUI expectancies and other mechanisms. The findings, overall, suggest that parental influence remains important even through late adolescence. Parental monitoring, in particular, might help to reduce unstructured socializing with peers, drinking, and affiliation with peers who engage in DUI. Parental monitoring may also foster beliefs about the risks of DUI. Conversely, parents' own DUI behavior may normalize drinking and DUI behaviors, thus countering monitoring efforts.

  15. Identifying Social Mechanisms for the Prevention of Adolescent Drinking and Driving

    Science.gov (United States)

    Chen, Meng-Jinn; Grube, Joel W.; Nygaard, Peter; Miller, Brenda A.

    2008-01-01

    This study identifies social mechanisms that might help prevent youth from being involved in driving under the influence of alcohol (DUI) and riding with drinking drivers (RWDD). Data collected through telephone surveys with 1,534 adolescents and young adults aged 15–20 years (mean = 17.6, SD = 1.6) in California, USA were analyzed. Structural equation modeling analyses showed that DUI and RWDD were strongly related to drinking in unstructured situations, modeling of DUI by peers and parents, and perceived peer approval or disapproval of DUI. DUI outcome expectancies were indirectly related to DUI and RWDD through situational drinking. Parental monitoring and DUI law enforcement were also indirectly related to DUI and RWDD through DUI expectancies and other mechanisms. The findings, overall, suggest that parental influence remains important even through late adolescence. Parental monitoring, in particular, might help to reduce unstructured socializing with peers, drinking, and affiliation with peers who engage in DUI. Parental monitoring may also foster beliefs about the risks of DUI. Conversely, parents’ own DUI behavior may normalize drinking and DUI behaviors, thus countering monitoring efforts. PMID:18329409

  16. Identifying Intraplate Mechanism by B-Value Calculations in the South of Java Island

    Science.gov (United States)

    Bagus Suananda Y., Ida; Aufa, Irfan; Harlianti, Ulvienin

    2018-03-01

    Java is the most populous island in Indonesia with 50 million people live there. This island geologically formed at the Eurasia plate margin by the subduction of the Australian oceanic crust. At the south part of Java, beside the occurrence of 2-plate convergence earthquake (interplate), there are also the activities of the intraplate earthquake. Research for distinguish this 2 different earthquake type is necessary for estimating the behavior of the earthquake that may occur. The aim of this research is to map the b-value in the south of Java using earthquake data from 1963 until 2008. The research area are divided into clusters based on the epicenter mapping results with magnitude more than 4 and three different depth (0-30 km, 30-60 km, 60-100 km). This location clustering indicate group of earthquakes occurred by the same structure or mechanism. On some cluster in the south of Java, b-value obtained are between 0.8 and 1.25. This range of b-value indicates the region was intraplate earthquake zone, with 0.72-1.2 b-value range is the indication of intraplate earthquake zone. The final validation is to determine the mechanism of a segment done by correlating the epicenter and b-value plot with the available structural geology data. Based on this research, we discover that the earthquakes occur in Java not only the interplate earthquake, the intraplate earthquake also occurred here. By identifying the mechanism of a segment in the south of Java, earthquake characterization that may occur can be done for developing the accurate earthquake disaster mitigation system.

  17. 41 CFR 102-85.175 - Are the standard level services for cleaning, mechanical operation, and maintenance identified in...

    Science.gov (United States)

    2010-07-01

    ... services for cleaning, mechanical operation, and maintenance identified in an OA? 102-85.175 Section 102-85... of Service § 102-85.175 Are the standard level services for cleaning, mechanical operation, and maintenance identified in an OA? Unless specified otherwise in the OA, standard level services for cleaning...

  18. A critical view of the mechanism(s) of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Implications for human safety assessment.

    Science.gov (United States)

    Rozman, K

    1989-01-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been an important issue in occupational and environmental health for nearly two decades. During this period scientists have studied its possible impacts on exposed human populations. At the same time enormous efforts were made to elucidate the mechanism of TCDD action in various biological models. This paper provides a critical view of the advances made towards understanding the mechanism of TCDD action. Major topics discussed include the Ah-receptor hypothesis, TCDD as a thyroid hormone agonist, TCDD and vitamin A deficiency, TCDD's effect on receptor regulation, and its effect on intermediary metabolism including related hormonal responses. Although the exact mechanism of TCDD action is not yet known, more information is available on the toxicity of this compound than perhaps on that of any other substance. This wealth of information allows important conclusions regarding the assessment of acute, as well as of chronic, toxicities of TCDD for humans. There is no documented case of human death as a result of exposure to TCDD. It appears that humans are acutely less sensitive to TCDD than some animal species. The cause of TCDD-induced lethality in rats is a progressive lethal hypoglycemia due to inhibition of gluconeogenesis. Regulation of this metabolic pathway is quite different amongst species, although primates share great similarities. The assumption that the cause of TCDD-induced death in primates, in analogy to rats, is inhibition of gluconeogenesis would suggest that the acute toxicity of TCDD in humans would be in the range seen in rhesus monkeys (70-300 micrograms/kg). These values are about midway between the most (guinea pig) and least (hamster) sensitive species. TCDD is not a genotoxic agent and not an initiator, but promoter of tumor formation. There is considerable evidence that promotion of cancer, like any other chronic end point of toxicity, is a threshold-type biological process. Therefore, a linear

  19. Photodegradation of the azole fungicide climbazole by ultraviolet irradiation under different conditions: Kinetics, mechanism and toxicity evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Wang-Rong; Ying, Guang-Guo, E-mail: guang-guo.ying@gig.ac.cn; Zhao, Jian-Liang; Liu, You-Sheng; Hu, Li-Xin; Yao, Li; Liang, Yan-Qiu; Tian, Fei

    2016-11-15

    Highlights: • Climbazole (CZ) could be effectively degraded under UV-254 irradiation. • CZ underwent direct and self-sensitized photolysis involving ROS. • The main photodegradation by-products of CZ were identified and semi-quantitated. • Pathway includes hydroxylative dechlorination, dechlorination, and de-pinacolone. • The toxicity of the photodegradation system reduced after UV-254 irradiation. - Abstract: Climbazole (CZ) has been known to persist in various environmental media, and may cause potential risks to aquatic organisms. This study investigated the photodegradation of CZ by ultraviolet (UV, 254 nm) under different conditions. The results revealed that CZ could be effectively degraded in aqueous solutions under UV-254 irradiation with a half-life of 9.78 min (pH = 7.5), and the photodegradation followed pseudo-first-order kinetics. pH had almost no effect on its rate constants and quantum yields; but the water quality of natural waters could affect the photolysis of CZ, and the coexisting constituents such as Fe{sup 3+}, NO{sub 3}{sup −}, and HA obviously inhibited its photolysis. The addition of different radical scavengers also inhibited the photodegradation of CZ due to the reduction of reactive oxygen species (ROS). CZ underwent direct and self-sensitized photolysis involving ROS. Based on the identified photodegradation by-products, the proposed pathways included hydroxylative dechlorination, dechlorination and de-pinacolone. Moreover, toxicity evaluation using duckweed found significant toxicity reduction in the photodegradation system of CZ after the irradiation of UV-254, and the remaining by-products did not pose extra toxicity compared with CZ itself. These findings from present study suggest that CZ in effluent could be further reduced by applying UV photolysis treatment.

  20. The effectiveness of processed grapefruit-seed extract as an antibacterial agent: II. Mechanism of action and in vitro toxicity.

    Science.gov (United States)

    Heggers, John P; Cottingham, John; Gusman, Jean; Reagor, Lee; McCoy, Lana; Carino, Edith; Cox, Robert; Zhao, Jian-Gang; Reagor, Lana

    2002-06-01

    Recent testimonials report grapefruit-seed extract, or GSE (Citricidal) to be effective against more than 800 bacterial and viral strains, 100 strains of fungus, and a large number of single and multicelled parasites. This study investigated GSE for antibacterial activity at varying time intervals and concentration levels and tissue toxicity at varying concentrations in an effort to determine if a concentration existed that was both microbicidal and nontoxic and in what period of time. Gram-negative and gram-positive isolates were introduced into graduated dilutions of GSE (twofold concentrations ranging from 1:1, through 1:512) for determination of bacterial activity. In vitro assays with human skin fibroblast cells were also performed at the same dilutions to determine toxicity. These tests indicated that from the 1:1 through the 1:128 concentrations, GSE remained toxic as well as bactericidal. However, test results indicated that at the 1:512 dilution, GSE remained bactericidal, but completely nontoxic. The initial data shows GSE to have antimicrobial properties against a wide range of gram-negative and gram-positive organisms at dilutions found to be safe. With the aid of scanning transmission electron microscopy (STEM), the mechanism of GSE's antibacterial activity was revealed. It was evident that GSE disrupts the bacterial membrane and liberates the cytoplasmic contents within 15 minutes after contact even at more dilute concentrations.

  1. Elucidating the mechanisms of nickel compound uptake: A review of particulate and nano-nickel endocytosis and toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Muñoz, Alexandra; Costa, Max, E-mail: Max.Costa@nyumc.org

    2012-04-01

    Nickel (Ni) is a worldwide pollutant and contaminant that humans are exposed to through various avenues resulting in multiple toxic responses — most alarming is its clear carcinogenic nature. A variety of particulate Ni compounds persist in the environment and can be distinguished by characteristics such as solubility, structure, and surface charge. These characteristics influence cellular uptake and toxicity. Some particulate forms of Ni are carcinogenic and are directly and rapidly endocytized by cells. A series of studies conducted in the 1980s observed this process, and we have reanalyzed the results of these studies to help elucidate the molecular mechanism of particulate Ni uptake. Originally the process of uptake observed was described as phagocytosis, however in the context of recent research we hypothesize that the process is macropinocytosis and/or clathrin mediated endocytosis. Primary considerations in determining the route of uptake here include calcium dependence, particle size, and inhibition through temperature and pharmacological approaches. Particle characteristics that influenced uptake include size, charge, surface characteristics, and structure. This discussion is relevant in the context of nanoparticle studies and the emerging interest in nano-nickel (nano-Ni), where toxicity assessments require a clear understanding of the parameters of particulate uptake and where establishment of such parameters is often obscured through inconsistencies across experimental systems. In this regard, this review aims to carefully document one system (particulate nickel compound uptake) and characterize its properties.

  2. Bioassay-guided isolation of active principles from Nigerian medicinal plants identifies new trypanocides with low toxicity and no cross-resistance to diamidines and arsenicals.

    Science.gov (United States)

    Ebiloma, Godwin Unekwuojo; Igoli, John Ogbaji; Katsoulis, Evangelos; Donachie, Anne-Marie; Eze, Anthonius; Gray, Alexander Ian; de Koning, Harry P

    2017-04-18

    Leaves from the plant species studied herein are traditionally used in northern Nigeria against various protozoan infections. However, none of these herbal preparations have been standardized, nor have their toxicity to mammalian cells been investigated. In search of improved and non-toxic active antiprotozoal principles that are not cross-resistant with current anti-parasitics, we here report the results of the in vitro screening of extracts from seven selected medicinal plant species (Centrosema pubescens, Moringa oleifera, Tridax procumbens, Polyalthia longifolia, Newbouldia laevis, Eucalyptus maculate, Jathropha tanjorensis), used traditionally to treat kinetoplastid infections in Nigeria, and the isolation of their bioactive principles. To investigate the efficacies of medicinal plant extracts, and of compounds isolated therefrom, against kinetoplastid parasites, assess cross-resistance to existing chemotherapy, and assay their toxicity against mammalian cells in vitro. Plants were extracted with hexane, ethyl acetate and methanol. Active principles were isolated by bioassay-led fractionation, testing for trypanocidal activity, and identified using NMR and mass spectrometry. EC 50 values for their activity against wild-type and multi-drug resistant Trypanosoma brucei were obtained using the viability indicator dye resazurin. Seven medicinal plants were evaluated for activity against selected kinetoplastid parasites. The result shows that crude extracts and isolated active compounds from Polyalthia longifolia and Eucalyptus maculata, in particular, display promising activity against drug-sensitive and multi-drug resistant Trypanosoma brucei. The EC 50 value of a clerodane (16α-hydroxy-cleroda-3,13(14)-Z-dien-15,16-olide) isolated from Polyalthia longifolia was as low as 0.38µg/mL, while a triterpenoid (3β,13β-dihydroxy-urs-11-en-28-oic acid) isolated from Eucalyptus maculata displayed an EC 50 of 1.58µg/mL. None of the isolated compounds displayed toxicity

  3. Nanoparticulate-induced toxicity and related mechanism in vitro and in vivo

    International Nuclear Information System (INIS)

    Kim, Hye Won; Ahn, Eun-Kyung; Jee, Bo Keun; Yoon, Hyoung-Kyu; Lee, Kweon Haeng; Lim, Young

    2009-01-01

    In urban areas, the quantity of exhaust particles from vehicle emissions is tremendous and has been regarded as the main contributor to particulate matter (PM) pollution. Recently, the nano-sized PM on public health has begun to raise the attention. The increased toxicity of nanoparticulate can be largely explained by their small size, high airborne concentration, extensive surface area and high content of organic carbon and transition metals. We have attempted to address the toxicity of nano sized-particlulate matter by comparing various particulates including micro-SiO 2 (mSiO 2 ), nano-SiO 2 (nSiO 2 ), micro-TiO 2 (mTiO 2 ), and nano-TiO 2 (nTiO 2 ) in RAW264.7 cells and in vivo. The cell viability of all particulates decreased dose dependently. 24-h incubation with nSiO2 demonstrated apoptosis in RAW264.7 using Annexin-V binding immunofluorescent microscopy, but not in any other particulates. In vivo, cytotoxicity of nanosized was higher than micro-sized particulates. As higher the concentration of particulates, the more pulmonary injury and neutrophilic infiltration were observed in nano-sized than micro-sized particulates, respectively. Particularly, 5.0 mg/kg of mTiO 2 never shows any increase of neutrophile even with high cellularity of total cells and macrophages. From these results, we suggested that particulate-induced respiratory toxicity be influenced by component, size, and dose of particulates including the characteristic nature of the target cells in vitro and in vivo.

  4. Effectiveness and Mechanisms of Antagonism of Toxic Effects of Cyanide by Alpha-Keto Acids.

    Science.gov (United States)

    1986-12-31

    until the miss-w near death. Lethal blood levels of cyanide in alpha-KG treated animl. as levels of 5-7 mcg cyani0e, which so 5-7 times the expected...lethal levels . rwm these studies, alpha-KC is effettive in antagonising administered dos of CH of five time the lethal dose before the toxic effects are...parameters in the dog .................. 26 Table 6 The effects of cyanide on 2,3 diphosphoglyceric acid .......... 28 Table 7 Stability of solution of ci

  5. VARIATIONS IN REPRODUCTIVE TOXICANT IDENTIFICATION

    Energy Technology Data Exchange (ETDEWEB)

    Simmons, F

    2008-05-13

    Reproductive toxicants are a very important class of compounds. They present unique hazards to those of child bearing ages, perform their 'dirty work' using a wide variety of mechanisms on a number of different organs, and are regulatorily important. Because of all of this, properly identifying reproductive toxicants is important, but fraught with difficulty. In this paper we will describe types or reproductive toxicants, their importance, and both mistakes and good practices that people who are not experts in reproductive toxicology may use in their attempts to identify them. Additionally, this paper will focus on chemical reproductive toxicants and will not address biological agents that could affect reproductive toxicity although many principles outlined here could be applied to that endeavor.

  6. Vitiligo blood transcriptomics provides new insights into disease mechanisms and identifies potential novel therapeutic targets.

    Science.gov (United States)

    Dey-Rao, Rama; Sinha, Animesh A

    2017-01-28

    Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy. Unsupervised clustering methods of the VL-blood dataset demonstrate a "disease-state"-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as "hidden" (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional "hot spot" that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets. We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address

  7. A high throughput live transparent animal bioassay to identify non-toxic small molecules or genes that regulate vertebrate fat metabolism for obesity drug development

    Directory of Open Access Journals (Sweden)

    Woollett Laura A

    2008-08-01

    Full Text Available Abstract Background The alarming rise in the obesity epidemic and growing concern for the pathologic consequences of the metabolic syndrome warrant great need for development of obesity-related pharmacotherapeutics. The search for such therapeutics is severely limited by the slow throughput of animal models of obesity. Amenable to placement into a 96 well plate, zebrafish larvae have emerged as one of the highest throughput vertebrate model organisms for performing small molecule screens. A method for visually identifying non-toxic molecular effectors of fat metabolism using a live transparent vertebrate was developed. Given that increased levels of nicotinamide adenine dinucleotide (NAD via deletion of CD38 have been shown to prevent high fat diet induced obesity in mice in a SIRT-1 dependent fashion we explored the possibility of directly applying NAD to zebrafish. Methods Zebrafish larvae were incubated with daily refreshing of nile red containing media starting from a developmental stage of equivalent fat content among siblings (3 days post-fertilization, dpf and continuing with daily refreshing until 7 dpf. Results PPAR activators, beta-adrenergic agonists, SIRT-1 activators, and nicotinic acid treatment all caused predicted changes in fat, cholesterol, and gene expression consistent with a high degree of evolutionary conservation of fat metabolism signal transduction extending from man to zebrafish larvae. All changes in fat content were visually quantifiable in a relative fashion using live zebrafish larvae nile red fluorescence microscopy. Resveratrol treatment caused the greatest and most consistent loss of fat content. The resveratrol tetramer Vaticanol B caused loss of fat equivalent in potency to resveratrol alone. Significantly, the direct administration of NAD decreased fat content in zebrafish. Results from knockdown of a zebrafish G-PCR ortholog previously determined to decrease fat content in C. elegans support that future GPR

  8. Light-activated phenalen-1-one bactericides: efficacy, toxicity and mechanism compared with benzalkonium chloride.

    Science.gov (United States)

    Muehler, Denise; Sommer, Kerstin; Wennige, Sara; Hiller, Karl-Anton; Cieplik, Fabian; Maisch, Tim; Späth, Andreas

    2017-11-01

    Five photoactive compounds with variable elongated alkyl-substituents in a phenalen-1-one structure were examined in view of structural similarity to the antimicrobial agent benzalkonium chloride (BAC). All phenalen-1-ones and BAC were evaluated for their antimicrobial properties against Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, Pseudomonas aeruginosa and for their eukaryotic toxicity against normal human epidermal keratinocyte (NHEK) cells to narrow down the BAC-like effect and the photodynamic effect depending on the chemical structure. All compounds were investigated for effective concentration ranges, where a bacterial reduction of 5 log 10 is achieved, while an NHEK survival of 80% is ensured. Effective concentration ranges were found for four out of five photoactive compounds, but not for BAC and the compound with BAC-like alkyl chain length. Chain length size and polar area of the respective head-groups of phenalen-1-one compounds or BAC showed an influence on the incorporation inside lipid membranes and thus, head-groups may have an impact on the toxicity of antimicrobials.

  9. The harmful chemistry behind krokodil (desomorphine) synthesis and mechanisms of toxicity.

    Science.gov (United States)

    Alves, Emanuele Amorim; Grund, Jean-Paul Cornelis; Afonso, Carlos Manuel; Netto, Annibal Duarte Pereira; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

    2015-04-01

    "Krokodil" is the street name for the homemade injectable mixture that has been used as a cheap substitute for heroin. Its use begun in Russia and Ukraine and nowadays is being spread over several other countries. Desomorphine is the semi-synthetic opioid claimed to be the main component of krokodil and considered to be responsible for its psychoactive characteristics. The starting materials for desomorphine synthesis are codeine tablets, alkali solutions, organic solvent, acidified water, iodine and red phosphorus, all of which are easily available in retail outlets, such as supermarkets, drugstores, etc. The resulting product is a light brown liquid that is called krokodil. People who inject krokodil present a great variety of serious signs and symptoms, including thrombophlebitis, ulcerations, gangrene, and necrosis, quickly evolving to limb amputation and death. These effects are thought to result from the toxic components produced as byproducts during the homemade drug synthesis. In this work, we reviewed several aspects of krokodil use, including its epidemiology, pharmacology and the chemical properties of the main active ingredient (desomorphine). To enhance our understanding of the clinical and toxic effects and to support the implementation of harm reduction measures, we also describe the "bathtub chemistry" of krokodil and the content of the final solution. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Probing molecular mechanisms of the Hsp90 chaperone: biophysical modeling identifies key regulators of functional dynamics.

    Directory of Open Access Journals (Sweden)

    Anshuman Dixit

    Full Text Available Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based "conformational selection" of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected

  11. The Vallecas Project: a cohort to identify early markers and mechanisms of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Javier eOlazarán

    2015-09-01

    Full Text Available Introduction. Alzheimer’s disease (AD is a major threat for the well-being of an increasingly aged world population. The physiopathological mechanisms of late-onset AD are multiple, possibly heterogeneous, and not well understood. Different combinations of variables from several domains (i.e., clinical, neuropsychological, structural, and biochemical markers may predict dementia conversion, according to distinct physiopathological pathways, in different groups of subjects. Methods. We launched the Vallecas Project (VP, a cohort study of non-demented people aged 70 to 85, to characterize the social, clinical, neuropsychological, structural, and biochemical underpinnings of AD inception. Given the exploratory nature of the VP, multidimensional and machine learning techniques will be applied, in addition to the traditional multivariate statistical methods. Results. A total of 1,169 subjects were recruited between October 2011 and December 2013. Mean age was 74.4 years (SD 3.9, 63.5% of the subjects were women, and 17.9% of the subjects were carriers of at least one ε4 allele of the apolipoprotein E (APOE gene. Cognitive diagnoses at inclusion were as follows: normal cognition 93.0% and mild cognitive impairment (MCI 7.0% (3.1% amnestic MCI, 0.1% non-amnestic MCI, 3.8% mixed MCI. Blood samples were obtained and stored for future determinations in 99.9% of the subjects and 3T magnetic resonance imaging (MRI study was conducted in 89.9% of the volunteers. The cohort is being followed up annually for four years after the baseline. Conclusion. We have established a valuable homogeneous single-center cohort which, by identifying groups of variables associated with high risk of MCI or dementia conversion, should help to clarify the early physiopathological mechanisms of AD and should provide avenues for prompt diagnosis and AD prevention.

  12. Isotopic evidence for identifying the mechanism of salinization of groundwater in Bacolod City,Negros Occidental

    International Nuclear Information System (INIS)

    Castaneda, Soledad S.; Almoneda, Rosalinda V.; Sucgang, Raymond J.; Desengano, Daisy; Lim, Fatima

    2008-01-01

    Saline water is easily identified by measurement of the conductivity of the ionic species in the water. In groundwater, it is important to identify the mechanism of salinization for proper management of the resource. Salinization may come from: a) leaching of salts by percolating water, b) intrusion of modern saltwater bodies of connate water, and c) concentration of dissolved salts due to evaporation. The salinity and isotopic concentrations of 18 O, 2 H, and 3 H of the water sources were used to assess the processes which lead to the salinization of groundwater in Bacolod City, Negros Occidental. The isotopic composition of deep groundwater, river water, and springs cluster along the LMWL with δ 18 O ranging from -7.9 ''promille'' to -6.5 ''promille'' and δ 2 H ranging from -52.6 ''promille'' to -39.1''promille''. Two isotopically distinct groups of deep groundwater were deleated; the higher elevation wells yielding isotopically depleted waters while the lowland wells yielding relatively enriched water with higher conductivity. The shallow coastal wells exhibited more enriched isotope values with δ 18 O values from 6.10 ''promille''-5.61''promille'' and δ 2 H from -43.1''promille'' to -38.8''promille'' and highest conductivity. The relative enrichment in the isotopic composition of the deep groundwater in the lowland and the shallow groundwater along the coast is attributed to saltwater intrusion. The process of salinization in these waters is differentiated based on the relationship between their isotopic compositions and the chlorine concentrations. The high salinity of the isotopically enriched and old deep groundwater inland is attributed to mixing with connate water. On the other hand , mixing with modern sea water is evident in the deep and shallow coastal wells. (author)

  13. Computational consideration on advanced oxidation degradation of phenolic preservative, methylparaben, in water: mechanisms, kinetics, and toxicity assessments

    Energy Technology Data Exchange (ETDEWEB)

    Gao, Yanpeng [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); An, Taicheng, E-mail: antc99@gig.ac.cn [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); Fang, Hansun [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Ji, Yuemeng; Li, Guiying [State Key Laboratory of Organic Geochemistry and Guangdong Key Laboratory of Environmental Resources Utilization and Protection, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640 (China)

    2014-08-15

    Graphical abstract: - Highlights: • Computational approach is effective to reveal the transformation mechanism of MPB. • MPB degradation was more dependent on the [{sup •} OH] than temperature during AOPs. • O{sub 2} could enhance MPB degradation, but more harmful products were formed. • The risks of MPB products in natural waters should be considered seriously. • The risks of MPB products can be overlooked in AOPs due to short half-time. - Abstract: Hydroxyl radicals ({sup •} OH) are strong oxidants that can degrade organic pollutants in advanced oxidation processes (AOPs). The mechanisms, kinetics, and toxicity assessment of the {sup •} OH-initiated oxidative degradation of the phenolic preservative, methylparaben (MPB), were systematically investigated using a computational approach, as the supplementary information for experimental data. Results showed that MPB can be initially attacked by {sup •} OH via OH-addition and H-abstraction routes. Among these routes, the {sup •} OH addition to the C atom at the ortho-position of phenolic hydroxyl group was the most significant route. However, the methyl-H-abstraction route also cannot be neglected. Further, the formed transient intermediates, OH-adduct ({sup •} MPB-OH{sub 1}) and dehydrogenated radical ({sup •} MPB(-H)α), could be easily transformed to several stable degradation products in the presence of O{sub 2} and {sup •} OH. To better understand the potential toxicity of MPB and its products to aquatic organisms, both acute and chronic toxicities were assessed computationally at three trophic levels. Both MPB and its products, particularly the OH-addition products, are harmful to aquatic organisms. Therefore, the application of AOPs to remove MPB should be carefully performed for safe water treatment.

  14. Rapid Inhibition Profiling in Bacillus subtilis to Identify the Mechanism of Action of New Antimicrobials.

    Science.gov (United States)

    Lamsa, Anne; Lopez-Garrido, Javier; Quach, Diana; Riley, Eammon P; Pogliano, Joe; Pogliano, Kit

    2016-08-19

    Increasing antimicrobial resistance has become a major public health crisis. New antimicrobials with novel mechanisms of action (MOA) are desperately needed. We previously developed a method, bacterial cytological profiling (BCP), which utilizes fluorescence microscopy to rapidly identify the MOA of antimicrobial compounds. BCP is based upon our discovery that cells treated with antibiotics affecting different metabolic pathways generate different cytological signatures, providing quantitative information that can be used to determine a compound's MOA. Here, we describe a system, rapid inhibition profiling (RIP), for creating cytological profiles of new antibiotic targets for which there are currently no chemical inhibitors. RIP consists of the fast, inducible degradation of a target protein followed by BCP. We demonstrate that degrading essential proteins in the major metabolic pathways for DNA replication, transcription, fatty acid biosynthesis, and peptidoglycan biogenesis in Bacillus subtilis rapidly produces cytological profiles closely matching that of antimicrobials targeting the same pathways. Additionally, RIP and antibiotics targeting different steps in fatty acid biosynthesis can be differentiated from each other. We utilize RIP and BCP to show that the antibacterial MOA of four nonsteroidal anti-inflammatory antibiotics differs from that proposed based on in vitro data. RIP is a versatile method that will extend our knowledge of phenotypes associated with inactivating essential bacterial enzymes and thereby allow for screening for molecules that inhibit novel essential targets.

  15. Mechanism of myocardial toxicity induced by bupivacaine%布比卡因致心肌毒性的机制

    Institute of Scientific and Technical Information of China (English)

    段然

    2016-01-01

    Bupivacaine has become a widely used local anesthetic,but exhibits a strong tendency to cardiac toxicity when accidentally administered intravenously.Numerous animals studies aimed at elucidating the mechanism of bupivacaine's cardiotoxicity focused on the direct inhibition of myocardial.However,recent studies have led to speculating that the cardiovascular toxicity of bupivacaine is mediated,at least in part,by drug actions within the central nervous system.It has been found that epinephrine,a β-adrenergic agonist,can not rescue or even exacerbate the cardiotoxicity of bupivacaine.Experiments are needed to explore further the underlying mechanism.%布比卡因误入血管后会引起严重的心脏毒性.布比卡因的心脏毒性不仅具有直接的心肌毒性作用,而且能够通过中枢神经系统引起间接的心肌毒性.最近报道称布比卡因过量或误入血管能够引起交感神经系统异常兴奋.同时,临床研究显示肾上腺素不能解救甚至会加重布比卡因的心脏中毒,但其机制仍需进一步证实.

  16. Trichothecene Mycotoxins Inhibit Mitochondrial Translation—Implication for the Mechanism of Toxicity

    Directory of Open Access Journals (Sweden)

    Susan McCormick

    2011-12-01

    Full Text Available Fusarium head blight (FHB reduces crop yield and results in contamination of grains with trichothecene mycotoxins. We previously showed that mitochondria play a critical role in the toxicity of a type B trichothecene. Here, we investigated the direct effects of type A and type B trichothecenes on mitochondrial translation and membrane integrity in Saccharomyces cerevisiae. Sensitivity to trichothecenes increased when functional mitochondria were required for growth, and trichothecenes inhibited mitochondrial translation at concentrations, which did not inhibit total translation. In organello translation in isolated mitochondria was inhibited by type A and B trichothecenes, demonstrating that these toxins have a direct effect on mitochondrial translation. In intact yeast cells trichothecenes showed dose-dependent inhibition of mitochondrial membrane potential and reactive oxygen species, but only at doses higher than those affecting mitochondrial translation. These results demonstrate that inhibition of mitochondrial translation is a primary target of trichothecenes and is not secondary to the disruption of mitochondrial membranes.

  17. Resistance may be an important mechanism by which marine microbes respond to environmental toxicants*1

    Science.gov (United States)

    Capriulo, Gerard M.; Flanzenbaum, Jeffrey; Wurster, Charles F.; Rowland, R. George

    1983-11-01

    The hypothesis, that at least certain marine microbial organisms respond to toxic stress by the development of resistance, was tested using the hypotric marine ciliate Euplotes vannus Muller as the test organism. Resistance to polychlorinated biphenyls (PCB, Aroclor 1254) was developed in E. vannus by exposing the animals to progressively higher PCB concentrations during a period of several months. The resistance to PCB persisted for at least 80 days (greater than 40 generations) after final exposure. This suggests either that genetic selection or persistent (lasting over many cell division cycles) phenotypic trait modification, possibly in the form of Dauermodification, had occurred. If resistance were widespread among marine microbial organisms in polluted environments it would be an important consideration in evaluating the long-term biological impact of both natural and man-induced chemical stress.

  18. Molecular interaction of 2-mercaptobenzimidazole with catalase reveals a potentially toxic mechanism of the inhibitor.

    Science.gov (United States)

    Teng, Yue; Zou, Luyi; Huang, Ming; Zong, Wansong

    2014-12-01

    2-Mercaptobenzimidazole (MBI) is widely utilized as a corrosion inhibitor, copper-plating brightener and rubber accelerator. The residue of MBI in the environment possesses a potential risk to human health. In this work, the toxic interaction of MBI with the important antioxidant enzyme catalase (CAT) was investigated using spectroscopic and molecular docking methods under physiological conditions. MBI can spontaneously bind with CAT with one binding site through hydrogen bonds and van der Waals forces to form MBI-CAT complex. The molecular docking study revealed that MBI bound into the CAT interface of chains B and C, which led to some conformational and microenvironmental changes of CAT and further resulted in the inhibition of CAT activity. This present study provides direct evidence at a molecular level to show that exposure to MBI could induce changes in the structure and function of the enzyme CAT. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Oxidative degradation of triclosan by potassium permanganate: Kinetics, degradation products, reaction mechanism, and toxicity evaluation.

    Science.gov (United States)

    Chen, Jing; Qu, Ruijuan; Pan, Xiaoxue; Wang, Zunyao

    2016-10-15

    In this study, we systematically investigated the potential applicability of potassium permanganate for removal of triclosan (TCS) in water treatment. A series of kinetic experiments were carried out to study the influence of various factors, including the pH, oxidant doses, temperature, and presence of typical anions (Cl(-), SO4(2-), NO3(-)), humic acid (HA), and fulvic acid (FA) on triclosan removal. The optimal reaction conditions were: pH = 8.0, [TCS]0:[KMnO4]0 = 1:2.5, and T = 25 °C, where 20 mg/L of TCS could be completely degraded in 120 s. However, the rate of TCS (20 μg/L) oxidation by KMnO4 ([TCS]0:[KMnO4]0 = 1:2.5) was 1.64 × 10(-3) mg L(-1)·h(-1), lower than that at an initial concentration of 20 mg/L (2.24 × 10(3) mg L(-1)·h(-1)). A total of eleven products were detected by liquid chromatography-quadrupole-time-of-flight-mass spectrometry (LC-Q-TOF-MS) analysis, including phenol and its derivatives, benzoquinone, an organic acid, and aldehyde. Two main reaction pathways involving CO bond cleavage (-C(8)O(7)-) and benzene ring opening (in the less chlorinated benzene ring) were proposed, and were further confirmed based on frontier electron density calculations and point charges. Furthermore, the changes in the toxicity of the reaction solution during TCS oxidation by KMnO4 were evaluated by using both the luminescent bacteria Photobacterium phosphoreum and the water flea Daphnia magna. The toxicity of 20 mg/L triclosan to D. magna and P. phosphoreum after 60 min was reduced by 95.2% and 43.0%, respectively. Phenol and 1,4-benzoquinone, the two representative degradation products formed during permanganate oxidation, would yield low concentrations of DBPs (STHMFP, 20.99-278.97 μg/mg; SHAAFP, 7.86 × 10(-4)-45.77 μg/mg) after chlorination and chloramination. Overall, KMnO4 can be used as an effective oxidizing agent for TCS removal in water and wastewater treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Atom Tunneling in the Hydroxylation Process of Taurine/α-Ketoglutarate Dioxygenase Identified by Quantum Mechanics/Molecular Mechanics Simulations.

    Science.gov (United States)

    Álvarez-Barcia, Sonia; Kästner, Johannes

    2017-06-01

    Taurine/α-ketoglutarate dioxygenase is one of the most studied α-ketoglutarate-dependent dioxygenases (αKGDs), involved in several biotechnological applications. We investigated the key step in the catalytic cycle of the αKGDs, the hydrogen transfer process, by a quantum mechanics/molecular mechanics approach (B3LYP/CHARMM22). Analysis of the charge and spin densities during the reaction demonstrates that a concerted mechanism takes place, where the H atom transfer happens simultaneously with the electron transfer from taurine to the Fe═O cofactor. We found the quantum tunneling of the hydrogen atom to increase the rate constant by a factor of 40 at 5 °C. As a consequence, a quite high kinetic isotope effect close to 60 is obtained, which is consistent with the experimental value.

  1. Study on the mechanism of toxicity development by analysis of interactions among RI-labelled biopolymers

    International Nuclear Information System (INIS)

    Koizumi, Shinji

    1997-01-01

    In order to find the directly targetting molecule(s) of toxic substances which are produced in various working environments and to elucidate the natural functions of such molecules in the body. The interactions between an assumed target molecule, ZRF and a sequence in metallothionein II A gene, MRE were investigated using electrophoresis. When double stranded DNA of which binding region was labelled with 32 P was mixed with ZRF, any DNA-protein complex was not detectable on denatured polyacrylamide gel electrophoresis, but Zn-dependent complex formation was observed when labelled in the presence of BrdUTP and the specific band disappeared after the treatment with nuclease. And UV radiation was essential for the complex formation under the conditions of denatured gel, however the complex formed by un-denatured gel electrophoresis was markedly reduced by UV radiation, indicating that the cross-linking reaction should be done at a low dose of UV. Since the nuclease preparation used was contaminated with protease, it was needed to choose an appropriate amount of the preparation. Although there remain some problems, it was found that the present procedure by SDS-polyacrylamide gel electrophoresis was available for detection of the cross-linking between DNA and protein. (M.N.)

  2. Epigenetics as a mechanism linking developmental exposures to long-term toxicity

    DEFF Research Database (Denmark)

    Barouki, R; Melén, E; Herceg, Z

    2018-01-01

    A variety of experimental and epidemiological studies lend support to the Developmental Origin of Health and Disease (DOHaD) concept. Yet, the actual mechanisms accounting for mid- and long-term effects of early-life exposures remain unclear. Epigenetic alterations such as changes in DNA methylat......A variety of experimental and epidemiological studies lend support to the Developmental Origin of Health and Disease (DOHaD) concept. Yet, the actual mechanisms accounting for mid- and long-term effects of early-life exposures remain unclear. Epigenetic alterations such as changes in DNA...

  3. Mechanisms of toxicity and biomarkers of flavoring and flavor enhancing chemicals in emerging tobacco and non-tobacco products.

    Science.gov (United States)

    Kaur, Gurjot; Muthumalage, Thivanka; Rahman, Irfan

    2018-05-15

    Tobacco products containing flavorings, such as electronic nicotine delivery devices (ENDS) or e-cigarettes, cigars/cigarillos, waterpipes, and heat-not-burn devices (iQOS) are continuously evolving. In addition to increasing the exposure of teenagers and adults to nicotine containing flavoring products and flavoring enhancers, chances of nicotine addiction through chronic use and abuse also increase. These flavorings are believed to be safe for ingestion, but little information is available about their effects on the lungs. In this review, we have discussed the in vitro and in vivo data on toxicity of flavoring chemicals in lung cells. We have further discussed the common flavoring agents, such as diacetyl and menthol, currently available detection methods, and the toxicological mechanisms associated with oxidative stress, inflammation, mucociliary clearance, and DNA damage in cells, mice, and humans. Finally, we present potential biomarkers that could be utilized for future risk assessment. This review provides crucial parameters important for evaluation of risk associated with flavoring agents and flavoring enhancers used in tobacco products and ENDS. Future studies can be designed to address the potential toxicity of inhaled flavorings and their biomarkers in users as well as in chronic exposure studies. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Inhibitory and toxic effects of extracellular self-DNA in litter: a mechanism for negative plant-soil feedbacks?

    Science.gov (United States)

    Mazzoleni, Stefano; Bonanomi, Giuliano; Incerti, Guido; Chiusano, Maria Luisa; Termolino, Pasquale; Mingo, Antonio; Senatore, Mauro; Giannino, Francesco; Cartenì, Fabrizio; Rietkerk, Max; Lanzotti, Virginia

    2015-02-01

    Plant-soil negative feedback (NF) is recognized as an important factor affecting plant communities. The objectives of this work were to assess the effects of litter phytotoxicity and autotoxicity on root proliferation, and to test the hypothesis that DNA is a driver of litter autotoxicity and plant-soil NF. The inhibitory effect of decomposed litter was studied in different bioassays. Litter biochemical changes were evaluated with nuclear magnetic resonance (NMR) spectroscopy. DNA accumulation in litter and soil was measured and DNA toxicity was assessed in laboratory experiments. Undecomposed litter caused nonspecific inhibition of root growth, while autotoxicity was produced by aged litter. The addition of activated carbon (AC) removed phytotoxicity, but was ineffective against autotoxicity. Phytotoxicity was related to known labile allelopathic compounds. Restricted (13) C NMR signals related to nucleic acids were the only ones negatively correlated with root growth on conspecific substrates. DNA accumulation was observed in both litter decomposition and soil history experiments. Extracted total DNA showed evident species-specific toxicity. Results indicate a general occurrence of litter autotoxicity related to the exposure to fragmented self-DNA. The evidence also suggests the involvement of accumulated extracellular DNA in plant-soil NF. Further studies are needed to further investigate this unexpected function of extracellular DNA at the ecosystem level and related cellular and molecular mechanisms. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  5. Caesium accumulation by microorganisms: uptake mechanisms, cation competition, compartmentalization and toxicity

    International Nuclear Information System (INIS)

    Avery, S.V.

    1995-01-01

    The continued release of caesium radioisotopes into the environment has led to a resurgence of interest in microbe-Cs interactions. Caesium exists almost exclusively as the monovalent cation Cs + in the natural environment. Although Cs + is a weak Lewis acid that exhibits a low tendency to form complexes with ligands, its chemical similarity to the biologically essential alkali cation K + facilitates high levels of metabolism-dependent intracellular accumulation. Microbial Cs + (K + ) uptake is generally mediated by monovalent cation transport systems located on the plasma membrane. These differ widely in specificity for alkali cations and consequently microorganisms display large differences in their ability to accumulate Cs + ; Cs + appears to have an equal or greater affinity than K + for transport in certain microorganisms. Microbial Cs + accumulation is markedly influenced by the presence of external cations, e.g. K + , Na + , NH 4 + and H + , and is generally accompanied by an approximate stoichiometric exchange for intracellular K + . However, stimulation of growth of K + -starved microbial cultures by Cs + is limited and it has been proposed that it is not the presence of Cs + in cells that is growth inhibitory but rather the resulting loss of K + . Increased microbial tolerance to Cs + may result from sequestration of Cs + in vacuoles or changes in the activity and/or specificity of transport systems mediating Cs + uptake. The precise intracellular target(s) for Cs + - induced toxicity has yet to be clearly defined, although certain internal structures, e.g. ribosomes, become unstable in the presence of Cs + and Cs + is known to substitute poorly for K + in the activation of many K + -requiring enzymes. (author)

  6. Assessing mechanisms of toxicant response in the amphipod Melita plumulosa through transcriptomic profiling.

    Science.gov (United States)

    Hook, Sharon E; Osborn, Hannah L; Spadaro, David A; Simpson, Stuart L

    2014-01-01

    This study describes the function of transcripts with altered abundance in the epibenthic amphipod, Melita plumulosa, following whole-sediment exposure to a series of common environmental contaminants. M. plumulosa were exposed for 48 h to sediments spiked and equilibrated with the following contaminants at concentrations predicted to cause sublethal effects to reproduction: porewater ammonia 30 mg L(-1); bifenthrin at 100 μg kg(-1); fipronil at 50 μg kg(-1); 0.6% diesel; 0.3% crude oil; 250 mg Cu kg(-1); 400 mg Ni kg(-1); and 400 mg Zn kg(-1). RNA was extracted and hybridized against a custom Agilent microarray developed for this species. Although the microarray represented a partial transcriptome and not all features on the array could be annotated, unique transcriptomic profiles were generated for each of the contaminant exposures. Hierarchical clustering grouped the expression profiles together by contaminant class, with copper and zinc, the petroleum products and nickel, and the pesticides each forming a distinct cluster. Many of the transcriptional changes observed were consistent with patterns previously described in other crustaceans. The changes in the transcriptome demonstrated that contaminant exposure caused changes in digestive function, growth and moulting, and the cytoskeleton following metal exposure, whereas exposure to petroleum products caused changes in carbohydrate metabolism, xenobiotic metabolism and hormone cycling. Functional analysis of these gene expression profiles can provide a better understanding of modes of toxic action and permits the prediction of mixture effects within contaminated ecosystems. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

  7. A Method for Identifying the Mechanical Parameters in Resistance Spot Welding Machines

    DEFF Research Database (Denmark)

    Wu, Pei; Zhang, Wenqi; Bay, Niels

    2003-01-01

    Mechanical dynamic responses of resistance welding machine have a significant influence on weld quality and electrode service life, it must be considered when the real welding production is carried out or the welding process is stimulated. The mathematical models for characterizing the mechanical...

  8. Brown algae overproduce cell wall polysaccharides as a protection mechanism against the heavy metal toxicity

    International Nuclear Information System (INIS)

    Andrade, Leonardo R.; Leal, Raquel N.; Noseda, Miguel; Duarte, Maria Eugenia R.; Pereira, Mariana S.; Mourao, Paulo A.S.; Farina, Marcos; Amado Filho, Gilberto M.

    2010-01-01

    Brown algae are often used as heavy metal biomonitors and biosorbents because they can accumulate high concentrations of metals. Cation-exchange performed by cell wall polysaccharides is pointed out as the main chemical mechanism for the metal sequestration. Here, we biochemically investigated if the brown alga Padina gymnospora living in a heavy metal contaminated area would modify their polysaccharidic content. We exposed non-living biomass to Cd and Pb and studied the metals adsorption and localization. We found that raw dried polysaccharides, sulfate groups, uronic acids, fucose, mannose, and galactose were significantly higher in contaminated algae compared with the control ones. Metal concentrations adsorbed by non-living biomass were rising comparatively to the tested concentrations. Electron microscopy showed numerous granules in the cell walls and X-ray microanalysis revealed Cd as the main element. We concluded that P. gymnospora overproduces cell wall polysaccharides when exposed to high metal concentrations as a defense mechanism.

  9. Bringing in vitro analysis closer to in vivo: Studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling.

    Science.gov (United States)

    Verheijen, Marcha; Schrooders, Yannick; Gmuender, Hans; Nudischer, Ramona; Clayton, Olivia; Hynes, James; Niederer, Steven; Cordes, Henrik; Kuepfer, Lars; Kleinjans, Jos; Caiment, Florian

    2018-05-24

    Doxorubicin (DOX) is a chemotherapeutic agent of which the medical use is limited due to cardiotoxicity. While acute cardiotoxicity is reversible, chronic cardiotoxicity is persistent or progressive, dose-dependent and irreversible. While DOX mechanisms of action are not fully understood yet, 3 toxicity processes are known to occur in vivo: cardiomyocyte dysfunction, mitochondrial dysfunction and cell death. We present an in vitro experimental design aimed at detecting DOX-induced cardiotoxicity by obtaining a global view of the induced molecular mechanisms through RNA-sequencing. To better reflect the in vivo situation, human 3D cardiac microtissues were exposed to physiologically-based pharmacokinetic (PBPK) relevant doses of DOX for 2 weeks. We analysed a therapeutic and a toxic dosing profile. Transcriptomics analysis revealed significant gene expression changes in pathways related to "striated muscle contraction" and "respiratory electron transport", thus suggesting mitochondrial dysfunction as an underlying mechanism for cardiotoxicity. Furthermore, expression changes in mitochondrial processes differed significantly between the doses. Therapeutic dose reflects processes resembling the phenotype of delayed chronic cardiotoxicity, while toxic doses resembled acute cardiotoxicity. Overall, these results demonstrate the capability of our innovative in vitro approach to detect the three known mechanisms of DOX leading to toxicity, thus suggesting its potential relevance for reflecting the patient situation. Our study also demonstrated the importance of applying physiologically relevant doses during toxicological research, since mechanisms of acute and chronic toxicity differ. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Nanosecond pulsed electric field incorporation technique to predict molecular mechanisms of teratogenicity and developmental toxicity of estradiol-17β on medaka embryos.

    Science.gov (United States)

    Yamaguchi, Akemi; Ishibashi, Hiroshi; Kono, Susumu; Iida, Midori; Uchida, Masaya; Arizono, Koji; Tominaga, Nobuaki

    2018-05-01

    Herein, we propose using a nanosecond pulsed electric field (nsPEF) technique to assess teratogenicity and embryonic developmental toxicity of estradiol-17β (E 2 ) and predict the molecular mechanisms of teratogenicity and embryonic developmental defects caused by E 2 on medaka (Oryzias latipes). The 5 hour post-fertilization embryos were exposed to co-treatment with 10 μm E 2 and nsPEF for 2 hours and then continuously cultured under non-E 2 and nsPEF conditions until hatching. Results documented that the time to hatching of embryos was significantly delayed in comparison to the control group and that typical abnormal embryo development, such as the delay of blood vessel formation, was observed. For DNA microarray analysis, 6 day post-fertilization embryos that had been continuously cultured under the non-E 2 and nsPEF condition after 2 hour co-treatments were used. DNA microarray analysis identified 542 upregulated genes and one downregulated gene in the 6 day post-fertilization embryos. Furthermore, bioinformatic analyses using differentially expressed genes revealed that E 2 exposure affected various gene ontology terms, such as response to hormone stimulus. The network analysis also documented that the estrogen receptor α in the mitogen-activated protein kinase signaling pathway may be involved in regulating several transcription factors, such as FOX, AKT1 and epidermal growth factor receptor. These results suggest that our nsPEF technique is a powerful tool for assessing teratogenicity and embryonic developmental toxicity of E 2 and predict their molecular mechanisms in medaka embryos. Copyright © 2017 John Wiley & Sons, Ltd.

  11. Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

    Science.gov (United States)

    Cagno, Valeria; Andreozzi, Patrizia; D'Alicarnasso, Marco; Jacob Silva, Paulo; Mueller, Marie; Galloux, Marie; Le Goffic, Ronan; Jones, Samuel T.; Vallino, Marta; Hodek, Jan; Weber, Jan; Sen, Soumyo; Janeček, Emma-Rose; Bekdemir, Ahmet; Sanavio, Barbara; Martinelli, Chiara; Donalisio, Manuela; Rameix Welti, Marie-Anne; Eleouet, Jean-Francois; Han, Yanxiao; Kaiser, Laurent; Vukovic, Lela; Tapparel, Caroline; Král, Petr; Krol, Silke; Lembo, David; Stellacci, Francesco

    2018-02-01

    Viral infections kill millions yearly. Available antiviral drugs are virus-specific and active against a limited panel of human pathogens. There are broad-spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (~190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV.

  12. Algorithm of Molecular and Biological Assessment of the Mechanisms of Sensitivity to Drug Toxicity by the Example of Cyclophosphamide.

    Science.gov (United States)

    Telegin, L Yu; Sarmanaev, S Kh; Devichenskii, V M; Tutelyan, V A

    2018-01-01

    Comparative study of the liver, blood, and spleen of DBA/2JSto and BALB/cJLacSto mice sensitive and resistant to acute toxicity of the cyclophosphamide allowed us to reveal basic toxicity biomarkers of this antitumor and immunosuppressive agent. Obtained results can be used for the development of an algorithm for evaluation of toxic effects of drugs and food components.

  13. Non destructive methods for evaluating the mechanical properties of cemented toxic wastes

    Energy Technology Data Exchange (ETDEWEB)

    De Angelis, G. [ENEA, Centro Ricerche Casaccia, Rome (Italy). Dipt. Ambiente

    1999-07-01

    Measurements of resonant frequency and ultrasonic pulse velocity proved quite useful in order to follow the development of mechanical properties of cemented wastes in laboratory scale. Values of the elastic modulus (Young's modulus), shear and Poisson' s ratio have been obtained from these techniques and compared with dimensional movements and mechanical strength determined on the same formulations. The influence of crack formation on resonant frequency and quenching coefficient has also been evaluated in one case, in order to demonstrate the validity of such techniques for verifying any modification in the internal structure of the material. Sclerometric hardness was also determined on small samples and related to the compressive strength. However sclerometric measurements on full scale samples did not prove reliable. [Italian] Misure di frequenza di risonanza e di diffusione degli impulsi ultrasonici si sono rilevate un utile metodo di indagine a livello di laboratorio per meglio comprendere lo sviluppo delle proprieta' meccaniche dei rifiuti tossici condizionati in matrice cementizia. I valori del modulo di elasticita' (o modulo di Young), del modulo a torsione e del rapporto di Poisson, ottenuti mediante queste tecniche, sono stati messi in relazione con le variazioni dimensionali e con le proprieta' meccaniche di campioni ottenuti dallo stesso impasto. In un singolo caso e' stato valutato anche l'effetto che la formazione di crepe nel materiale esercita sul valore del picco di risonanza e sul coefficiente di smorzamento, allo scopo di dimostrare la validita' di queste tecniche nella verifica di modifiche insorte nella struttura interna di tali prodotti. Sono state fatte anche determinazioni di durezza per mezzo dello sclerometro, correlando i valori ottenuti con la resistenza alla compressione, mettendo altresi' in evidenza la non applicabilita' di tale metodo a manufatti preparati industrialmente.

  14. Identifying the Oscillatory Mechanism of the Glucose Oxidase-Catalase Coupled Enzyme System.

    Science.gov (United States)

    Muzika, František; Jurašek, Radovan; Schreiberová, Lenka; Radojković, Vuk; Schreiber, Igor

    2017-10-12

    We provide experimental evidence of periodic and aperiodic oscillations in an enzymatic system of glucose oxidase-catalase in a continuous-flow stirred reactor coupled by a membrane with a continuous-flow reservoir supplied with hydrogen peroxide. To describe such dynamics, we formulate a detailed mechanism based on partial results in the literature. Finally, we introduce a novel method for estimation of unknown kinetic parameters. The method is based on matching experimental data at an oscillatory instability with stoichiometric constraints of the mechanism formulated by applying the stability theory of reaction networks. This approach has been used to estimate rate coefficients in the catalase part of the mechanism. Remarkably, model simulations show good agreement with the observed oscillatory dynamics, including apparently chaotic intermittent behavior. Our method can be applied to any reaction system with an experimentally observable dynamical instability.

  15. Plasma Proteomic Analysis May Identify New Markers for Radiation-Induced Lung Toxicity in Patients With Non-Small-Cell Lung Cancer

    International Nuclear Information System (INIS)

    Cai Xuwi; Shedden, Kerby; Ao Xiaoping; Davis, Mary

    2010-01-01

    Purpose: To study whether radiation induces differential changes in plasma proteomics in patients with and without radiation-induced lung toxicity (RILT) of Grade ≥2 (RILT2). Methods and Materials: A total of 57 patients with NSCLC received radiation therapy (RT) were eligible. Twenty patients, 6 with RILT2 with tumor stage matched to 14 without RILT2, were enrolled for this analysis. Platelet-poor plasma was obtained before RT, at 2, 4, 6 weeks during RT, and 1 and 3 months after RT. Plasma proteomes were compared using a multiplexed quantitative proteomics approach involving ExacTag labeling, reverse-phase high-performance liquid chromatography and nano-LC electrospray tandem mass spectrometry. Variance components models were used to identify the differential protein expression between patients with and without RILT2. Results: More than 100 proteins were identified and quantified. After excluding proteins for which there were not at least 2 subjects with data for at least two time points, 76 proteins remained for this preliminary analysis. C4b-binding protein alpha chain, Complement C3, and Vitronectin had significantly higher expression levels in patients with RILT2 compared with patients without RILT2, based on both the data sets of RT start to 3 months post-RT (p < 0.01) and RT start to the end of RT (p < 0.01). The expression ratios of patients with RILT2 vs. without RILT2 were 1.60, 1.36, 1.46, and 1.66, 1.34, 1.46, for the above three proteins, respectively. Conclusions: This proteomic approach identified new plasma protein markers for future studies on RILT prediction.

  16. Gene expression analysis reveals new possible mechanisms of vancomycin-induced nephrotoxicity and identifies gene markers candidates.

    Science.gov (United States)

    Dieterich, Christine; Puey, Angela; Lin, Sylvia; Lyn, Sylvia; Swezey, Robert; Furimsky, Anna; Fairchild, David; Mirsalis, Jon C; Ng, Hanna H

    2009-01-01

    Vancomycin, one of few effective treatments against methicillin-resistant Staphylococcus aureus, is nephrotoxic. The goals of this study were to (1) gain insights into molecular mechanisms of nephrotoxicity at the genomic level, (2) evaluate gene markers of vancomycin-induced kidney injury, and (3) compare gene expression responses after iv and ip administration. Groups of six female BALB/c mice were treated with seven daily iv or ip doses of vancomycin (50, 200, and 400 mg/kg) or saline, and sacrificed on day 8. Clinical chemistry and histopathology demonstrated kidney injury at 400 mg/kg only. Hierarchical clustering analysis revealed that kidney gene expression profiles of all mice treated at 400 mg/kg clustered with those of mice administered 200 mg/kg iv. Transcriptional profiling might thus be more sensitive than current clinical markers for detecting kidney damage, though the profiles can differ with the route of administration. Analysis of transcripts whose expression was changed by at least twofold compared with vehicle saline after high iv and ip doses of vancomycin suggested the possibility of oxidative stress and mitochondrial damage in vancomycin-induced toxicity. In addition, our data showed changes in expression of several transcripts from the complement and inflammatory pathways. Such expression changes were confirmed by relative real-time reverse transcription-polymerase chain reaction. Finally, our results further substantiate the use of gene markers of kidney toxicity such as KIM-1/Havcr1, as indicators of renal injury.

  17. The Toxicity of Nanoparticles Depends on Multiple Molecular and Physicochemical Mechanisms

    Directory of Open Access Journals (Sweden)

    Yue-Wern Huang

    2017-12-01

    Full Text Available Nanotechnology is an emerging discipline that studies matters at the nanoscale level. Eventually, the goal is to manipulate matters at the atomic level to serve mankind. One growing area in nanotechnology is biomedical applications, which involve disease management and the discovery of basic biological principles. In this review, we discuss characteristics of nanomaterials, with an emphasis on transition metal oxide nanoparticles that influence cytotoxicity. Identification of those properties may lead to the design of more efficient and safer nanosized products for various industrial purposes and provide guidance for assessment of human and environmental health risk. We then investigate biochemical and molecular mechanisms of cytotoxicity that include oxidative stress-induced cellular events and alteration of the pathways pertaining to intracellular calcium homeostasis. All the stresses lead to cell injuries and death. Furthermore, as exposure to nanoparticles results in deregulation of the cell cycle (i.e., interfering with cell proliferation, the change in cell number is a function of cell killing and the suppression of cell proliferation. Collectively, the review article provides insights into the complexity of nanotoxicology.

  18. Transcriptional analysis and molecular dynamics simulations reveal the mechanism of toxic metals removal and efflux pumps in Lysinibacillus sphaericus OT4b.31

    KAUST Repository

    Shaw, Dario Rangel

    2017-11-23

    Lysinibacillus sphaericus strain OT4b.31 is a bacterium widely applied in bioremediation processes of hydrocarbon and metal polluted environments. In this study, we identified the molecular mechanism underlying the Pb2+ and Cr6+ resistance. Metal uptake and temporal transcription patterns of metal resistance operons were evaluated using reverse-transcribed quantitative PCR amplification. The function of the resistance determinants was studied applying docking and in silico mutagenesis methods. The results revealed that the adaptation of Lysinibacillus sphaericus OT4b.31 to elevated levels of lead and chromium involves the pbr and chr operons which comprise a transcriptional regulatory component (pbrR and chrB) and efflux ATPases (pbrA and chrA) to expel ions from the cytoplasm. Expression of metal resistance genes was constitutive and specifically inducible to the exposure of Pb2+ and Cr6+. The simultaneous presence of cations didn\\'t affect the bioaccumulation of metals, evidencing the multimetal resistance of L. sphaericus. Docking analysis revealed the key metal-protein interactions and the conformational changes after metal or ATP binding. Results showed that residues with aromatic rings or imidazole in the catalytic domain are crucial for metal binding and achievement of the function. To our knowledge, this is the first report of a specific mechanism for lead and chromium resistance in Lysinibacillus genus. From the findings of this study, it is possible to suggest the bacterium as a suitable candidate for rapid toxic metals bioremediation processes.

  19. Toxic effects and possible mechanisms of hydrogen sulfide and/or ammonia on porcine oocyte maturation in vitro.

    Science.gov (United States)

    Yang, Lei-Lei; Zhao, Yong; Luo, Shi-Ming; Ma, Jun-Yu; Ge, Zhao-Jia; Shen, Wei; Yin, Shen

    2018-03-15

    Previous studies suggest that hydrogen sulfide (H 2 S) and ammonia (NH 3 ) are two major air pollutants which can cause damage to porcine health. However, the mechanisms underlying toxic effects of these compounds on porcine oocyte maturation are not clear. To clarify the mechanism, we evaluated the oocyte quality by detecting some events during oocytes maturation. In our study, porcine oocytes were cultured with different concentrations of Na 2 S and/or NH 4 Cl in vitro and the rate of the first polar body extrusion decreased significantly. Also, actin filament was seriously disrupted to damage the cytoskeleton which resulted in reduced rate of oocyte maturation. We explored the reactive oxygen species (ROS) generation and found that the ROS level was increased significantly after Na 2 S treatment but not after NH 4 Cl treatment. Moreover, early stage apoptosis rate was significantly increased and autophagy protein LC3 B expression level was higher in oocytes treated with Na 2 S and/or NH 4 Cl, which might be caused by ROS elevation. Additionally, exposure to Na 2 S and/or NH 4 Cl also caused ROS generation and early apoptosis in cumulus cells, which might further affect oocyte maturation in vitro. In summary, our data suggested that exposure to H 2 S and/or NH 3 decreased porcine oocyte maturation in vitro, which might be caused by actin disruption, ROS generation, early apoptosis and autophagy. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Neurofilament phosphorylation and disruption: A possible mechanism of chronic aluminium toxicity in Wistar rats

    International Nuclear Information System (INIS)

    Kaur, Amarpreet; Joshi, Kusum; Minz, Ranjana Walker; Gill, Kiran Dip

    2006-01-01

    The present study was designed to investigate the possible effects of chronic aluminium exposure on neurofilament phosphorylation and its subsequent disruption in various regions of the rat brain. An intra-gastric dose of aluminium (10 mg/kg bw for 12 weeks) resulted in a marked enhancement of Ca 2+ /CaM dependent protein kinase activity as compared to cAMP dependent protein kinase. The levels of phosphoprotein phosphatase were found to be significantly depleted only in the cerebral cortex. After in vitro phosphorylation using [ 32 γ-P] ATP, various proteins were resolved on one-dimensional 8% SDS-PAGE, stained with Coomassie Blue and autoradiographed. The amount of 32 P-incorporated was quantified using ADOPE PHOTOSHOP (7.0). The 200 kDa neurofilament protein was identified using immunoblotting. Finally, the extent of phosphorylation induced neurofilamentous damage was assessed using immunocytochemical studies. The cytoskeletal proteins were found to be aggregated and disrupted in all the three neuronal regions following 12 weeks of aluminium treatment. This study lends further support to the possible role of aluminium as a potent neurotoxic agent and in the etiopathogenisis of various neurodegenerative diseases

  1. How viral capsids adapt to mismatched cargoes—identifying mechanisms of morphology control with simulations

    Science.gov (United States)

    Elrad, Oren

    2009-03-01

    During the replication of many viruses, hundreds to thousands of protein subunits assemble around the viral nucleic acid to form a protein shell called a capsid. Most viruses form one particular structure with astonishing fidelity; yet, recent experiments demonstrate that capsids can assemble with different sizes and morphologies to accommodate nucleic acids or other cargoes such as functionalized nanoparticles. In this talk, we will explore the mechanisms of simultaneous assembly and cargo encapsidation with a computational model that describes the assembly of icosahedral capsids around functionalized nanoparticles. With this model, we find parameter values for which subunits faithfully form empty capsids with a single morphology, but adaptively assemble into different icosahedral morphologies around nanoparticles with different diameters. Analyzing trajectories in which adaptation is or is not successful sheds light on the mechanisms by which capsid morphology may be controlled in vitro and in vivo, and suggests experiments to test these mechanisms. We compare the simulation results to recent experiments in which Brome Mosaic Virus capsid proteins assemble around functionalized nanoparticles, and describe how future experiments can test the model predictions.

  2. Identifying the mechanism : is there a bank lending channel of monetary transmission in the Netherlands?

    NARCIS (Netherlands)

    Kakes, J

    The paper investigates the role of bank lending in the monetary transmission process in the Netherlands. The Johansen approach is used to identify supply and demand relationships in the credit market, and it is concluded from the short-run dynamics that this market is demand-determined. In this way,

  3. Free allocation in the European Emissions Trading System (EU ETS): identifying efficient mechanisms through to 2030

    International Nuclear Information System (INIS)

    Jalard, Matthieu; Alberola, Emilie

    2015-11-01

    In a world with asymmetrical climate policies, the conclusions of the European Council of October 2014 agreed on continuing the allocation of free CO 2 emissions allowances beyond 2020 to industrial sectors in the EU ETS. This statement has been confirmed in the European Commission's proposal to revise EU ETS directive for phase IV disclosed in July 2015. The stated objective is to ensure that the most efficient industrial installations do not face undue carbon costs which would lead to carbon leakages. Furthermore, free allocations should not undermine the incentive to cut CO 2 emissions, lead to distortions or windfall profits and reduce the auctioning share of allowances. From 2013 to 2020, the allocation of free allowances has been defined according to harmonized European rules based on benchmarks (carbon intensity targets) and historical output adjusted to the free allocation cap by applying the Cross-Sectoral Correction Factor (CSCF). What would be the impact of pursuing the current mechanism through to 2030? Does the EU Commissions' proposal of 15 July respond to the Council's requirements? Which alternative mechanisms could do so? This study examines four scenarios and their potential consequences. - Scenario 1 continues the current free allocation mechanism until 2030. The volume of free allocations thus calculated would be higher than the available free allocation cap and would need to be reduced by a Cross-Sectoral Correction Factor (CSCF) of 66% in 2030. Carbon costs would thus increase for all installations, regardless their exposure to carbon leakages, reducing the protection of most exposed sectors, while widely allocating sectors with limited exposure. - Scenario 2 analyses the proposal to implement an allocation mechanism based on recent industrial output combined with appropriate updating of benchmarks. This allocation method is more effective in combating carbon leakage, as it gives clearer incentive to maintain domestic production

  4. Antibacterial mechanisms of a novel type picosecond laser-generated silver-titanium nanoparticles and their toxicity to human cells.

    Science.gov (United States)

    Korshed, Peri; Li, Lin; Liu, Zhu; Mironov, Aleksandr; Wang, Tao

    2018-01-01

    In this study, we explored the antibacterial mechanisms for a novel type of Ag-TiO 2 compound nanoparticles (NPs) produced from an Ag-TiO 2 alloy using a picosecond laser and evaluated the toxicity of the Ag-TiO 2 NPs to a range of human cell types. Transmission electron microscopy was used to determine the morphology, shapes, and size distribution of the laser-generated Ag-TiO 2 NPs. UV-visible spectrometer was used to confirm the shift of light absorbance of the NPs toward visible light wavelength. Results showed that the laser-generated Ag-TiO 2 NPs had significant antibacterial activities against both Gram-negative and Gram-positive bacterial strains, including Escherichia coli, Pseudomonas aeruginosa , and the methicillin-resistant Staphylococcus aureus . Increased level of reactive oxygen species was produced by E. coli after exposure to the Ag-TiO 2 NPs, which was accompanied with lipid peroxidation, glutathione depletion, disintegration of cell membrane and protein leakage, leading to the cell death. Five types of human cells originated from lung (A549), liver (HePG2), kidney (HEK293), endothelium cells (human coronary artery endothelial cells [hCAECs]), and skin (human dermal fibroblast cells [HDFc]) were used to evaluate the cytotoxicity of the laser-generated Ag-TiO 2 NPs. A weak but statistically significant decrease in cell proliferation was observed for hCAECs, A549 and HDFc cells when co-cultured with 2.5 µg/mL or 20 µg/mL of the laser-generated Ag-TiO 2 NPs for 48 hours. However, this effect was no longer apparent when a higher concentration of NPs (20 µg/mL) was used after 72 hours of co-culture with human cells, suggesting a possible adaptive process in the cells had occurred. We conclude that picosecond laser-generated Ag-TiO 2 NPs have a broad spectrum of antibacterial effect, including against the drug-resistant strain, with multiple underlying molecular mechanisms and low human cell toxicity. The antimicrobial properties of the new type of

  5. Identifying deformation mechanisms in the NEEM ice core using EBSD measurements

    Science.gov (United States)

    Kuiper, Ernst-Jan; Weikusat, Ilka; Drury, Martyn R.; Pennock, Gill M.; de Winter, Matthijs D. A.

    2015-04-01

    Deformation of ice in continental sized ice sheets determines the flow behavior of ice towards the sea. Basal dislocation glide is assumed to be the dominant deformation mechanism in the creep deformation of natural ice, but non-basal glide is active as well. Knowledge of what types of deformation mechanisms are active in polar ice is critical in predicting the response of ice sheets in future warmer climates and its contribution to sea level rise, because the activity of deformation mechanisms depends critically on deformation conditions (such as temperature) as well as on the material properties (such as grain size). One of the methods to study the deformation mechanisms in natural materials is Electron Backscattered Diffraction (EBSD). We obtained ca. 50 EBSD maps of five different depths from a Greenlandic ice core (NEEM). The step size varied between 8 and 25 micron depending on the size of the deformation features. The size of the maps varied from 2000 to 10000 grid point. Indexing rates were up to 95%, partially by saving and reanalyzing the EBSP patterns. With this method we can characterize subgrain boundaries and determine the lattice rotation configurations of each individual subgrain. Combining these observations with arrangement/geometry of subgrain boundaries the dislocation types can be determined, which form these boundaries. Three main types of subgrain boundaries have been recognized in Antarctic (EDML) ice core¹². Here, we present the first results obtained from EBSD measurements performed on the NEEM ice core samples from the last glacial period, focusing on the relevance of dislocation activity of the possible slip systems. Preliminary results show that all three subgrain types, recognized in the EDML core, occur in the NEEM samples. In addition to the classical boundaries made up of basal dislocations, subgrain boundaries made of non-basal dislocations are also common. ¹Weikusat, I.; de Winter, D. A. M.; Pennock, G. M.; Hayles, M

  6. Identifying a cooperative control mechanism between an applied field and the environment of open quantum systems

    Science.gov (United States)

    Gao, Fang; Rey-de-Castro, Roberto; Wang, Yaoxiong; Rabitz, Herschel; Shuang, Feng

    2016-05-01

    Many systems under control with an applied field also interact with the surrounding environment. Understanding the control mechanisms has remained a challenge, especially the role played by the interaction between the field and the environment. In order to address this need, here we expand the scope of the Hamiltonian-encoding and observable-decoding (HE-OD) technique. HE-OD was originally introduced as a theoretical and experimental tool for revealing the mechanism induced by control fields in closed quantum systems. The results of open-system HE-OD analysis presented here provide quantitative mechanistic insights into the roles played by a Markovian environment. Two model open quantum systems are considered for illustration. In these systems, transitions are induced by either an applied field linked to a dipole operator or Lindblad operators coupled to the system. For modest control yields, the HE-OD results clearly show distinct cooperation between the dynamics induced by the optimal field and the environment. Although the HE-OD methodology introduced here is considered in simulations, it has an analogous direct experimental formulation, which we suggest may be applied to open systems in the laboratory to reveal mechanistic insights.

  7. Biomechanical approaches to identify and quantify injury mechanisms and risk factors in women's artistic gymnastics.

    Science.gov (United States)

    Bradshaw, Elizabeth J; Hume, Patria A

    2012-09-01

    Targeted injury prevention strategies, based on biomechanical analyses, have the potential to help reduce the incidence and severity of gymnastics injuries. This review outlines the potential benefits of biomechanics research to contribute to injury prevention strategies for women's artistic gymnastics by identification of mechanisms of injury and quantification of the effects of injury risk factors. One hundred and twenty-three articles were retained for review after searching electronic databases using key words, including 'gymnastic', 'biomech*', and 'inj*', and delimiting by language and relevance to the paper aim. Impact load can be measured biomechanically by the use of instrumented equipment (e.g. beatboard), instrumentation on the gymnast (accelerometers), or by landings on force plates. We need further information on injury mechanisms and risk factors in gymnastics and practical methods of monitoring training loads. We have not yet shown, beyond a theoretical approach, how biomechanical analysis of gymnastics can help reduce injury risk through injury prevention interventions. Given the high magnitude of impact load, both acute and accumulative, coaches should monitor impact loads per training session, taking into consideration training quality and quantity such as the control of rotation and the height from which the landings are executed.

  8. Multi-omics approach identifies molecular mechanisms of plant-fungus mycorrhizal interaction

    Directory of Open Access Journals (Sweden)

    Peter E Larsen

    2016-01-01

    Full Text Available In mycorrhizal symbiosis, plant roots form close, mutually beneficial interactions with soil fungi. Before this mycorrhizal interaction can be established however, plant roots must be capable of detecting potential beneficial fungal partners and initiating the gene expression patterns necessary to begin symbiosis. To predict a plant root – mycorrhizal fungi sensor systems, we analyzed in vitro experiments of Populus tremuloides (aspen tree and Laccaria bicolor (mycorrhizal fungi interaction and leveraged over 200 previously published transcriptomic experimental data sets, 159 experimentally validated plant transcription factor binding motifs, and more than 120-thousand experimentally validated protein-protein interactions to generate models of pre-mycorrhizal sensor systems in aspen root. These sensor mechanisms link extracellular signaling molecules with gene regulation through a network comprised of membrane receptors, signal cascade proteins, transcription factors, and transcription factor biding DNA motifs. Modeling predicted four pre-mycorrhizal sensor complexes in aspen that interact with fifteen transcription factors to regulate the expression of 1184 genes in response to extracellular signals synthesized by Laccaria. Predicted extracellular signaling molecules include common signaling molecules such as phenylpropanoids, salicylate, and, jasmonic acid. This multi-omic computational modeling approach for predicting the complex sensory networks yielded specific, testable biological hypotheses for mycorrhizal interaction signaling compounds, sensor complexes, and mechanisms of gene regulation.

  9. Identifying Toxic Impacts of Metals Potentially Released during Deep-Sea Mining—A Synthesis of the Challenges to Quantifying Risk

    Directory of Open Access Journals (Sweden)

    Chris Hauton

    2017-11-01

    Full Text Available In January 2017, the International Seabed Authority released a discussion paper on the development of Environmental Regulations for deep-sea mining (DSM within the Area Beyond National Jurisdiction (the “Area”. With the release of this paper, the prospect for commercial mining in the Area within the next decade has become very real. Moreover, within nations' Exclusive Economic Zones, the exploitation of deep-sea mineral ore resources could take place on very much shorter time scales and, indeed, may have already started. However, potentially toxic metal mixtures may be released at sea during different stages of the mining process and in different physical phases (dissolved or particulate. As toxicants, metals can disrupt organism physiology and performance, and therefore may impact whole populations, leading to ecosystem scale effects. A challenge to the prediction of toxicity is that deep-sea ore deposits include complex mixtures of minerals, including potentially toxic metals such as copper, cadmium, zinc, and lead, as well as rare earth elements. Whereas the individual toxicity of some of these dissolved metals has been established in laboratory studies, the complex and variable mineral composition of seabed resources makes the a priori prediction of the toxic risk of DSM extremely challenging. Furthermore, although extensive data quantify the toxicity of metals in solution in shallow-water organisms, these may not be representative of the toxicity in deep-sea organisms, which may differ biochemically and physiologically and which will experience those toxicants under conditions of low temperature, high hydrostatic pressure, and potentially altered pH. In this synthesis, we present a summation of recent advances in our understanding of the potential toxic impacts of metal exposure to deep-sea meio- to megafauna at low temperature and high pressure, and consider the limitation of deriving lethal limits based on the paradigm of exposure to

  10. Identifying Mechanical Properties of Viscoelastic Materials in Time Domain Using the Fractional Zener Model

    Directory of Open Access Journals (Sweden)

    Ana Paula Delowski Ciniello

    Full Text Available Abstract The present paper aims at presenting a methodology for characterizing viscoelastic materials in time domain, taking into account the fractional Zener constitutive model and the influence of temperature through Williams, Landel, and Ferry’s model. To that effect, a set of points obtained experimentally through uniaxial tensile tests with different constant strain rates is considered. The approach is based on the minimization of the quadratic relative distance between the experimental stress-strain curves and the corresponding ones given by the theoretical model. In order to avoid the local minima in the process of optimization, a hybrid technique based on genetic algorithms and non-linear programming techniques is used. The methodology is applied in the characterization of two different commercial viscoelastic materials. The results indicate that the proposed methodology is effective in identifying thermorheologically simple viscoelastic materials.

  11. Tumor-Protective Mechanism Identified from Premature Aging Disease | Center for Cancer Research

    Science.gov (United States)

    Hutchinson-Gilford Progeria Syndrome (HGPS) is an extraordinarily rare genetic disorder caused by a mutation in the LMNA gene, which encodes architectural proteins of the human cell nucleus. The mutation causes the production of a mutant protein called progerin. Patients with HGPS display signs of premature aging, such as hair loss, slowed growth, weakening of bone and joint integrity, and cardiovascular disease. Most die in their mid-teens of heart disease or stroke. Intriguingly, these patients do not develop another aging-related disease, cancer, despite having dramatically elevated levels of DNA damage. Tom Misteli, Ph.D., of CCR’s Laboratory of Receptor Biology and Gene Expression, and his colleagues hypothesized that, rather than patients not living long enough to develop cancer, a resistance mechanism was operating in HGPS cells to prevent cancer formation. To begin testing this idea, the researchers transformed fibroblasts from HGPS patients or age-matched, healthy controls with telomerase, constitutively-activated HRAS, and SV40 large and small T antigens. Transformed HGPS cells displayed morphological changes and increased proliferation similar to transformed controls but formed fewer colonies in soft agar and fewer tumors when injected into mice. When the investigators examined global gene expression in the two populations of cells, they found that transformed HGPS cells failed to activate many of the genes that are induced in response to transformation in controls, including oncogenic and proliferation pathways. In addition the transformed HGPS cells were unable to undergo oncogenic de-differentiation. Importantly, the tumor resistance in HGPS cells was due to the presence of the progerin protein, which was both necessary and sufficient to protect cells from oncogenic transformation. Together these results suggested that HGPS cells resist cancer-inducing stimuli by not undergoing the genetic reprogramming necessary for tumor initiation. The scientists

  12. ULF Wave Activity in the Magnetosphere: Resolving Solar Wind Interdependencies to Identify Driving Mechanisms

    Science.gov (United States)

    Bentley, S. N.; Watt, C. E. J.; Owens, M. J.; Rae, I. J.

    2018-04-01

    Ultralow frequency (ULF) waves in the magnetosphere are involved in the energization and transport of radiation belt particles and are strongly driven by the external solar wind. However, the interdependency of solar wind parameters and the variety of solar wind-magnetosphere coupling processes make it difficult to distinguish the effect of individual processes and to predict magnetospheric wave power using solar wind properties. We examine 15 years of dayside ground-based measurements at a single representative frequency (2.5 mHz) and a single magnetic latitude (corresponding to L ˜ 6.6RE). We determine the relative contribution to ULF wave power from instantaneous nonderived solar wind parameters, accounting for their interdependencies. The most influential parameters for ground-based ULF wave power are solar wind speed vsw, southward interplanetary magnetic field component Bzstill account for significant amounts of power. We suggest that these three parameters correspond to driving by the Kelvin-Helmholtz instability, formation, and/or propagation of flux transfer events and density perturbations from solar wind structures sweeping past the Earth. We anticipate that this new parameter reduction will aid comparisons of ULF generation mechanisms between magnetospheric sectors and will enable more sophisticated empirical models predicting magnetospheric ULF power using external solar wind driving parameters.

  13. An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

    Science.gov (United States)

    Boldt, Karsten; van Reeuwijk, Jeroen; Lu, Qianhao; Koutroumpas, Konstantinos; Nguyen, Thanh-Minh T; Texier, Yves; van Beersum, Sylvia E C; Horn, Nicola; Willer, Jason R; Mans, Dorus A; Dougherty, Gerard; Lamers, Ideke J C; Coene, Karlien L M; Arts, Heleen H; Betts, Matthew J; Beyer, Tina; Bolat, Emine; Gloeckner, Christian Johannes; Haidari, Khatera; Hetterschijt, Lisette; Iaconis, Daniela; Jenkins, Dagan; Klose, Franziska; Knapp, Barbara; Latour, Brooke; Letteboer, Stef J F; Marcelis, Carlo L; Mitic, Dragana; Morleo, Manuela; Oud, Machteld M; Riemersma, Moniek; Rix, Susan; Terhal, Paulien A; Toedt, Grischa; van Dam, Teunis J P; de Vrieze, Erik; Wissinger, Yasmin; Wu, Ka Man; Apic, Gordana; Beales, Philip L; Blacque, Oliver E; Gibson, Toby J; Huynen, Martijn A; Katsanis, Nicholas; Kremer, Hannie; Omran, Heymut; van Wijk, Erwin; Wolfrum, Uwe; Kepes, François; Davis, Erica E; Franco, Brunella; Giles, Rachel H; Ueffing, Marius; Russell, Robert B; Roepman, Ronald

    2016-05-13

    Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.

  14. Mechanism(s of Toxic Action of Zn2+ and Selenite: A Study on AS-30D Hepatoma Cells and Isolated Mitochondria

    Directory of Open Access Journals (Sweden)

    Elena A. Belyaeva

    2011-01-01

    Full Text Available Mitochondria of AS-30D rat ascites hepatoma cells are found to be the main target for Zn2+ and sodium selenite (Na2SeO3. High [mu]M concentrations of Zn2+ or selenite were strongly cytotoxic, killing the AS-30D cells by both apoptotic and necrotic ways. Both Zn2+ and selenite produced strong changes in intracellular generation of reactive oxygen species (ROS and the mitochondrial dysfunction via the mitochondrial electron transport chain (mtETC disturbance, the membrane potential dissipation, and the mitochondrial permeability transition pore opening. The significant distinctions in toxic action of Zn2+ and selenite on AS-30D cells were found. Selenite induced a much higher intracellular ROS level (the early event compared to Zn2+ but a lower membrane potential loss and a lower decrease of the uncoupled respiration rate of the cells, whereas the mtETC disturbance was the early and critical event in the mechanism of Zn2+ cytotoxicity. Sequences of events manifested in the mitochondrial dysfunction produced by the metal/metalloid under test are compared with those obtained earlier for Cd2+, Hg2+, and Cu2+ on the same model system.

  15. Recursive expectation-maximization clustering: A method for identifying buffering mechanisms composed of phenomic modules

    Science.gov (United States)

    Guo, Jingyu; Tian, Dehua; McKinney, Brett A.; Hartman, John L.

    2010-06-01

    Interactions between genetic and/or environmental factors are ubiquitous, affecting the phenotypes of organisms in complex ways. Knowledge about such interactions is becoming rate-limiting for our understanding of human disease and other biological phenomena. Phenomics refers to the integrative analysis of how all genes contribute to phenotype variation, entailing genome and organism level information. A systems biology view of gene interactions is critical for phenomics. Unfortunately the problem is intractable in humans; however, it can be addressed in simpler genetic model systems. Our research group has focused on the concept of genetic buffering of phenotypic variation, in studies employing the single-cell eukaryotic organism, S. cerevisiae. We have developed a methodology, quantitative high throughput cellular phenotyping (Q-HTCP), for high-resolution measurements of gene-gene and gene-environment interactions on a genome-wide scale. Q-HTCP is being applied to the complete set of S. cerevisiae gene deletion strains, a unique resource for systematically mapping gene interactions. Genetic buffering is the idea that comprehensive and quantitative knowledge about how genes interact with respect to phenotypes will lead to an appreciation of how genes and pathways are functionally connected at a systems level to maintain homeostasis. However, extracting biologically useful information from Q-HTCP data is challenging, due to the multidimensional and nonlinear nature of gene interactions, together with a relative lack of prior biological information. Here we describe a new approach for mining quantitative genetic interaction data called recursive expectation-maximization clustering (REMc). We developed REMc to help discover phenomic modules, defined as sets of genes with similar patterns of interaction across a series of genetic or environmental perturbations. Such modules are reflective of buffering mechanisms, i.e., genes that play a related role in the maintenance

  16. The toxicity and the acaricidal mechanism against Psoroptes cuniculi of the methanol extract of Adonis coerulea Maxim.

    Science.gov (United States)

    Shang, Xiaofei; Guo, Xiao; Yang, Feng; Li, Bing; Pan, Hu; Miao, Xiaolou; Zhang, Jiyu

    2017-06-15

    Adonis coerulea Maxim. is a perennial herbaceous plant that grows in scrub, grassy slope areas, and as traditional medicine it has been used to treat animal acariasis for thousands of years. In this paper, we aimed to study the acute toxicity and cytotoxicity of the methanol extract of A. coerulea (MEAC) in vivo and in vitro for supporting the clinic uses. The acaricidal activity and the mechanism of action against Psoroptes cuniculi were investigated. The results showed that isoorientin, luteolin and apigenin were the primary compounds in MEAC. The toxicity test showed that median lethal dose (LD 50 ) and the 50% inhibitory concentration (IC 50 ) of MEAC were estimated to be more than 5000mg/kg in mice in vivo and more than 50mg/ml against RAW 264.7 and GM00637 cells in the 3-(4, 5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide (MTT) test. After culturing with MEAC, the activities of superoxide dismutase (SOD), catalase (CAT), malonyldialdehyde (MDA), glutathione-S-transferase (GST), acetylcholinesterase (AChE) and Na + -K + -ATPase of mites were evaluated. Compared with the control group, SOD activity of MEAC-treated group of mites was inhibited, and CAT activity was activated at the preliminary phase but was gradually inhibited over the period of incubation. MDA content reached a peak at 6h and then gradually decreased. However, GST activity in the mites was activated in a dose- and time-dependent manner. AChE and Na + -K + -ATPase activities related to neural conduction, vital functions and the transmembrane ion gradient of the mites were inhibited. MEAC is safe in the given doses in both the in vitro and the in vivo tests, can be applied in the clinic and it had good acaricidal activity. The extension of the incubation time in the mites led to dynamic disequilibrium between the production and clearing of superoxide anions, a disruption of the energy metabolism and the transmembrane ion gradient, and the inhibition of motor function. These factors may

  17. Identifying the cellular mechanisms of symbiont-induced epithelial morphogenesis in the squid-Vibrio association.

    Science.gov (United States)

    Koropatnick, Tanya; Goodson, Michael S; Heath-Heckman, Elizabeth A C; McFall-Ngai, Margaret

    2014-02-01

    The symbiotic association between the Hawaiian bobtail squid Euprymna scolopes and the luminous marine bacterium Vibrio fischeri provides a unique opportunity to study epithelial morphogenesis. Shortly after hatching, the squid host harvests bacteria from the seawater using currents created by two elaborate fields of ciliated epithelia on the surface of the juvenile light organ. After light organ colonization, the symbiont population signals the gradual loss of the ciliated epithelia through apoptosis of the cells, which culminates in the complete regression of these tissues. Whereas aspects of this process have been studied at the morphological, biochemical, and molecular levels, no in-depth analysis of the cellular events has been reported. Here we describe the cellular structure of the epithelial field and present evidence that the symbiosis-induced regression occurs in two steps. Using confocal microscopic analyses, we observed an initial epithelial remodeling, which serves to disable the function of the harvesting apparatus, followed by a protracted regression involving actin rearrangements and epithelial cell extrusion. We identified a metal-dependent gelatinolytic activity in the symbiont-induced morphogenic epithelial fields, suggesting the involvement of Zn-dependent matrix metalloproteinase(s) (MMP) in light organ morphogenesis. These data show that the bacterial symbionts not only induce apoptosis of the field, but also change the form, function, and biochemistry of the cells as part of the morphogenic program.

  18. Characterization of the branched antimicrobial peptide M6 by analyzing its mechanism of action and in vivo toxicity.

    Science.gov (United States)

    Pini, Alessandro; Giuliani, Andrea; Falciani, Chiara; Fabbrini, Monica; Pileri, Silvia; Lelli, Barbara; Bracci, Luisa

    2007-06-01

    We analyzed functional activity of the antimicrobial peptide M6 in vitro and in vivo. The peptide was identified by our group by phage library selection, rational modification and synthesis in a tetrabranched form (Pini et al., Antimicrob. Agents Chemother. 2005; 49: 2665-72). We found that it binds lipopolysaccharide, causes perforation of cell membranes without destroying external cell morphology and strongly binds DNA. The latter feature suggests that it could inhibit metabolic pathways, blocking DNA replication and/or transcription. We also observed that M6 does not stimulate humoral immune response when repeatedly administered to animals. We also analyzed M6 toxicity when administered to animals by intraperitoneal or by intravenous injection, determining a preliminary LD50 (125 and 37.5 mg/kg, respectively), which suggested that M6 could be used in vivo. These features make the antimicrobial branched peptide M6 a promising candidate for the development of a new antibacterial drug. Copyright (c) 2007 European Peptide Society and John Wiley & Sons, Ltd.

  19. Antibacterial mechanisms of a novel type picosecond laser-generated silver-titanium nanoparticles and their toxicity to human cells

    Directory of Open Access Journals (Sweden)

    Korshed P

    2017-12-01

    Full Text Available Peri Korshed,1 Lin Li,2 Zhu Liu,3 Aleksandr Mironov,4 Tao Wang1 1School of Biological Science, Faculty of Biology, Medicine and Health, 2Laser Processing Research Centre, School of Mechanical, Aerospace and Civil Engineering, 3School of Materials, 4Core Research Facilities, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK Abstract: In this study, we explored the antibacterial mechanisms for a novel type of Ag-TiO2 compound nanoparticles (NPs produced from an Ag-TiO2 alloy using a picosecond laser and evaluated the toxicity of the Ag-TiO2 NPs to a range of human cell types. Transmission electron microscopy was used to determine the morphology, shapes, and size distribution of the laser-generated Ag-TiO2 NPs. UV-visible spectrometer was used to confirm the shift of light absorbance of the NPs toward visible light wavelength. Results showed that the laser-generated Ag-TiO2 NPs had significant antibacterial activities against both Gram-negative and Gram-positive bacterial strains, including Escherichia coli, Pseudomonas aeruginosa, and the methicillin-resistant Staphylococcus aureus. Increased level of reactive oxygen species was produced by E. coli after exposure to the Ag-TiO2 NPs, which was accompanied with lipid peroxidation, glutathione depletion, disintegration of cell membrane and protein leakage, leading to the cell death. Five types of human cells originated from lung (A549, liver (HePG2, kidney (HEK293, endothelium cells (human coronary artery endothelial cells [hCAECs], and skin (human dermal fibroblast cells [HDFc] were used to evaluate the cytotoxicity of the laser-generated Ag-TiO2 NPs. A weak but statistically significant decrease in cell proliferation was observed for hCAECs, A549 and HDFc cells when co-cultured with 2.5 µg/mL or 20 µg/mL of the laser-generated Ag-TiO2 NPs for 48 hours. However, this effect was no longer apparent when a higher concentration of NPs (20 µg/mL was used after 72

  20. Leaf cDNA-AFLP analysis reveals novel mechanisms for boron-induced alleviation of aluminum-toxicity in Citrus grandis seedlings.

    Science.gov (United States)

    Wang, Liu-Qing; Yang, Lin-Tong; Guo, Peng; Zhou, Xin-Xing; Ye, Xin; Chen, En-Jun; Chen, Li-Song

    2015-10-01

    Little information is available on the molecular mechanisms of boron (B)-induced alleviation of aluminum (Al)-toxicity. 'Sour pummelo' (Citrus grandis) seedlings were irrigated for 18 weeks with nutrient solution containing different concentrations of B (2.5 or 20μM H3BO3) and Al (0 or 1.2mM AlCl3·6H2O). B alleviated Al-induced inhibition in plant growth accompanied by lower leaf Al. We used cDNA-AFLP to isolate 127 differentially expressed genes from leaves subjected to B and Al interactions. These genes were related to signal transduction, transport, cell wall modification, carbohydrate and energy metabolism, nucleic acid metabolism, amino acid and protein metabolism, lipid metabolism and stress responses. The ameliorative mechanisms of B on Al-toxicity might be related to: (a) triggering multiple signal transduction pathways; (b) improving the expression levels of genes related to transport; (c) activating genes involved in energy production; and (d) increasing amino acid accumulation and protein degradation. Also, genes involved in nucleic acid metabolism, cell wall modification and stress responses might play a role in B-induced alleviation of Al-toxicity. To conclude, our findings reveal some novel mechanisms on B-induced alleviation of Al-toxicity at the transcriptional level in C. grandis leaves. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Cluster Analysis of an International Pressure Pain Threshold Database Identifies 4 Meaningful Subgroups of Adults With Mechanical Neck Pain

    DEFF Research Database (Denmark)

    Walton, David M; Kwok, Timothy S H; Mehta, Swati

    2017-01-01

    OBJECTIVE: To determine pressure pain detection threshold (PPDT) related phenotypes of individuals with mechanical neck pain that may be identifiable in clinical practice. METHODS: This report describes a secondary analysis of 5 independent, international mechanical neck pain databases of PPDT...... values taken at both a local and distal region (total N=1176). Minor systematic differences in mean PPDT values across cohorts necessitated z-transformation before analysis, and each cohort was split into male and female sexes. Latent profile analysis (LPA) using the k-means approach was undertaken...... to identify the most parsimonious set of PPDT-based phenotypes that were both statistically and clinically meaningful. RESULTS: LPA revealed 4 distinct clusters named according to PPDT levels at the local and distal zones: low-low PPDT (67%), mod-mod (25%), mod-high (4%), and high-high (4%). Secondary...

  2. RNA sequencing of Populus x canadensis roots identifies key molecular mechanisms underlying physiological adaption to excess zinc.

    Directory of Open Access Journals (Sweden)

    Andrea Ariani

    Full Text Available Populus x canadensis clone I-214 exhibits a general indicator phenotype in response to excess Zn, and a higher metal uptake in roots than in shoots with a reduced translocation to aerial parts under hydroponic conditions. This physiological adaptation seems mainly regulated by roots, although the molecular mechanisms that underlie these processes are still poorly understood. Here, differential expression analysis using RNA-sequencing technology was used to identify the molecular mechanisms involved in the response to excess Zn in root. In order to maximize specificity of detection of differentially expressed (DE genes, we consider the intersection of genes identified by three distinct statistical approaches (61 up- and 19 down-regulated and validate them by RT-qPCR, yielding an agreement of 93% between the two experimental techniques. Gene Ontology (GO terms related to oxidation-reduction processes, transport and cellular iron ion homeostasis were enriched among DE genes, highlighting the importance of metal homeostasis in adaptation to excess Zn by P. x canadensis clone I-214. We identified the up-regulation of two Populus metal transporters (ZIP2 and NRAMP1 probably involved in metal uptake, and the down-regulation of a NAS4 gene involved in metal translocation. We identified also four Fe-homeostasis transcription factors (two bHLH38 genes, FIT and BTS that were differentially expressed, probably for reducing Zn-induced Fe-deficiency. In particular, we suggest that the down-regulation of FIT transcription factor could be a mechanism to cope with Zn-induced Fe-deficiency in Populus. These results provide insight into the molecular mechanisms involved in adaption to excess Zn in Populus spp., but could also constitute a starting point for the identification and characterization of molecular markers or biotechnological targets for possible improvement of phytoremediation performances of poplar trees.

  3. Toxicological effects of multi-walled carbon nanotubes on Saccharomyces cerevisiae: The uptake kinetics and mechanisms and the toxic responses

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Song; Zhu, Bin; Huang, Aiguo [College of Animal Science and Technology, Northwest A& F University, Yangling 712100 (China); Hu, Yang [College of Science, Northwest A& F University, Yangling 712100 (China); Wang, Gaoxue, E-mail: wanggaoxue@126.com [College of Animal Science and Technology, Northwest A& F University, Yangling 712100 (China); Ling, Fei, E-mail: feiling@nwsuaf.edu.cn [College of Animal Science and Technology, Northwest A& F University, Yangling 712100 (China)

    2016-11-15

    Highlights: • MWCNTs (<100 mg/L) were not toxic to S. cerevisiae. • MWCNTs were internalized in S. cerevisiae cells by three pathways. • The uptake kinetics and the subcellular distribution of MWCNTs in S. cerevisiae cells were shown. • S. cerevisiae cells were undergoing apoptosis by mitochondrial impairment pathway. - Abstract: Using Saccharomyces cerevisiae as an experimental model, the potential toxicological effects of oxidized multi-walled carbon nanotubes (MWCNTs) were investigated following exposure to 0–600 mg/L for 24 h. Results indicated that MWCNTs (>100 mg/L) had adverse effects on the cell proliferation. MWCNTs were clearly visible in lysosome, vacuole, endosome, mitochondria, multivesicular body and localization in the perinuclear region. The uptake kinetics data demonstrated that the maximum MWCNTs content (209.61 mg/g) was reached at 3 h, and a steady state was reached after 18 h. Based on the combined results of transmission electron microscope, endocytosis inhibition experiments and endocytosis-related genes (END3, END6, Sla2 and Rsp5) expression analysis, we elucidated MWCNTs uptake mechanism: (i) via a direct penetration of single MWCNTs; (ii) via endocytosis of single MWCNTs; and (iii) via endocytosis of MWCNTs aggregates. The percentage of apoptosis was significant increased at 600 mg/L. The decrease of mitochondrial transmembrane potential and the leakage of cytochrome c shown dose-dependent manners. Interestingly, there was no significant increase of reactive oxygen species (ROS). The apoptosis-related genes (SOD1, SOD2, Yca1, Nma111 and Nuc1) were significant changed. These results obtained in our study demonstrated that oxidized MWCNTs induce Saccharomyces cerevisiae apoptosis via mitochondrial impairment pathway.

  4. A novel statistical algorithm for gene expression analysis helps differentiate pregnane X receptor-dependent and independent mechanisms of toxicity.

    Directory of Open Access Journals (Sweden)

    M Ann Mongan

    Full Text Available Genome-wide gene expression profiling has become standard for assessing potential liabilities as well as for elucidating mechanisms of toxicity of drug candidates under development. Analysis of microarray data is often challenging due to the lack of a statistical model that is amenable to biological variation in a small number of samples. Here we present a novel non-parametric algorithm that requires minimal assumptions about the data distribution. Our method for determining differential expression consists of two steps: 1 We apply a nominal threshold on fold change and platform p-value to designate whether a gene is differentially expressed in each treated and control sample relative to the averaged control pool, and 2 We compared the number of samples satisfying criteria in step 1 between the treated and control groups to estimate the statistical significance based on a null distribution established by sample permutations. The method captures group effect without being too sensitive to anomalies as it allows tolerance for potential non-responders in the treatment group and outliers in the control group. Performance and results of this method were compared with the Significant Analysis of Microarrays (SAM method. These two methods were applied to investigate hepatic transcriptional responses of wild-type (PXR(+/+ and pregnane X receptor-knockout (PXR(-/- mice after 96 h exposure to CMP013, an inhibitor of β-secretase (β-site of amyloid precursor protein cleaving enzyme 1 or BACE1. Our results showed that CMP013 led to transcriptional changes in hallmark PXR-regulated genes and induced a cascade of gene expression changes that explained the hepatomegaly observed only in PXR(+/+ animals. Comparison of concordant expression changes between PXR(+/+ and PXR(-/- mice also suggested a PXR-independent association between CMP013 and perturbations to cellular stress, lipid metabolism, and biliary transport.

  5. Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A

    International Nuclear Information System (INIS)

    Sanders, J. Michael; Coulter, Sherry J.; Knudsen, Gabriel A.; Dunnick, June K.; Kissling, Grace E.; Birnbaum, Linda S.

    2016-01-01

    Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250 mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24 h following administration of the last of five daily oral doses of 250 mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats. - Highlights: • Perturbation of estrogen homeostasis in TBBPA-treated female rats was investigated. • Gene expression changes were observed in the liver and uterus of these rats. • Genes associated with estrogen biosynthesis and metabolism were affected. • Genes associated with thyroid homeostasis and cell division/growth were affected. • A mechanism of uterine toxicity via endocrine disruption was indicated.

  6. Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A

    Energy Technology Data Exchange (ETDEWEB)

    Sanders, J. Michael, E-mail: sander10@mail.nih.gov [Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Coulter, Sherry J.; Knudsen, Gabriel A. [Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Dunnick, June K.; Kissling, Grace E. [National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Birnbaum, Linda S. [Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States)

    2016-05-01

    Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250 mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24 h following administration of the last of five daily oral doses of 250 mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats. - Highlights: • Perturbation of estrogen homeostasis in TBBPA-treated female rats was investigated. • Gene expression changes were observed in the liver and uterus of these rats. • Genes associated with estrogen biosynthesis and metabolism were affected. • Genes associated with thyroid homeostasis and cell division/growth were affected. • A mechanism of uterine toxicity via endocrine disruption was indicated.

  7. Low-solubility particles and a Trojan-horse type mechanism of toxicity: the case of cobalt oxide on human lung cells

    International Nuclear Information System (INIS)

    Ortega, Richard; Roudeau, Stephane; Perrin, Laura; Carmona, Asuncion; Bresson, Carole; Darolles, Carine; Aloin, Valerie; Malard, Veronique; Gautier, Celine; Janin, Myriam; Floriani, Magali

    2014-01-01

    The mechanisms of toxicity of metal oxide particles towards lung cells are far from being understood. In particular, the relative contribution of intracellular particulate versus solubilized fractions is rarely considered as it is very challenging to assess, especially for low-solubility particles such as cobalt oxide (Co_3O_4). This study was possible owing to two highly sensitive, independent, analytical techniques, based on single-cell analysis, using ion beam microanalysis, and on bulk analysis of cell lysates, using mass spectrometry. Our study shows that cobalt oxide particles, of very low solubility in the culture medium, are readily incorporated by BEAS-2B human lung cells through endocytosis via the clathrin-dependent pathway. They are partially solubilized at low pH within lysosomes, leading to cobalt ions release. Solubilized cobalt was detected within the cytoplasm and the nucleus. As expected from these low-solubility particles, the intracellular solubilized cobalt content is small compared with the intracellular particulate cobalt content, in the parts-per-thousand range or below. However, we were able to demonstrate that this minute fraction of intracellular solubilized cobalt is responsible for the overall toxicity. Cobalt oxide particles are readily internalized by pulmonary cells via the endo-lysosomal pathway and can lead, through a Trojan-horse mechanism, to intracellular release of toxic metal ions over long periods of time, involving specific toxicity. (authors)

  8. Biotoxicity assessment and toxicity mechanism on coal gasification wastewater (CGW): A comparative analysis of effluent from different treatment processes.

    Science.gov (United States)

    Ma, Weiwei; Han, Yuxing; Xu, Chunyan; Han, Hongjun; Zhu, Hao; Li, Kun; Zheng, Mengqi

    2018-05-04

    Even though coal gasification wastewater (CGW) treated by various biochemical treatment processes generally met the national discharge standard, its potential biotoxicity was still unknown. Therefore, in this study, bioassay with Tetrahymena thermophila (T. thermophila) was conducted to comprehensively evaluate the variation of biotoxicity in raw CGW and the treated effluent from lab-scale micro-electrolysis integrated with biological reactor (MEBR), single iron-carbon micro-electrolysis (ICME) and conventional activated sludge (CAS) processes. The results illustrated that raw CGW presented intensive acute toxicity with 24 h EC 50 value of 8.401% and toxic unit (TU) value of 11.90. Moreover, it performed significant cell membrane destruction and DNA damage even at 10% dilution concentration. The toxicant identification results revealed that multiple toxic polar compounds such as phenolic, heterocyclic and polycyclic aromatic compounds were the main contributors for biotoxicity. Furthermore, these compounds could accelerate oxidative stress, thereby inducing oxidative damage of cell membrane and DNA. As for treated effluent, TU value was decreased by 90.58% in MEBR process. An effective biotoxicity reduction was achieved in MEBR process owing to high removal efficiency in polar organic toxicants. In contrast, effluent from ICME and CAS processes presented relatively high acute toxicity and genotoxicity, because various heterocyclic and polycyclic aromatic compounds were difficult to be degraded in these processes. Therefore, it was suggested that MEBR was a potential and feasible process for improving CGW treatment and minimizing ecological risk. Copyright © 2018. Published by Elsevier B.V.

  9. Teaching assistants’ performance at identifying common introductory student difficulties in mechanics revealed by the Force Concept Inventory

    Directory of Open Access Journals (Sweden)

    Alexandru Maries

    2016-05-01

    Full Text Available The Force Concept Inventory (FCI has been widely used to assess student understanding of introductory mechanics concepts by a variety of educators and physics education researchers. One reason for this extensive use is that many of the items on the FCI have strong distractor choices which correspond to students’ alternate conceptions in mechanics. Instruction is unlikely to be effective if instructors do not know the common alternate conceptions of introductory physics students and explicitly take into account students’ initial knowledge states in their instructional design. Here, we discuss research involving the FCI to evaluate one aspect of the pedagogical content knowledge of teaching assistants (TAs: knowledge of introductory student alternate conceptions in mechanics as revealed by the FCI. For each item on the FCI, the TAs were asked to identify the most common incorrect answer choice of introductory physics students. This exercise was followed by a class discussion with the TAs related to this task, including the importance of knowing student difficulties in teaching and learning. Then, we used FCI pretest and post-test data from a large population (∼900 of introductory physics students to assess the extent to which TAs were able to identify alternate conceptions of introductory students related to force and motion. In addition, we carried out think-aloud interviews with graduate students who had more than two semesters of teaching experience in recitations to examine how they reason about the task. We find that while the TAs, on average, performed better than random guessing at identifying introductory students’ difficulties with FCI content, they did not identify many common difficulties that introductory physics students have after traditional instruction. We discuss specific alternate conceptions, the extent to which TAs are able to identify them, and results from the think-aloud interviews that provided valuable information

  10. Mechanisms of change in psychotherapy for depression: An empirical update and evaluation of research aimed at identifying psychological mediators.

    Science.gov (United States)

    Lemmens, Lotte H J M; Müller, Viola N L S; Arntz, Arnoud; Huibers, Marcus J H

    2016-12-01

    We present a systematic empirical update and critical evaluation of the current status of research aimed at identifying a variety of psychological mediators in various forms of psychotherapy for depression. We summarize study characteristics and results of 35 relevant studies, and discuss the extent to which these studies meet several important requirements for mechanism research. Our review indicates that in spite of increased attention for the topic, advances in theoretical consensus about necessities for mechanism research, and sophistication of study designs, research in this field is still heterogeneous and unsatisfactory in methodological respect. Probably the biggest challenge in the field is demonstrating the causal relation between change in the mediator and change in depressive symptoms. The field would benefit from a further refinement of research methods to identify processes of therapeutic change. Recommendations for future research are discussed. However, even in the most optimal research designs, explaining psychotherapeutic change remains a challenge. Psychotherapy is a multi-dimensional phenomenon that might work through interplay of multiple mechanisms at several levels. As a result, it might be too complex to be explained in relatively simple causal models of psychological change. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. A systems biology strategy to identify molecular mechanisms of action and protein indicators of traumatic brain injury.

    Science.gov (United States)

    Yu, Chenggang; Boutté, Angela; Yu, Xueping; Dutta, Bhaskar; Feala, Jacob D; Schmid, Kara; Dave, Jitendra; Tawa, Gregory J; Wallqvist, Anders; Reifman, Jaques

    2015-02-01

    The multifactorial nature of traumatic brain injury (TBI), especially the complex secondary tissue injury involving intertwined networks of molecular pathways that mediate cellular behavior, has confounded attempts to elucidate the pathology underlying the progression of TBI. Here, systems biology strategies are exploited to identify novel molecular mechanisms and protein indicators of brain injury. To this end, we performed a meta-analysis of four distinct high-throughput gene expression studies involving different animal models of TBI. By using canonical pathways and a large human protein-interaction network as a scaffold, we separately overlaid the gene expression data from each study to identify molecular signatures that were conserved across the different studies. At 24 hr after injury, the significantly activated molecular signatures were nonspecific to TBI, whereas the significantly suppressed molecular signatures were specific to the nervous system. In particular, we identified a suppressed subnetwork consisting of 58 highly interacting, coregulated proteins associated with synaptic function. We selected three proteins from this subnetwork, postsynaptic density protein 95, nitric oxide synthase 1, and disrupted in schizophrenia 1, and hypothesized that their abundance would be significantly reduced after TBI. In a penetrating ballistic-like brain injury rat model of severe TBI, Western blot analysis confirmed our hypothesis. In addition, our analysis recovered 12 previously identified protein biomarkers of TBI. The results suggest that systems biology may provide an efficient, high-yield approach to generate testable hypotheses that can be experimentally validated to identify novel mechanisms of action and molecular indicators of TBI. © 2014 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

  12. The association between type of spine fracture and the mechanism of trauma: A useful tool for identifying mechanism of trauma on legal medicine field.

    Science.gov (United States)

    Aghakhani, Kamran; Kordrostami, Roya; Memarian, Azadeh; Asl, Nahid Dadashzadeh; Zavareh, Fatemeh Noorian

    2018-05-01

    Determining the association between mechanism of trauma, and the type of spine column fracture is a useful approach for exactly describing spine injury on forensic medicine field. We aimed to determine mechanism of trauma based on distribution of the transition of spinal column fractures. This cross-sectional survey was performed on 117 consecutive patients with the history of spinal trauma who were admitted to emergency ward of Rasoul-e-Akram Hospital in Tehran, Iran from April 2015 to March 2016. The baseline characteristics were collected by reviewing the hospital recorded files. With respect to mechanism of fracture, 63.2% of fractures were caused by falling, 30.8% by collisions with motor vehicles, and others caused by the violence. Regarding site of fracture, lumbosacral was affected in 47.9%, thoracic in 29.9%, and cervical in 13.7%. Regarding type of fracture, burst fracture was the most common type (71.8%) followed by compressive fracture (14.5%). The site of fracture was specifically associated with the mechanism of injury; the most common injuries induced by falling from height were found in lumbosacral and cervical sites, and the most frequent injuries by traffic accidents were found in thoracic site; also the injuries following violence were observed more in lumbar vertebrae. The burst fractures were more revealed in the patients affected by falling from height and by traffic accidents, and both burst and compressive fractures were more observed with the same result in the patients injured with violence (p = 0.003). The type of spine fracture due to trauma is closely associated with the mechanism of trauma that can be helpful in legal medicine to identify the mechanism of trauma in affected patients. Copyright © 2018. Published by Elsevier Ltd.

  13. Defended to the Nines: 25 Years of Resistance Gene Cloning Identifies Nine Mechanisms for R Protein Function[OPEN

    Science.gov (United States)

    2018-01-01

    Plants have many, highly variable resistance (R) gene loci, which provide resistance to a variety of pathogens. The first R gene to be cloned, maize (Zea mays) Hm1, was published over 25 years ago, and since then, many different R genes have been identified and isolated. The encoded proteins have provided clues to the diverse molecular mechanisms underlying immunity. Here, we present a meta-analysis of 314 cloned R genes. The majority of R genes encode cell surface or intracellular receptors, and we distinguish nine molecular mechanisms by which R proteins can elevate or trigger disease resistance: direct (1) or indirect (2) perception of pathogen-derived molecules on the cell surface by receptor-like proteins and receptor-like kinases; direct (3) or indirect (4) intracellular detection of pathogen-derived molecules by nucleotide binding, leucine-rich repeat receptors, or detection through integrated domains (5); perception of transcription activator-like effectors through activation of executor genes (6); and active (7), passive (8), or host reprogramming-mediated (9) loss of susceptibility. Although the molecular mechanisms underlying the functions of R genes are only understood for a small proportion of known R genes, a clearer understanding of mechanisms is emerging and will be crucial for rational engineering and deployment of novel R genes. PMID:29382771

  14. Defended to the Nines: 25 Years of Resistance Gene Cloning Identifies Nine Mechanisms for R Protein Function.

    Science.gov (United States)

    Kourelis, Jiorgos; van der Hoorn, Renier A L

    2018-02-01

    Plants have many, highly variable resistance ( R ) gene loci, which provide resistance to a variety of pathogens. The first R gene to be cloned, maize ( Zea mays ) Hm1 , was published over 25 years ago, and since then, many different R genes have been identified and isolated. The encoded proteins have provided clues to the diverse molecular mechanisms underlying immunity. Here, we present a meta-analysis of 314 cloned R genes. The majority of R genes encode cell surface or intracellular receptors, and we distinguish nine molecular mechanisms by which R proteins can elevate or trigger disease resistance: direct (1) or indirect (2) perception of pathogen-derived molecules on the cell surface by receptor-like proteins and receptor-like kinases; direct (3) or indirect (4) intracellular detection of pathogen-derived molecules by nucleotide binding, leucine-rich repeat receptors, or detection through integrated domains (5); perception of transcription activator-like effectors through activation of executor genes (6); and active (7), passive (8), or host reprogramming-mediated (9) loss of susceptibility. Although the molecular mechanisms underlying the functions of R genes are only understood for a small proportion of known R genes, a clearer understanding of mechanisms is emerging and will be crucial for rational engineering and deployment of novel R genes. © 2018 American Society of Plant Biologists. All rights reserved.

  15. Export Mechanisms of Persistent Toxic Substances (PTSs) in Urban Land Uses during Rainfall-Runoff Events: Experimental and Modeling Studies

    Science.gov (United States)

    Zheng, Y.; Luo, X.; Lin, Z.

    2016-12-01

    The urban environment has a variety of Persistent Toxic Substances (PTS), such as Polycyclic Aromatic Hydrocarbons (PAHs) and mercury. Soil in pervious lands and dust deposited on impervious surfaces are two major sinks of PTSs in urbanized areas, which could contribute significant nonpoint source loadings of PTSs to adjacent waterbodies during rainfall-runoff events and therefore jeopardize aquatic ecosystems. However, PTSs have been much less understood regarding their export mechanisms in urban land uses, and efforts to model nonpoint source pollution processes of PTSs have been rare. We designed and performed in-lab rainfall-runoff simulation experiments to investigate transport of PAHs and mercury by runoff from urban soils. Organic petrology analysis (OPA) techniques were introduced to analyze the soil and sediment compositions. Our study revealed the limitation of the classic enrichment theory which attributes enrichment of pollutants in eroded sediment solely to the sediment's particle size distribution and adopts simple relationships between enrichment ratio and sediment flux. We found that carbonaceous materials (CMs) in soil are the direct and major sorbents for PAHs and mercury, and highly different in content, mobility and adsorption capacity for the PTSs. Anthropogenic CMs like black carbon components largely control the transport of soil PAHs, while humic substances have a dominant influence on the transport of soil mercury. A model was further developed to estimate the enrichment ratio of PAHs, which innovatively applies the fugacity concept.We also conducted field studies on export of PAHs by runoff from urban roads. A variable time-step model was developed to simulate the continuous cycles of PAH buildup and washoff on urban roads. The dependence of the pollution level on antecedent weather conditions was investigated and embodied in the model. The applicability of this approach and its value to environmental management was demonstrated by a case

  16. Toxicity alarm: Case history

    International Nuclear Information System (INIS)

    Hogan, D.; Retallack, J.

    1993-01-01

    In late fall 1991, the Novacor petrochemical plant near Joffre, Alberta experienced a toxicity alarm, the first since its startup 14 years ago. Fish exposed to a normal toxicity test were stressed within 2 h and showed 100% mortality after 24 h. A history of the events leading up to, during, and after the toxicity alarm is presented. The major effluent sources were three cooling water systems. Although these sources are well characterized, the event causes were not immediately clear. Initial toxic screening indicated that one was very toxic, another moderately toxic, and the third not toxic at all. All three systems utilized the same chemical treatment program to avoid fouling: stabilized phosphates with minor variants. The most toxic of the cooling systems operated at 10-12 cycles, had three chemicals for biocide control, and had three makeup streams. Toxic and nontoxic system characteristics were compared. An in-depth modified toxicity identification and evaluation program was then performed to identify and evaluate the cause of the toxicity alarm for future prevention. The most probable causes of toxicity were identified by elimination. The combination of high numbers of cycles, hydrocarbons in the makeup water, and bromine added as an antifoulant resulted in formation of aromatic bromamines which are capable of causing the toxic condition experienced. 2 tabs

  17. Identifying Green Infrastructure as a Basis for an Incentive Mechanism at the Municipality Level in Biscay (Basque Country

    Directory of Open Access Journals (Sweden)

    Gloria Rodríguez-Loinaz

    2018-01-01

    Full Text Available The contributions of green infrastructure (GI to human well-being have been widely recognised; however, pathways for its systematic implementation are missing. Local governments can play a crucial role in the conservation of GI, and a formal recognition of this role in budgeting systems would foster the inclusion of GI in their agenda. The aim of this study is to identify the principal components of GI at the local level to form a basis for a compensatory economic scheme. We identified the principal components of GI based on the mapping of biodiversity conservation and ecosystem services provision. Furthermore, we analysed the potentiality of an incentive mechanism to promote GI based on the protection status of GI. Finally, an incentive mechanism to promote GI at the municipality level was proposed. The results showed that the GI of Biscay is mainly composed of the natural forests presented in the area, and that 50% of the principal components of the GI are not protected. Furthermore, one third of the protected principal components of the GI only has protection at the municipality level. So, we propose a Payment for Ecosystem Services (PES-like scheme at the municipality level based on the cover of natural forests, where the objective is the conservation and promotion of the GI.

  18. Protection of HepG2 cells against acrolein toxicity by 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide via glutathione-mediated mechanism.

    Science.gov (United States)

    Shah, Halley; Speen, Adam M; Saunders, Christina; Brooke, Elizabeth A S; Nallasamy, Palanisamy; Zhu, Hong; Li, Y Robert; Jia, Zhenquan

    2015-10-01

    Acrolein is an environmental toxicant, mainly found in smoke released from incomplete combustion of organic matter. Several studies showed that exposure to acrolein can lead to liver damage. The mechanisms involved in acrolein-induced hepatocellular toxicity, however, are not completely understood. This study examined the cytotoxic mechanisms of acrolein on HepG2 cells. Acrolein at pathophysiological concentrations was shown to cause apoptotic cell death and an increase in levels of protein carbonyl and thiobarbituric acid reactive acid substances. Acrolein also rapidly depleted intracellular glutathione (GSH), GSH-linked glutathione-S-transferases, and aldose reductase, three critical cellular defenses that detoxify reactive aldehydes. Results further showed that depletion of cellular GSH by acrolein preceded the loss of cell viability. To further determine the role of cellular GSH in acrolein-mediated cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. It was observed that depletion of cellular GSH by BSO led to a marked potentiation of acrolein-mediated cytotoxicity in HepG2 cells. To further assess the contribution of these events to acrolein-induced cytotoxicity, triterpenoid compound 2-cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) was used for induction of GSH. Induction of GSH by CDDO-Im afforded cytoprotection against acrolein toxicity in HepG2 cells. Furthermore, BSO significantly inhibited CDDO-Im-mediated induction in cellular GSH levels and also reversed cytoprotective effects of CDDO-Im in HepG2 cells. These results suggest that GSH is a predominant mechanism underlying acrolein-induced cytotoxicity as well as CDDO-Im-mediated cytoprotection. This study may provide understanding on the molecular action of acrolein which may be important to develop novel strategies for the prevention of acrolein-mediated toxicity. © 2014 by the Society for Experimental Biology and Medicine.

  19. Utilization of metabonomics to identify serum biomarkers in murine H22 hepatocarcinoma and deduce antitumor mechanism of Rhizoma Paridis saponins.

    Science.gov (United States)

    Qiu, Peiyu; Man, Shuli; Yang, He; Fan, Wei; Yu, Peng; Gao, Wenyuan

    2016-08-25

    Murine H22 hepatocarcinoma model is so popular to be used for the preclinical anticancer candidate's evaluation. However, the metabolic biomarkers of this model were not identified. Meanwhile, Rhizoma Paridis saponins (RPS) as natural products have been found to show strong antitumor activity, while its anti-cancer mechanism is not clear. To search for potential metabolite biomarkers of this model, serum metabonomics approach was applied to detect the variation of metabolite biomarkers and the related metabolism genes and signaling pathway were used to deduce the antitumor mechanisms of RPS. As a result, ten serum metabolites were identified in twenty-four mice including healthy mice, non-treated cancer mice, RPS-treated cancer mice and RPS-treated healthy mice. RPS significantly decreased tumor weight correlates to down-regulating lactate, acetate, N-acetyl amino acid and glutamine signals (p < 0.05), which were marked metabolites screened according to the very important person (VIP), loading plot and receiver operating characteristic curve (ROC) tests. For the analysis of metabolic enzyme related genes, RPS reversed the aerobic glycolysis through activating tumor suppressor p53 and PTEN, and suppressed FASN to inhibit lipogenesis. What's more, RPS repressed Myc and GLS expression and decreased glutamine level. The regulating PI3K/Akt/mTOR and HIF-1α/Myc/Ras networks also participated in these metabolic changes. Taken together, RPS suppressed ATP product made the tumor growth slow, which indicated a good anti-cancer effect and new angle for understanding the mechanism of RPS. In conclusion, this study demonstrated that the utility of (1)H NMR metabolic profiles taken together with tumor weight and viscera index was a promising screening tool for evaluating the antitumor effect of candidates. In addition, RPS was a potent anticancer agent through inhibiting cancer cellular metabolism to suppress proliferation in hepatoma H22 tumor murine, which promoted the

  20. Study of the aging processes in polyurethane adhesives using thermal treatment and differential calorimetric, dielectric, and mechanical techniques ; 1, identifying the aging processes ; 2, quantifying the aging effect

    CERN Document Server

    Althouse, L P

    1979-01-01

    Study of the aging processes in polyurethane adhesives using thermal treatment and differential calorimetric, dielectric, and mechanical techniques ; 1, identifying the aging processes ; 2, quantifying the aging effect

  1. Kinetic mechanism of an aldehyde reductase of Saccharomyces cerevisiae that relieves toxicity of furfural and 5-hydroxymethylfurfural

    Science.gov (United States)

    An effective means of relieving the toxicity of furan aldehydes, furfural (FFA) and 5-hydroxymethylfurfural (HMF), on fermenting organisms is essential for achieving efficient fermentation of lignocellulosic biomass to ethanol and other products. Ari1p, an aldehyde reductase from Saccharomyces cerev...

  2. Normobaric pulmonary oxygen toxicity : experimental studies on the mechanism of the protective role of endotoxin and the role of surfactant.

    NARCIS (Netherlands)

    J. Klein (Jan)

    1991-01-01

    textabstractAdministration of above-ambient oxygen tensions, necessary for treatment of severe hypoxemia caused by respiratory failure or acute lung injury, is potentially toxic for the lungs. This thesis is based on six articles dealing with this topic: one review article and five articles

  3. Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

    Science.gov (United States)

    Kaneto, Hideaki; Obata, Atsushi; Shimoda, Masashi; Kimura, Tomohiko; Hirukawa, Hidenori; Okauchi, Seizo; Matsuoka, Taka-Aki; Kaku, Kohei

    2016-01-01

    Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

  4. Genotoxic potential of montmorillonite clay mineral and alteration in the expression of genes involved in toxicity mechanisms in the human hepatoma cell line HepG2.

    Science.gov (United States)

    Maisanaba, Sara; Hercog, Klara; Filipic, Metka; Jos, Ángeles; Zegura, Bojana

    2016-03-05

    Montmorillonite, also known as Cloisite(®)Na(+) (CNa(+)), is a natural clay with a wide range of well-documented and novel applications, such as pharmaceutical products or food packaging. Although considered a low toxic product, the expected increased exposure to CNa(+) arises concern on the potential consequences on human and environmental health especially as its genotoxicity has scarcely been investigated so far. Thus, we investigated, for the first time, the influence of non-cytotoxic concentrations of CNa(+) (15.65, 31.25 and 62.5 μg/mL) on genomic instability of human hepatoma cell line (HepG2) by determining the formation of micronuclei (MNi), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) with the Cytokinesis block micronucleus cytome assay. Further on we studied the influence of CNa(+) on the expression of several genes involved in toxicity mechanisms using the real-time quantitative PCR. The results showed that CNa(+) increased the number of MNi, while the numbers of NBUDs and NPBs were not affected. In addition it deregulated genes in all the groups studied, mainly after longer time of exposure. These findings provide the evidence that CNa(+) is potentially genotoxic. Therefore further studies that will elucidate the molecular mechanisms involved in toxic activity of CNa(+) are needed for hazard identification and human safety assessment. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Effects of nanomolar copper on water plants—Comparison of biochemical and biophysical mechanisms of deficiency and sublethal toxicity under environmentally relevant conditions

    Energy Technology Data Exchange (ETDEWEB)

    Thomas, George, E-mail: george.thomas@uni.kn [Universität Konstanz, Mathematisch-Naturwissenschaftliche Sektion, Fachbereich Biologie, D-78457 Konstanz (Germany); Stärk, Hans-Joachim, E-mail: ha-jo.staerk@ufz.de [UFZ – Helmholtz Centre for Environmental Research, Department of Analytical Chemistry, Permoserstr. 15, D-04318 Leipzig (Germany); Wellenreuther, Gerd, E-mail: Gerd.wellenreuther@desy.de [HASYLAB at DESY, Notkestr. 85, 22603 Hamburg (Germany); Dickinson, Bryan C., E-mail: bryan.dickinson@gmail.com [Harvard University, Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge, MA 02138 (United States); Küpper, Hendrik, E-mail: hendrik.kuepper@uni-konstanz.de [Universität Konstanz, Mathematisch-Naturwissenschaftliche Sektion, Fachbereich Biologie, D-78457 Konstanz (Germany); University of South Bohemia, Faculty of Biological Sciences and Institute of Physical Biology, Branišovská 31, CZ-370 05 České Budejovice (Czech Republic)

    2013-09-15

    Highlights: •We found different optimal Cu requirement for different physiological mechanisms. •Kinetics and concentration thresholds of damage mechanisms were established. •Cu toxicity caused internal Cu re-distribution and inhibition of Zn uptake. •Cu deficient plants released Cu, indicating lack of high-affinity Cu transporters. •Cu deficiency caused re-distribution of zinc in the plant. -- Abstract: Toxicity and deficiency of essential trace elements like Cu are major global problems. Here, environmentally relevant sub-micromolar concentrations of Cu (supplied as CuSO{sub 4}) and simulations of natural light- and temperature cycles were applied to the aquatic macrophyte Ceratophyllum demersum. Growth was optimal at 10 nM Cu, while PSII activity (F{sub v}/F{sub m}) was maximal around 2 nM Cu. Damage to the PSII reaction centre was the first target of Cu toxicity, followed by disturbed regulation of heat dissipation (NPQ). Only after that, electron transport through PSII (Φ{sub PSII}) was inhibited, and finally chlorophylls decreased. Copper accumulation in the plants was stable until 10 nM Cu in solution, but strongly increased at higher concentrations. The vein was the main storage site for Cu up to physiological concentrations (10 nM). At toxic levels it was also sequestered to the epidermis and mesophyll until export from the vein became inhibited, accompanied by inhibition of Zn uptake. Copper deficiency led to a complete stop of growth at “0” nM Cu after 6 weeks. This was accompanied by high starch accumulation although electron flow through PSII (Φ{sub PSII}) decreased from 2 weeks, followed by decrease in pigments and increase of non photochemical quenching (NPQ). Release of Cu from the plants below 10 nM Cu supply in the nutrient solution indicated lack of high-affinity Cu transporters, and on the tissue level copper deficiency led to a re-distribution of zinc.

  6. Using Chlorella vulgaris to treat toxic excess sludge extract, and identification of its response mechanism by proteomics approach.

    Science.gov (United States)

    Wang, Lu; Wang, Hualin; Chen, Xiurong; Xu, Yan; Zhou, Tianjun; Wang, Xiaoxiao; Lu, Qian; Ruan, Roger

    2018-04-01

    Chlorella vulgaris was cultivated in varying proportions of toxic sludge extracts obtained from a sequencing batch reactor for treating synthetic wastewater containing chlorophenols. C. vulgaris could reduce the ecotoxicity from sludge extracts, and a positive correlation was noted between ecotoxicity removal and total organic carbon removal. In terms of cell density, the optimal proportion of sludge extracts required for the cultivation of C. vulgaris was lower than 50%. The correlation between protein content in per 10 6 algae and inhibition extent of ecotoxicity of the 5 groups on the day of inoculation (0.9182, p vulgaris produced proteins that involved in the stress response/redox system and energy metabolism/biosynthesis to respond to the toxic environment and some other proteins related to mixotrophic metabolism. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Functional mechanisms of drought tolerance in subtropical maize (Zea mays L.) identified using genome-wide association mapping.

    Science.gov (United States)

    Thirunavukkarasu, Nepolean; Hossain, Firoz; Arora, Kanika; Sharma, Rinku; Shiriga, Kaliyugam; Mittal, Swati; Mohan, Sweta; Namratha, Pottekatt Mohanlal; Dogga, Sreelatha; Rani, Tikka Shobha; Katragadda, Sumalini; Rathore, Abhishek; Shah, Trushar; Mohapatra, Trilochan; Gupta, Hari Shankar

    2014-12-24

    Earlier studies were focused on the genetics of temperate and tropical maize under drought. We identified genetic loci and their association with functional mechanisms in 240 accessions of subtropical maize using a high-density marker set under water stress. Out of 61 significant SNPs (11 were false-discovery-rate-corrected associations), identified across agronomic traits, models, and locations by subjecting the accessions to water stress at flowering stage, 48% were associated with drought-tolerant genes. Maize gene models revealed that SNPs mapped for agronomic traits were in fact associated with number of functional traits as follows: stomatal closure, 28; flowering, 15; root development, 5; detoxification, 4; and reduced water potential, 2. Interactions of these SNPS through the functional traits could lead to drought tolerance. The SNPs associated with ABA-dependent signalling pathways played a major role in the plant's response to stress by regulating a series of functions including flowering, root development, auxin metabolism, guard cell functions, and scavenging reactive oxygen species (ROS). ABA signalling genes regulate flowering through epigenetic changes in stress-responsive genes. ROS generated by ABA signalling are reduced by the interplay between ethylene, ABA, and detoxification signalling transductions. Integration of ABA-signalling genes with auxin-inducible genes regulates root development which in turn, maintains the water balance by regulating electrochemical gradient in plant. Several genes are directly or indirectly involved in the functioning of agronomic traits related to water stress. Genes involved in these crucial biological functions interacted significantly in order to maintain the primary as well as exclusive functions related to coping with water stress. SNPs associated with drought-tolerant genes involved in strategic biological functions will be useful to understand the mechanisms of drought tolerance in subtropical maize.

  8. Genetic Mechanisms of Coffee Extract Protection in a Caenorhabditis elegans Model of β-Amyloid Peptide Toxicity

    OpenAIRE

    Dostal, Vishantie; Roberts, Christine M.; Link, Christopher D.

    2010-01-01

    Epidemiological studies have reported that coffee and/or caffeine consumption may reduce Alzheimer's disease (AD) risk. We found that coffee extracts can similarly protect against β-amyloid peptide (Aβ) toxicity in a transgenic Caenorhabditis elegans Alzheimer's disease model. The primary protective component(s) in this model is not caffeine, although caffeine by itself can show moderate protection. Coffee exposure did not decrease Aβ transgene expression and did not need to be present during...

  9. Effects of nanomolar cadmium concentrations on water plants - comparison of biochemical and biophysical mechanisms of toxicity under environmentally relevant conditions

    OpenAIRE

    Andresen, Elisa

    2014-01-01

    In this thesis, the effects of the highly toxic heavy metal cadmium (Cd) on the rootless aquatic model plant Ceratophyllum demersum are investigated on the biochemical and biophysical level. The experiments were carried out using environmentally relevant conditions, i.e. light and temperature followed a sinusoidal cycle, a low biomass to water ratio resembled the situation in oligotrophic lakes and a continuous exchange of the defined nutrient solution ensured that metal uptake into the plant...

  10. Comparative proteomic analysis of fluoride treated rat bone provides new insights into the molecular mechanisms of fluoride toxicity.

    Science.gov (United States)

    Wei, Yan; Zeng, Beibei; Zhang, Hua; Chen, Cheng; Wu, Yanli; Wang, Nanlan; Wu, Yanqiu; Zhao, Danqing; Zhao, Yuxi; Iqbal, Javed; Shen, Liming

    2018-07-01

    Long-term excessive intake of fluoride (F) could lead to chronic fluorosis. To explore the underlying molecular mechanisms, present study is designed to elucidate the effect of fluoride on proteome expression of bone in sodium fluoride (NaF)-treated SD rats. Hematoxylin and eosin (H&E) staining was used to determine the severity of osteofluorosis, and bone samples were submitted for iTRAQ analysis. The results showed that the cortical thickness and trabecular area of femur bone in medium- and high-dose groups were higher than in control group. Contrary to this, trabecular area was reduced in the low-dose group, indicating that the bone mass was increased in medium- and high-dose groups, and decreased in the low-dose group. Thirteen (13), 35, and 34 differentially expressed proteins were identified in low-, medium-, and high-dose group, respectively. The medium- and high-dose groups shared a more similar protein expression pattern. These proteins were mainly associated with collagen metabolism, proteoglycans (PGs), matrix metalloproteinases (MMPs), etc. The results suggested that the effect of NaF on SD rats is in a dose-dependent manner. Some key proteins found here may be involved in affecting the bone tissues and bone marrow or muscle, and account for the complex pathology and clinical symptoms of fluorosis. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Using a standing-tree acoustic tool to identify forest stands for the production of mechanically-graded lumber.

    Science.gov (United States)

    Paradis, Normand; Auty, David; Carter, Peter; Achim, Alexis

    2013-03-12

    This study investigates how the use of a Hitman ST300 acoustic sensor can help identify the best forest stands to be used as supply sources for the production of Machine Stress-Rated (MSR) lumber. Using two piezoelectric sensors, the ST300 measures the velocity of a mechanical wave induced in a standing tree. Measurements were made on 333 black spruce (Picea mariana (Mill.) BSP) trees from the North Shore region, Quebec (Canada) selected across a range of locations and along a chronosequence of elapsed time since the last fire (TSF). Logs were cut from a subsample of 39 trees, and sawn into 77 pieces of 38 mm × 89 mm cross-section before undergoing mechanical testing according to ASTM standard D-4761. A linear regression model was developed to predict the static modulus of elasticity of lumber using tree acoustic velocity and stem diameter at 1.3 m above ground level (R2 = 0.41). Results suggest that, at a regional level, 92% of the black spruce trees meet the requirements of MSR grade 1650Fb-1.5E, whilst 64% and 34% meet the 2100Fb-1.8E and 2400Fb-2.0E, respectively. Mature stands with a TSF < 150 years had 11 and 18% more boards in the latter two categories, respectively, and therefore represented the best supply source for MSR lumber.

  12. Global transcriptomic profiling of aspen trees under elevated [CO2] to identify potential molecular mechanisms responsible for enhanced radial growth.

    Science.gov (United States)

    Wei, Hairong; Gou, Jiqing; Yordanov, Yordan; Zhang, Huaxin; Thakur, Ramesh; Jones, Wendy; Burton, Andrew

    2013-03-01

    Aspen (Populus tremuloides) trees growing under elevated [CO(2)] at a free-air CO(2) enrichment (FACE) site produced significantly more biomass than control trees. We investigated the molecular mechanisms underlying the observed increase in biomass by producing transcriptomic profiles of the vascular cambium zone (VCZ) and leaves, and then performed a comparative study to identify significantly changed genes and pathways after 12 years exposure to elevated [CO(2)]. In leaves, elevated [CO(2)] enhanced expression of genes related to Calvin cycle activity and linked pathways. In the VCZ, the pathways involved in cell growth, cell division, hormone metabolism, and secondary cell wall formation were altered while auxin conjugation, ABA synthesis, and cytokinin glucosylation and degradation were inhibited. Similarly, the genes involved in hemicellulose and pectin biosynthesis were enhanced, but some genes that catalyze important steps in lignin biosynthesis pathway were inhibited. Evidence from systemic analysis supported the functioning of multiple molecular mechanisms that underpin the enhanced radial growth in response to elevated [CO(2)].

  13. Using Ecological Momentary Assessment to Identify Mechanisms of Change: An Application From a Pharmacotherapy Trial With Adolescent Cannabis Users.

    Science.gov (United States)

    Treloar Padovano, Hayley; Miranda, Robert

    2018-03-01

    The present study used youth's in vivo reports of subjective responses to cannabis while smoking in their natural environments to identify real-world mechanisms of topiramate treatment for cannabis misuse. Participants were 40 cannabis users (≥ twice weekly in past 30 days), ages 15-24 years (47.5% female), with at least one cannabis use episode during the final 3 weeks of a 6-week, randomized clinical trial. Youth reported subjective "high" while smoking, stimulation, sedation, stress, craving, and grams of marijuana used in the natural environment via wireless electronic devices. Bayesian multilevel structural equation modeling (MSEM) evaluated mediation via indirect effect tests. Significant within (daily) and between (person) variability and distinctive within and between effects supported the MSEM approach. Subjective high while smoking was significantly reduced for youth in the topiramate condition, relative to placebo, and the indirect effect of reduced subjective high on total grams of cannabis smoked that day was significant. Indirect effects through other subjective responses were not significant. The results of this initial study suggest that altering subjective responses to smoking, specifically subjective high, may be a key target for developing adjunctive pharmacotherapies for cannabis misuse. More generally, this work provides an example for applying ecological momentary assessment and analytic techniques to evaluate mechanisms of behavior change in longitudinal data.

  14. Effects of ZnO nanoparticles and Zn{sup 2+} on fluvial biofilms and the related toxicity mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Yi; Wang, Chao [Key Laboratory of Integrated Regulation and Resources Development on Shallow Lakes, Ministry of Education, Hohai University, Nanjing 210098 (China); College of Environment, Hohai University, Nanjing 210098 (China); Hou, Jun, E-mail: hhuhjyhj@126.com [Key Laboratory of Integrated Regulation and Resources Development on Shallow Lakes, Ministry of Education, Hohai University, Nanjing 210098 (China); College of Environment, Hohai University, Nanjing 210098 (China); Dai, Shanshan [Key Laboratory of Integrated Regulation and Resources Development on Shallow Lakes, Ministry of Education, Hohai University, Nanjing 210098 (China); College of Environment, Hohai University, Nanjing 210098 (China); Wang, Peifang, E-mail: pfwang2005@hhu.edu.cn [Key Laboratory of Integrated Regulation and Resources Development on Shallow Lakes, Ministry of Education, Hohai University, Nanjing 210098 (China); College of Environment, Hohai University, Nanjing 210098 (China); Miao, Lingzhan; Lv, Bowen; Yang, Yangyang; You, Guoxiang [Key Laboratory of Integrated Regulation and Resources Development on Shallow Lakes, Ministry of Education, Hohai University, Nanjing 210098 (China); College of Environment, Hohai University, Nanjing 210098 (China)

    2016-02-15

    Zinc oxide nanoparticles (ZnO NPs) used in consumer products are largely released into the environment through the wastewater stream. The health hazard of ZnO NPs and the contribution of dissolved Zn{sup 2+} in toxicity of ZnO NPs has attracted extensive worldwide attention. In this study, the toxic effects of ZnO nanoparticles (ZnO NPs) and the effects of dissolved Zn{sup 2+} on fluvial biofilms were investigated. At the end of the exposure time (21 days), scanning electron microscopy (SEM) images and bioaccumulation experiments revealed that large quantities of ZnO NPs were adsorbed on the biofilm. The algal biomasses were significantly decreased by six- and eleven-fold compared with the control (1.43 μg/L) by exposure to concentrations of 100 mg/L ZnO NPs and 7.85 mg/L Zn{sup 2+}, respectively. Moreover, under the same exposure conditions, the quantum yields presented contents of 53.33 and 33.33% relative to the control, and a shift in the community composition that manifested as a strong reduction in diatoms was observed from 7 days and reached 15.63 and 6.25% of the control after 21 days of exposure, respectively. The reductions in bacteria viability and reactive oxygen species (ROS) production were noticeably enhanced following exposure to 100 mg/L ZnO NPs and 7.85 mg/L Zn{sup 2+}, respectively. Additionally, the acute and rapid toxicity of Zn{sup 2+} and the increasing toxicity of the ZnO NPs with increased bioaccumulation were noted in the exposure experiment. - Highlights: • Fluvial biofilm was exposed to ZnO NPs and the dissolved Zn{sup 2+}. • Chl-a and Φ{sub M} decreased at high doses (100 and 7.85 mg/L of ZnO NPs and Zn{sup 2+}). • A shift in the algae community composition was observed at high dosage levels. • The enhanced production of ROS declined the bacteria viability. • Zn{sup 2+} was more toxic than that of the ZnO-NPs.

  15. Effects of ZnO nanoparticles and Zn"2"+ on fluvial biofilms and the related toxicity mechanisms

    International Nuclear Information System (INIS)

    Xu, Yi; Wang, Chao; Hou, Jun; Dai, Shanshan; Wang, Peifang; Miao, Lingzhan; Lv, Bowen; Yang, Yangyang; You, Guoxiang

    2016-01-01

    Zinc oxide nanoparticles (ZnO NPs) used in consumer products are largely released into the environment through the wastewater stream. The health hazard of ZnO NPs and the contribution of dissolved Zn"2"+ in toxicity of ZnO NPs has attracted extensive worldwide attention. In this study, the toxic effects of ZnO nanoparticles (ZnO NPs) and the effects of dissolved Zn"2"+ on fluvial biofilms were investigated. At the end of the exposure time (21 days), scanning electron microscopy (SEM) images and bioaccumulation experiments revealed that large quantities of ZnO NPs were adsorbed on the biofilm. The algal biomasses were significantly decreased by six- and eleven-fold compared with the control (1.43 μg/L) by exposure to concentrations of 100 mg/L ZnO NPs and 7.85 mg/L Zn"2"+, respectively. Moreover, under the same exposure conditions, the quantum yields presented contents of 53.33 and 33.33% relative to the control, and a shift in the community composition that manifested as a strong reduction in diatoms was observed from 7 days and reached 15.63 and 6.25% of the control after 21 days of exposure, respectively. The reductions in bacteria viability and reactive oxygen species (ROS) production were noticeably enhanced following exposure to 100 mg/L ZnO NPs and 7.85 mg/L Zn"2"+, respectively. Additionally, the acute and rapid toxicity of Zn"2"+ and the increasing toxicity of the ZnO NPs with increased bioaccumulation were noted in the exposure experiment. - Highlights: • Fluvial biofilm was exposed to ZnO NPs and the dissolved Zn"2"+. • Chl-a and Φ_M decreased at high doses (100 and 7.85 mg/L of ZnO NPs and Zn"2"+). • A shift in the algae community composition was observed at high dosage levels. • The enhanced production of ROS declined the bacteria viability. • Zn"2"+ was more toxic than that of the ZnO-NPs.

  16. Toxicity of heavy metals in the environment

    National Research Council Canada - National Science Library

    Oehme, F.W

    1978-01-01

    ... as the fundamental mechanisms of toxicity resulting from heavy metal chemicals. The more common toxic heavy metals, along with their biochemistry and associated clinical syndromes, are then described...

  17. Inhibition of basolateral branchial Na{sup +}/K{sup +}-ATPase may be the key mechanism for silver toxicity in fish

    Energy Technology Data Exchange (ETDEWEB)

    Ferguson, E.; Hogstrand, C. [Univ. of Kentucky, Lexington, KY (United States). T.H. Morgan School of Biological Science

    1995-12-31

    Recent studies of freshwater fish have indicated that the mechanism of silver toxicity may lie in the ability of the metal to compromise bronchial transport of Na{sup +} and Cl (Wood et al, 1994). As part of a study, investigating the physiological mechanisms of silver toxicity to marine fish, the effect of Ag{sup +} on Na{sup +}/K{sup +}-ATPase in isolated basolateral membranes (BLM) from gills of sea-water acclimated rainbow trout was analyzed. Silver inhibition of purified dog kidney Na{sup +}/K{sup +}-ATPase was studied in a pilot experiment and the results from this experiment were compared to those obtained for rainbow trout BLMS. Michaelis-Menten kinetics of Na{sup +}/K{sup +}-ATPase activity was performed during control conditions by varying the concentrations of Na+ and K+ in the assay medium while keeping the total salt concentration constant. Inhibition of Na{sup +}/K{sup +}-ATPase activities was investigated by adding 1 nM--1 {micro}M of Ag{sup +} to the medium. Assay conditions were optimized separately for dog and rainbow trout Na{sup +}/K{sup +}-ATPase. Results from both series indicate effect of Ag{sup +} at a concentration as low as 1 nM escalating to complete quenching at a Ag{sup +} activity of 1 {micro}M. These results suggest the key mechanism of silver toxicity in marine fish involves blockage of the Na{sup +}/K{sup +}-ATPase activity in the gill epithelium.

  18. The studies on the toxicity mechanism of environmentally hazardous natural (IAA) and synthetic (NAA) auxin--The experiments on model Arabidopsis thaliana and rat liver plasma membranes.

    Science.gov (United States)

    Hąc-Wydro, Katarzyna; Flasiński, Michał

    2015-06-01

    This paper concerns the studies towards membrane-damage effect of two auxins: indole-3-acetic acid - IAA and 1-naphthaleneacetic acid - NAA on plant (Arabidopsis thaliana) and animal (rat liver) model membranes. The foregoing auxins are plant growth regulators widely used in agriculture to control the quality of the crop. However, their accumulation in the environment makes them hazardous for the living organisms. The aim of our investigations was to compare the effect of natural (IAA) vs. synthetic (NAA) auxin on the organization of plant and animal model membranes and find a possible correlation between membrane-disturbing effect of these compounds and their toxicity. The collected data evidenced that auxins cause destabilization of membranes, decrease their condensation and weakens interactions of molecules. The alterations in the morphology of model systems were also noticed. The foregoing effects of auxins are concentration-dependent and additionally NAA was found to act on animal vs. plant membranes more selectively than IAA. Interestingly, both IAA and NAA induce the strongest disordering in model lipid system at the concentration, which is frequently reported as toxic to animal and plants. Based on the above findings it was proposed that membrane-damage effect induced by IAA and NAA may be important from the point of view of the mechanism of toxicity of these compounds and cannot be ignored in further investigations in this area. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Capture compound mass spectrometry sheds light on the molecular mechanisms of liver toxicity of two Parkinson drugs.

    Science.gov (United States)

    Fischer, Jenny J; Michaelis, Simon; Schrey, Anna K; Graebner, Olivia Graebner nee; Glinski, Mirko; Dreger, Mathias; Kroll, Friedrich; Koester, Hubert

    2010-01-01

    Capture compound mass spectrometry (CCMS) is a novel technology that helps understand the molecular mechanism of the mode of action of small molecules. The Capture Compounds are trifunctional probes: A selectivity function (the drug) interacts with the proteins in a biological sample, a reactivity function (phenylazide) irreversibly forms a covalent bond, and a sorting function (biotin) allows the captured protein(s) to be isolated for mass spectrometric analysis. Tolcapone and entacapone are potent inhibitors of catechol-O-methyltransferase (COMT) for the treatment of Parkinson's disease. We aimed to understand the molecular basis of the difference of both drugs with respect to side effects. Using Capture Compounds with these drugs as selectivity functions, we were able to unambiguously and reproducibly isolate and identify their known target COMT. Tolcapone Capture Compounds captured five times more proteins than entacapone Capture Compounds. Moreover, tolcapone Capture Compounds isolated mitochondrial and peroxisomal proteins. The major tolcapone-protein interactions occurred with components of the respiratory chain and of the fatty acid beta-oxidation. Previously reported symptoms in tolcapone-treated rats suggested that tolcapone might act as decoupling reagent of the respiratory chain (Haasio et al., 2002b). Our results demonstrate that CCMS is an effective tool for the identification of a drug's potential off targets. It fills a gap in currently used in vitro screens for drug profiling that do not contain all the toxicologically relevant proteins. Thereby, CCMS has the potential to fill a technological need in drug safety assessment and helps reengineer or to reject drugs at an early preclinical stage.

  20. Characterization of uranium effects on the zebra fish Danio rerio. Stress mechanisms, neuro-toxicity and mitochondrial metabolism

    International Nuclear Information System (INIS)

    Lerebours, Adelaide

    2009-12-01

    This research explored several biological effects of uranium (U) in zebra fish exposed to low waterborne uranium concentrations (20 and 100 microgram/L). In tissue specific study (brain, liver, skeletal muscles and gills) of transcriptional responses in 20 genes identified the nature of the potential U effects during 28 days of exposure followed by an 8-day depuration phase in connection with U bioaccumulation. Liver and gills accumulate high concentrations of U and the depuration is efficient contrary to the brain and muscles. U exposure induced a later response in liver (inflammatory process, apoptosis and detoxification) and gills (oxidative balance) and an early one in brain (neuronal response) and muscles (mitochondrial metabolism). Brain and muscles appear sensitive since defence mechanisms are inefficient above low concentrations. A further study on these two organs examined the function and protein content of the respiratory mitochondrial chain following U exposure. An inhibition of the respiratory control ratio for the lowest concentration, variation in the protein synthesis of the complex IV (induction of cytochrome c oxidase sub-unit I and IV) and histological damage (dilatation in brain and vacuolisation in muscles) were observed. Another study focused on the early effects on the brain and was accomplished through a large transcriptional analysis coupled with examinations of the olfactory bulb ultrastructure. A depression of genes encoding olfactory receptor or111-7 and or102-5 was observed as rapidly as 3 days post-exposure to the lowest concentration of U. These responses and histological injuries suggest that the olfactory system could be sensitive to U exposure. (author)

  1. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9-THC: Mechanism underlying greater toxicity?

    Science.gov (United States)

    Fantegrossi, William E.; Moran, Jeffery H.; Radominska-Pandya, Anna; Prather, Paul L.

    2013-01-01

    K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a “safe” and “legal” alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ9-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ9-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ9-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed “advantages” have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances. PMID:24084047

  2. Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity?

    Science.gov (United States)

    Fantegrossi, William E; Moran, Jeffery H; Radominska-Pandya, Anna; Prather, Paul L

    2014-02-27

    K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a "safe" and "legal" alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, ∆(9)-tetrahydrocannabinol (Δ(9)-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ(9)-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ(9)-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ(9)-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed "advantages" have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances. © 2013.

  3. Transcriptional analysis and molecular dynamics simulations reveal the mechanism of toxic metals removal and efflux pumps in Lysinibacillus sphaericus OT4b.31

    KAUST Repository

    Shaw, Dario Rangel; Dussan, Jenny

    2017-01-01

    Lysinibacillus sphaericus strain OT4b.31 is a bacterium widely applied in bioremediation processes of hydrocarbon and metal polluted environments. In this study, we identified the molecular mechanism underlying the Pb2+ and Cr6+ resistance. Metal

  4. Transcriptomic analysis in a Drosophila model identifies previously implicated and novel pathways in the therapeutic mechanism in neuropsychiatric disorders

    Directory of Open Access Journals (Sweden)

    Priyanka eSingh

    2011-03-01

    Full Text Available We have taken advantage of a newly described Drosophila model to gain insights into the potential mechanism of antiepileptic drugs (AEDs, a group of drugs that are widely used in the treatment of several neurological and psychiatric conditions besides epilepsy. In the recently described Drosophila model that is inspired by pentylenetetrazole (PTZ induced kindling epileptogenesis in rodents, chronic PTZ treatment for seven days causes a decreased climbing speed and an altered CNS transcriptome, with the latter mimicking gene expression alterations reported in epileptogenesis. In the model, an increased climbing speed is further observed seven days after withdrawal from chronic PTZ. We used this post-PTZ withdrawal regime to identify potential AED mechanism. In this regime, treatment with each of the five AEDs tested, namely, ethosuximide (ETH, gabapentin (GBP, vigabatrin (VGB, sodium valproate (NaVP and levetiracetam (LEV, resulted in rescuing of the altered climbing behavior. The AEDs also normalized PTZ withdrawal induced transcriptomic perturbation in fly heads; whereas AED untreated flies showed a large number of up- and down-regulated genes which were enriched in several processes including gene expression and cell communication, the AED treated flies showed differential expression of only a small number of genes that did not enrich gene expression and cell communication processes. Gene expression and cell communication related upregulated genes in AED untreated flies overrepresented several pathways - spliceosome, RNA degradation, and ribosome in the former category, and inositol phosphate metabolism, phosphatidylinositol signaling, endocytosis and hedgehog signaling in the latter. Transcriptome remodeling effect of AEDs was overall confirmed by microarray clustering that clearly separated the profiles of AED treated and untreated flies. Besides being consistent with previously implicated pathways, our results provide evidence for a role of

  5. Multiple bio-analytical methods to reveal possible molecular mechanisms of developmental toxicity in zebrafish embryos/larvae exposed to tris(2-butoxyethyl) phosphate

    International Nuclear Information System (INIS)

    Han, Zhihua; Wang, Qiangwei; Fu, Jie; Chen, Hongshan; Zhao, Ye; Zhou, Bingsheng; Gong, Zhiyuan; Wei, Si; Li, Jun; Liu, Hongling; Zhang, Xiaowei; Liu, Chunsheng; Yu, Hongxia

    2014-01-01

    Highlights: • TBEP exposure decreased the survival of zebrafish embryos/larvae. • TBEP exposure led to its bioconcentration in zebrafish lavare. • TBEP caused developmental toxicity by inhibiting the degradation and utilization of nutrients. • TBEP exposure caused developmental toxicity by inducing apoptosis. - Abstract: The flame retardant tris(2-butoxyethyl) phosphate (TBEP) is a frequently detected contaminant in the environment, wildlife and human milk. The potentially toxic effects of TBEP and their underlying molecular mechanisms have not been elucidated. Here, zebrafish embryos were exposed to different concentrations of TBEP from 4 hours of post-fertilization (hpf) to 120 hpf, and effects on embryonic development and global protein expression patterns examined. Our results demonstrate that treatment with TBEP (0.8–100 mg/L) causes a concentration- and time-dependent decrease in embryonic survival and the hatching percentage. The median lethal concentration was 10.7 mg/L at 120 hpf. Furthermore, exposure to 150 or 800 μg/L TBEP inhibited the degradation and utilization of vitellogenins and down-regulated the expression of proteins related to cation binding, and lipid transport, uptake and metabolism, accompanied by a decrease in heart rate and body length. Exposure to TBEP (150 or 800 μg/L) also decreased the expression of proteins involved in cell proliferation and DNA repair, and led to an increased number of apoptotic cells in the tail region. Collectively, our results suggest that exposure to TBEP causes toxicity in the developing zebrafish by inhibiting the degradation and utilization of nutrients from the mother and inducing apoptosis

  6. Multiple bio-analytical methods to reveal possible molecular mechanisms of developmental toxicity in zebrafish embryos/larvae exposed to tris(2-butoxyethyl) phosphate

    Energy Technology Data Exchange (ETDEWEB)

    Han, Zhihua [State Key Laboratory of Pollution Control and Resource Reuse and School of the Environment, Nanjing University, Nanjing 210023 (China); Wang, Qiangwei [State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072 (China); Fu, Jie [State Key Laboratory of Pollution Control and Resource Reuse and School of the Environment, Nanjing University, Nanjing 210023 (China); Chen, Hongshan [State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration, School of the Environment, Northeast Normal University, Changchun 130024 (China); Department of Biological Sciences, National University of Singapore (Singapore); Zhao, Ye [Department of Biological Sciences, National University of Singapore (Singapore); Zhou, Bingsheng [State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072 (China); Gong, Zhiyuan [Department of Biological Sciences, National University of Singapore (Singapore); Wei, Si; Li, Jun; Liu, Hongling; Zhang, Xiaowei [State Key Laboratory of Pollution Control and Resource Reuse and School of the Environment, Nanjing University, Nanjing 210023 (China); Liu, Chunsheng, E-mail: liuchunshengidid@126.com [State Key Laboratory of Pollution Control and Resource Reuse and School of the Environment, Nanjing University, Nanjing 210023 (China); Department of Biological Sciences, National University of Singapore (Singapore); College of Fisheries, Huazhong Agricultural University, Wuhan 430070 (China); Yu, Hongxia, E-mail: yuhx@nju.edu.cn [State Key Laboratory of Pollution Control and Resource Reuse and School of the Environment, Nanjing University, Nanjing 210023 (China)

    2014-05-01

    Highlights: • TBEP exposure decreased the survival of zebrafish embryos/larvae. • TBEP exposure led to its bioconcentration in zebrafish lavare. • TBEP caused developmental toxicity by inhibiting the degradation and utilization of nutrients. • TBEP exposure caused developmental toxicity by inducing apoptosis. - Abstract: The flame retardant tris(2-butoxyethyl) phosphate (TBEP) is a frequently detected contaminant in the environment, wildlife and human milk. The potentially toxic effects of TBEP and their underlying molecular mechanisms have not been elucidated. Here, zebrafish embryos were exposed to different concentrations of TBEP from 4 hours of post-fertilization (hpf) to 120 hpf, and effects on embryonic development and global protein expression patterns examined. Our results demonstrate that treatment with TBEP (0.8–100 mg/L) causes a concentration- and time-dependent decrease in embryonic survival and the hatching percentage. The median lethal concentration was 10.7 mg/L at 120 hpf. Furthermore, exposure to 150 or 800 μg/L TBEP inhibited the degradation and utilization of vitellogenins and down-regulated the expression of proteins related to cation binding, and lipid transport, uptake and metabolism, accompanied by a decrease in heart rate and body length. Exposure to TBEP (150 or 800 μg/L) also decreased the expression of proteins involved in cell proliferation and DNA repair, and led to an increased number of apoptotic cells in the tail region. Collectively, our results suggest that exposure to TBEP causes toxicity in the developing zebrafish by inhibiting the degradation and utilization of nutrients from the mother and inducing apoptosis.

  7. Newly Identified Wild Rice Accessions Conferring High Salt Tolerance Might Use a Tissue Tolerance Mechanism in Leaf

    Science.gov (United States)

    Prusty, Manas R.; Kim, Sung-Ryul; Vinarao, Ricky; Entila, Frederickson; Egdane, James; Diaz, Maria G. Q.; Jena, Kshirod K.

    2018-01-01

    Cultivated rice (Oryza sativa L.) is very sensitive to salt stress. So far a few rice landraces have been identified as a source of salt tolerance and utilized in rice improvement. These tolerant lines primarily use Na+ exclusion mechanism in root which removes Na+ from the xylem stream by membrane Na+ and K+ transporters, and resulted in low Na+ accumulation in shoot. Identification of a new donor source conferring high salt tolerance is imperative. Wild relatives of rice having wide genetic diversity are regarded as a potential source for crop improvement. However, they have been less exploited against salt stress. Here, we simultaneously evaluated all 22 wild Oryza species along with the cultivated tolerant lines including Pokkali, Nona Bokra, and FL478, and sensitive check varieties under high salinity (240 mM NaCl). Based on the visual salt injury score, three species (O. alta, O. latifolia, and O. coarctata) and four species (O. rhizomatis, O. eichingeri, O. minuta, and O. grandiglumis) showed higher and similar level of tolerance compared to the tolerant checks, respectively. All three CCDD genome species exhibited salt tolerance, suggesting that the CCDD genome might possess the common genetic factors for salt tolerance. Physiological and biochemical experiments were conducted using the newly isolated tolerant species together with checks under 180 mM NaCl. Interestingly, all wild species showed high Na+ concentration in shoot and low concentration in root unlike the tolerant checks. In addition, the wild-tolerant accessions showed a tendency of a high tissue tolerance in leaf, low malondialdehyde level in shoot, and high retention of chlorophyll in the young leaves. These results suggest that the wild species employ tissue tolerance mechanism to manage salt stress. Gene expression analyses of the key salt tolerance-related genes suggested that high Na+ in leaf of wild species might be affected by OsHKT1;4-mediated Na+ exclusion in leaf and the following Na

  8. Molecular mechanisms of the epithelial transport of toxic metal ions. Final report, September 1, 1975-December 31, 1985

    International Nuclear Information System (INIS)

    Wasserman, R.H.; Fullmer, C.S.

    1986-01-01

    Studies were undertaken to examine the effects of various factors on the intestinal absorption of cadmium, zinc, arsenate and lead as well as the toxic effects of cadmium and lead on the intestinal transport of calcium. Intestinal cadmium absorption was influenced by many of the same factors which influence calcium transport, although there was no direct evidence for a common transport pathway. Cadmium inhibited the intestinal absorption of calcium, primarily at the intestinal level, since no effect on the cholecalciferol endocrine system was observed. Many similarities and differences were documented for intestinal lead and calcium transport, suggesting that these two cations share some of the same transport components. The effect of dietary lead was far more severe under conditions of dietary calcium restriction, effectively eliminating the adaptation response via the cholecalciferol endocrine system. This effect was attributed partially to lead inhibition of renal production of the active hormone, although direct inhibition, at the intestinal level, was also suggested. Several members of the troponin C family of calcium-binding proteins were shown to bind lead in preference to calcium, suggesting that many of the toxic manifestations of lead may be related to perturbation of calcium-mediated cellular processes. 110 refs

  9. Mechanisms on boron-induced alleviation of aluminum-toxicity in Citrus grandis seedlings at a transcriptional level revealed by cDNA-AFLP analysis.

    Directory of Open Access Journals (Sweden)

    Xin-Xing Zhou

    Full Text Available The physiological and biochemical mechanisms on boron (B-induced alleviation of aluminum (B-toxicity in plants have been examined in some details, but our understanding of the molecular mechanisms underlying these processes is very limited. In this study, we first used the cDNA-AFLP to investigate the gene expression patterns in Citrus grandis roots responsive to B and Al interactions, and isolated 100 differentially expressed genes. Results showed that genes related to detoxification of reactive oxygen species (ROS and aldehydes (i.e., glutathione S-transferase zeta class-like isoform X1, thioredoxin M-type 4, and 2-alkenal reductase (NADP+-dependent-like, metabolism (i.e., carboxylesterases and lecithin-cholesterol acyltransferase-like 4-like, nicotianamine aminotransferase A-like isoform X3, thiosulfate sulfurtransferase 18-like isoform X1, and FNR, root isozyme 2, cell transport (i.e., non-specific lipid-transfer protein-like protein At2g13820-like and major facilitator superfamily protein, Ca signal and hormone (i.e., calcium-binding protein CML19-like and IAA-amino acid hydrolase ILR1-like 4-like, gene regulation (i.e., Gag-pol polyprotein and cell wall modification (i.e., glycosyl hydrolase family 10 protein might play a role in B-induced alleviation of Al-toxicity. Our results are useful not only for our understanding of molecular processes associated with B-induced alleviation of Al-toxicity, but also for obtaining key molecular genes to enhance Al-tolerance of plants in the future.

  10. Mechanisms on boron-induced alleviation of aluminum-toxicity in Citrus grandis seedlings at a transcriptional level revealed by cDNA-AFLP analysis.

    Science.gov (United States)

    Zhou, Xin-Xing; Yang, Lin-Tong; Qi, Yi-Ping; Guo, Peng; Chen, Li-Song

    2015-01-01

    The physiological and biochemical mechanisms on boron (B)-induced alleviation of aluminum (B)-toxicity in plants have been examined in some details, but our understanding of the molecular mechanisms underlying these processes is very limited. In this study, we first used the cDNA-AFLP to investigate the gene expression patterns in Citrus grandis roots responsive to B and Al interactions, and isolated 100 differentially expressed genes. Results showed that genes related to detoxification of reactive oxygen species (ROS) and aldehydes (i.e., glutathione S-transferase zeta class-like isoform X1, thioredoxin M-type 4, and 2-alkenal reductase (NADP+-dependent)-like), metabolism (i.e., carboxylesterases and lecithin-cholesterol acyltransferase-like 4-like, nicotianamine aminotransferase A-like isoform X3, thiosulfate sulfurtransferase 18-like isoform X1, and FNR, root isozyme 2), cell transport (i.e., non-specific lipid-transfer protein-like protein At2g13820-like and major facilitator superfamily protein), Ca signal and hormone (i.e., calcium-binding protein CML19-like and IAA-amino acid hydrolase ILR1-like 4-like), gene regulation (i.e., Gag-pol polyprotein) and cell wall modification (i.e., glycosyl hydrolase family 10 protein) might play a role in B-induced alleviation of Al-toxicity. Our results are useful not only for our understanding of molecular processes associated with B-induced alleviation of Al-toxicity, but also for obtaining key molecular genes to enhance Al-tolerance of plants in the future.

  11. Genotoxic potential of montmorillonite clay mineral and alteration in the expression of genes involved in toxicity mechanisms in the human hepatoma cell line HepG2

    Energy Technology Data Exchange (ETDEWEB)

    Maisanaba, Sara, E-mail: saramh@us.es [Area of Toxicology, Faculty of Pharmacy, University of Sevilla, Profesor García González no. 2, 41012 Seville (Spain); Hercog, Klara; Filipic, Metka [National Institute of Biology, Department for Genetic Toxicology and Cancer Biology, Vecna pot 111, 1000 Ljubljana (Slovenia); Jos, Ángeles [Area of Toxicology, Faculty of Pharmacy, University of Sevilla, Profesor García González no. 2, 41012 Seville (Spain); Zegura, Bojana [National Institute of Biology, Department for Genetic Toxicology and Cancer Biology, Vecna pot 111, 1000 Ljubljana (Slovenia)

    2016-03-05

    Highlights: • Cloisite{sup ®}Na{sup +} has a wide range of well-documented and novel applications. • Cloisite{sup ®}Na{sup +} induces micronucleus, but not nuclear bridges or nuclear buds in HepG2 cells. • Cloisite{sup ®}Na{sup +} induces changes in the gene expression. • Gene alteration is presented mainly after 24 h of exposure to Cloisite{sup ®}Na{sup +}. - Abstract: Montmorillonite, also known as Cloisite{sup ®}Na{sup +} (CNa{sup +}), is a natural clay with a wide range of well-documented and novel applications, such as pharmaceutical products or food packaging. Although considered a low toxic product, the expected increased exposure to CNa{sup +} arises concern on the potential consequences on human and environmental health especially as its genotoxicity has scarcely been investigated so far. Thus, we investigated, for the first time, the influence of non-cytotoxic concentrations of CNa{sup +} (15.65, 31.25 and 62.5 μg/mL) on genomic instability of human hepatoma cell line (HepG2) by determining the formation of micronuclei (MNi), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) with the Cytokinesis block micronucleus cytome assay. Further on we studied the influence of CNa{sup +} on the expression of several genes involved in toxicity mechanisms using the real-time quantitative PCR. The results showed that CNa{sup +} increased the number of MNi, while the numbers of NBUDs and NPBs were not affected. In addition it deregulated genes in all the groups studied, mainly after longer time of exposure. These findings provide the evidence that CNa{sup +} is potentially genotoxic. Therefore further studies that will elucidate the molecular mechanisms involved in toxic activity of CNa{sup +} are needed for hazard identification and human safety assessment.

  12. Protective mechanism of turmeric (Curcuma longa) on carbofuran-induced hematological and hepatic toxicities in a rat model.

    Science.gov (United States)

    Hossen, Md Sakib; Tanvir, E M; Prince, Maruf Billah; Paul, Sudip; Saha, Moumoni; Ali, Md Yousuf; Gan, Siew Hua; Khalil, Md Ibrahim; Karim, Nurul

    2017-12-01

    Turmeric (Curcuma longa L. [Zingiberaceae]) is used in the treatment of a variety of conditions including pesticide-induced toxicity. The study reports the antioxidant properties and the protective effects of turmeric against carbofuran (CF)-induced toxicity in rats. The antioxidant potential was determined by using free radicals scavenging activity and ferric reducing antioxidant power values. Male Wistar rats were randomly divided into four groups, designated as control, turmeric (100 mg/kg/day), CF (1 mg/kg/day) and turmeric (100 mg/kg/day) + CF (1 mg/kg/day) treatments. All of the doses were administered orally for 28 consecutive days. The biological activity of the turmeric and CF was determined by using several standard biochemical methods. Turmeric contains high concentrations of polyphenols (8.97 ± 0.15 g GAEs), flavonoids (5.46 ± 0.29 g CEs), ascorbic acid (0.06 ± 0.00 mg AEs) and FRAP value (1972.66 ± 104.78 μM Fe 2+ ) per 100 g of sample. Oral administration of CF caused significant changes in some of the blood indices, such as, mean corpuscular volume, corpuscular hemoglobin, white blood cell, platelet distribution width and induced severe hepatic injuries associated with oxidative stress, as observed by the significantly higher lipid peroxidation (LPO) levels when compared to control, while the activities of cellular antioxidant enzymes (including superoxide dismutase and glutathione peroxidase) were significantly suppressed in the liver tissue. Turmeric supplementation could protect against CF-induced hematological perturbations and hepatic injuries in rats, plausibly by the up-regulation of antioxidant enzymes and inhibition of LPO to confer the protective effect.

  13. Cytotoxicity and cellular mechanisms involved in the toxicity of CdS quantum dots in hemocytes and gill cells of the mussel Mytilus galloprovincialis

    Energy Technology Data Exchange (ETDEWEB)

    Katsumiti, A. [CBET Research Group, Dept. Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country (Spain); Gilliland, D. [EU Commission–Joint Research Centre, Institute of Health and Consumer Protection, NSB Unit, Ispra (Italy); Arostegui, I. [Department of Applied Mathematics, Statistics and Operations Research, Faculty of Science and Technology, University of the Basque Country UPV/EHU, Leioa (Spain); Cajaraville, M.P., E-mail: mirenp.cajaraville@ehu.es [CBET Research Group, Dept. Zoology and Animal Cell Biology, Faculty of Science and Technology and Research Centre for Experimental Marine Biology and Biotechnology PIE, University of the Basque Country UPV/EHU, Basque Country (Spain)

    2014-08-15

    Highlights: • CdS QDs were cytotoxic for mussel hemocytes and gill cells in vitro. • Ionic Cd was the most toxic form, followed by CdS QDs and bulk CdS. • CdS QDs altered oxidative balance and caused DNA damage in mussel cells. • CdS QDs caused a particle-specific immunostimulation on phagocytosis of hemocytes. • Conceptual models for cellular handling and toxicity of CdS QDs are proposed. - Abstract: CdS quantum dots (QDs) show a great promise for treatment and diagnosis of cancer and for targeted drug delivery, due to their size-tunable fluorescence and ease of functionalization for tissue targeting. In spite of their advantages it is important to determine if CdS QDs can exert toxicity on biological systems. In the present work, cytotoxicity of CdS QDs (5 nm) at a wide range of concentrations (0.001–100 mg Cd/L) was screened using neutral red (NR) and thiazolyl blue tetrazolium bromide (MTT) assays in isolated hemocytes and gill cells of mussels (Mytilus galloprovincialis). The mechanisms of action of CdS QDs were assessed at sublethal concentrations (0.31–5 mg Cd/L) in the same cell types through a series of functional in vitro assays: production of reactive oxygen species (ROS), catalase (CAT) activity, DNA damage, lysosomal acid phosphatase (AcP) activity, multixenobiotic resistance (MXR) transport activity, Na-K-ATPase activity (only in gill cells) and phagocytic activity and damage to actin cytoskeleton (only in hemocytes). Exposures to CdS QDs lasted for 24 h and were performed in parallel with exposures to bulk CdS and ionic Cd. Ionic Cd was the most toxic form to both cell types, followed by CdS QDs and bulk CdS. ROS production, DNA damage, AcP activity and MXR transport were significantly increased in both cell types exposed to the 3 forms of Cd. CAT activity increased in hemocytes exposed to the three forms of Cd while in gill cells only in those exposed to ionic Cd. No effects were found on hemocytes cytoskeleton integrity. Effects on

  14. The toxicity of NaF on BmN cells and a comparative proteomics approach to identify protein expression changes in cells under NaF-stress

    International Nuclear Information System (INIS)

    Chen, Liang; Chen, Huiqing; Yao, Chun; Chang, Cheng; Xia, Hengchuan; Zhang, Chunxia; Zhou, Yang; Yao, Qin; Chen, Keping

    2015-01-01

    Highlights: • On the cellular level, we identified IC 50 of NaF on BmN cell by flow cytometry. • High concentration of NaF gives effect on BmN cell morphology. • Five significantly differential proteins were identified by two-dimensional electrophoresis and mass spectrometry. • ALDH2 and WPH were up-regulated, while CRT and SCF were down-regulated, providing new information for metabolic pathway of fluoride. - Abstract: Fluorides negatively affect the development of organisms and are a threat to human health and environmental safety. In this study, Bombyx mori N cell line (BmN) were used to explore effects of NaF on insect cells. We found that 8 h (hrs) culture with high concentration of NaF (≥1 mM) induced significantly morphological changes. Dose-response curves of 72 h continuously cultured BmN treated with NaF showed that the half inhibitory concentration (IC 50 ) value was 56.60 μM. Treatment of BmN with 100 and 300 μM of NaF induced apoptosis and necrosis. 2-D electrophoresis of whole cell extracted from BmN showed that treatment with 300 μM NaF up-regulated 32 proteins and down-regulated 11 proteins when compared with controls. We identified 5 different proteins by MALDI-TOF MS, and 4 of them were identified for the first time, including 2 up-regulated proteins (mitochondrial aldehyde dehydrogenase ALDH2 and prohibitin protein WPH) and 2 down-regulated proteins (calreticulin precursor CRT and DNA supercoiling factor SCF). These observations were further confirmed by fluorescence quantitative PCR. Together, our data suggest that these target proteins could be regarded as targets influenced by NaF and also provide clues for studies on the response metabolism pathway under NaF stress

  15. The toxicity of NaF on BmN cells and a comparative proteomics approach to identify protein expression changes in cells under NaF-stress

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Liang; Chen, Huiqing [Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013 (China); Yao, Chun [Department of Stomatology, Zhenjiang First People’s Hospital, Zhenjiang, Jiangsu 212013 (China); Chang, Cheng; Xia, Hengchuan; Zhang, Chunxia; Zhou, Yang; Yao, Qin [Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013 (China); Chen, Keping, E-mail: kpchen@ujs.edu.cn [Institute of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu 212013 (China)

    2015-04-09

    Highlights: • On the cellular level, we identified IC{sub 50} of NaF on BmN cell by flow cytometry. • High concentration of NaF gives effect on BmN cell morphology. • Five significantly differential proteins were identified by two-dimensional electrophoresis and mass spectrometry. • ALDH2 and WPH were up-regulated, while CRT and SCF were down-regulated, providing new information for metabolic pathway of fluoride. - Abstract: Fluorides negatively affect the development of organisms and are a threat to human health and environmental safety. In this study, Bombyx mori N cell line (BmN) were used to explore effects of NaF on insect cells. We found that 8 h (hrs) culture with high concentration of NaF (≥1 mM) induced significantly morphological changes. Dose-response curves of 72 h continuously cultured BmN treated with NaF showed that the half inhibitory concentration (IC{sub 50}) value was 56.60 μM. Treatment of BmN with 100 and 300 μM of NaF induced apoptosis and necrosis. 2-D electrophoresis of whole cell extracted from BmN showed that treatment with 300 μM NaF up-regulated 32 proteins and down-regulated 11 proteins when compared with controls. We identified 5 different proteins by MALDI-TOF MS, and 4 of them were identified for the first time, including 2 up-regulated proteins (mitochondrial aldehyde dehydrogenase ALDH2 and prohibitin protein WPH) and 2 down-regulated proteins (calreticulin precursor CRT and DNA supercoiling factor SCF). These observations were further confirmed by fluorescence quantitative PCR. Together, our data suggest that these target proteins could be regarded as targets influenced by NaF and also provide clues for studies on the response metabolism pathway under NaF stress.

  16. FUNCTIONAL GENOMICS IDENTIFIES TIS21-DEPENDENT MECHANISMS AND PUTATIVE CANCER DRUG TARGETS UNDERLYING MEDULLOBLASTOMA SHH-TYPE DEVELOPMENT

    Directory of Open Access Journals (Sweden)

    Giulia Gentile

    2016-11-01

    Full Text Available We have recently generated a novel medulloblastoma (MB mouse model with activation of the Shh pathway and lacking the MB suppressor Tis21 (Patched1+-Tis21KO.ts main phenotype is a defect of migration of the cerebellar granule precursor cells (GCPs. By genomic analysis of GCPs in vivo, we identified as drug target and major responsible of this defect the down-regulation of the promigratory chemokine Cxcl3. Consequently, the GCPs remain longer in the cerebellum proliferative area, and the MB frequency is enhanced. Here, we further analyzed the genes deregulated in a Tis21-dependent manner (Patched1+-is21 wild-type versus Ptch1+-Tis21 knockout, among which are a number of down-regulated tumor inhibitors and up-regulated tumor facilitators, focusing on pathways potentially involved in the tumorigenesis and on putative new drug targets.The data analysis using bioinformatic tools revealed: i a link between the Shh signaling and the Tis21-dependent impairment of the GCPs migration, through a Shh-dependent deregulation of the clathrin-mediated chemotaxis operating in the primary cilium through the Cxcl3-Cxcr2 axis; ii a possible lineage shift of Shh-type GCPs toward retinal precursor phenotype the neural cell type involved in group 3 MB; iii the identification of a subset of putative drug targets for MB, involved, among the others, in the regulation of Hippo signaling and centrosome assembly. Finally, our findings define also the role of Tis21 in the regulation of gene expression, through epigenetic and RNA processing mechanisms, influencing the fate of the GCPs.

  17. An integrated omic analysis of hepatic alteration in medaka fish chronically exposed to cyanotoxins with possible mechanisms of reproductive toxicity.

    Science.gov (United States)

    Qiao, Qin; Le Manach, Séverine; Huet, Hélène; Duvernois-Berthet, Evelyne; Chaouch, Soraya; Duval, Charlotte; Sotton, Benoit; Ponger, Loïc; Marie, Arul; Mathéron, Lucrèce; Lennon, Sarah; Bolbach, Gérard; Djediat, Chakib; Bernard, Cécile; Edery, Marc; Marie, Benjamin

    2016-12-01

    Cyanobacterial blooms threaten human health as well as the population of other living organisms in the aquatic environment, particularly due to the production of natural toxic components, the cyanotoxin. So far, the most studied cyanotoxins are microcystins (MCs). In this study, the hepatic alterations at histological, proteome and transcriptome levels were evaluated in female and male medaka fish chronically exposed to 1 and 5 μg L -1 microcystin-LR (MC-LR) and to the extract of MC-producing Microcystis aeruginosa PCC 7820 (5 μg L -1 of equivalent MC-LR) by balneation for 28 days, aiming at enhancing our understanding of the potential reproductive toxicity of cyanotoxins in aquatic vertebrate models. Indeed, both MC and Microcystis extract adversely affect reproductive parameters including fecundity and egg hatchability. The liver of toxin treated female fish present glycogen storage loss and cellular damages. The quantitative proteomics analysis revealed that the quantities of 225 hepatic proteins are dysregulated. In particular, a notable decrease in protein quantities of vitellogenin and choriogenin was observed, which could explain the decrease in reproductive output. Liver transcriptome analysis through Illumina RNA-seq reveals that over 100-400 genes are differentially expressed under 5 μg L -1  MC-LR and Microcystis extract treatments, respectively. Ingenuity pathway analysis of the omic data attests that various metabolic pathways, such as energy production, protein biosynthesis and lipid metabolism, are disturbed by both MC-LR and the Microcystis extract, which could provoke the observed reproductive impairment. The transcriptomics analysis also constitutes the first report of the impairment of circadian rhythm-related gene induced by MCs. This study contributes to a better understanding of the potential consequences of chronic exposure of fish to environmental concentrations of cyanotoxins, suggesting that Microcystis extract could impact a

  18. National Air Toxic Assessments (NATA) Results

    Data.gov (United States)

    U.S. Environmental Protection Agency — The National Air Toxics Assessment was conducted by EPA in 2002 to assess air toxics emissions in order to identify and prioritize air toxics, emission source types...

  19. Acetaminophen-induced liver injury in rats and mice: Comparison of protein adducts, mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity

    International Nuclear Information System (INIS)

    McGill, Mitchell R.; Williams, C. David; Xie, Yuchao; Ramachandran, Anup; Jaeschke, Hartmut

    2012-01-01

    Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the West. In mice, APAP hepatotoxicity can be rapidly induced with a single dose. Because it is both clinically relevant and experimentally convenient, APAP intoxication has become a popular model of liver injury. Early data demonstrated that rats are resistant to APAP toxicity. As a result, mice are the preferred species for mechanistic studies. Furthermore, recent work has shown that the mechanisms of APAP toxicity in humans are similar to mice. Nevertheless, some investigators still use rats. New mechanistic information from the last forty years invites a reevaluation of the differences between these species. Comparison may provide interesting insights and confirm or exclude the rat as an option for APAP studies. To this end, we treated rats and mice with APAP and measured parameters of liver injury, APAP metabolism, oxidative stress, and activation of the c-Jun N-terminal kinase (JNK). Consistent with earlier data, we found that rats were highly resistant to APAP toxicity. Although overall APAP metabolism was similar in both species, mitochondrial protein adducts were significantly lower in rats. Accordingly, rats also had less oxidative stress. Finally, while mice showed extensive activation and mitochondrial translocation of JNK, this could not be detected in rat livers. These data support the hypothesis that mitochondrial dysfunction is critical for the development of necrosis after APAP treatment. Because mitochondrial damage also occurs in humans, rats are not a clinically relevant species for studies of APAP hepatotoxicity. Highlights: ► Acetaminophen overdose causes severe liver injury only in mice but not in rats. ► APAP causes hepatic GSH depletion and protein adduct formation in rats and mice. ► Less protein adducts were measured in rat liver mitochondria compared to mouse. ► No oxidant stress, peroxynitrite formation or JNK activation was present in rats. ► The

  20. Multiple bio-analytical methods to reveal possible molecular mechanisms of developmental toxicity in zebrafish embryos/larvae exposed to tris(2-butoxyethyl) phosphate.

    Science.gov (United States)

    Han, Zhihua; Wang, Qiangwei; Fu, Jie; Chen, Hongshan; Zhao, Ye; Zhou, Bingsheng; Gong, Zhiyuan; Wei, Si; Li, Jun; Liu, Hongling; Zhang, Xiaowei; Liu, Chunsheng; Yu, Hongxia

    2014-05-01

    The flame retardant tris(2-butoxyethyl) phosphate (TBEP) is a frequently detected contaminant in the environment, wildlife and human milk. The potentially toxic effects of TBEP and their underlying molecular mechanisms have not been elucidated. Here, zebrafish embryos were exposed to different concentrations of TBEP from 4 hours of post-fertilization (hpf) to 120 hpf, and effects on embryonic development and global protein expression patterns examined. Our results demonstrate that treatment with TBEP (0.8-100mg/L) causes a concentration- and time-dependent decrease in embryonic survival and the hatching percentage. The median lethal concentration was 10.7 mg/L at 120 hpf. Furthermore, exposure to 150 or 800 μg/L TBEP inhibited the degradation and utilization of vitellogenins and down-regulated the expression of proteins related to cation binding, and lipid transport, uptake and metabolism, accompanied by a decrease in heart rate and body length. Exposure to TBEP (150 or 800 μg/L) also decreased the expression of proteins involved in cell proliferation and DNA repair, and led to an increased number of apoptotic cells in the tail region. Collectively, our results suggest that exposure to TBEP causes toxicity in the developing zebrafish by inhibiting the degradation and utilization of nutrients from the mother and inducing apoptosis. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Leveraging Mechanism Simplicity and Strategic Averaging to Identify Signals from Highly Heterogeneous Spatial and Temporal Ozone Data

    Science.gov (United States)

    Brown-Steiner, B.; Selin, N. E.; Prinn, R. G.; Monier, E.; Garcia-Menendez, F.; Tilmes, S.; Emmons, L. K.; Lamarque, J. F.; Cameron-Smith, P. J.

    2017-12-01

    We summarize two methods to aid in the identification of ozone signals from underlying spatially and temporally heterogeneous data in order to help research communities avoid the sometimes burdensome computational costs of high-resolution high-complexity models. The first method utilizes simplified chemical mechanisms (a Reduced Hydrocarbon Mechanism and a Superfast Mechanism) alongside a more complex mechanism (MOZART-4) within CESM CAM-Chem to extend the number of simulated meteorological years (or add additional members to an ensemble) for a given modeling problem. The Reduced Hydrocarbon mechanism is twice as fast, and the Superfast mechanism is three times faster than the MOZART-4 mechanism. We show that simplified chemical mechanisms are largely capable of simulating surface ozone across the globe as well as the more complex chemical mechanisms, and where they are not capable, a simple standardized anomaly emulation approach can correct for their inadequacies. The second method uses strategic averaging over both temporal and spatial scales to filter out the highly heterogeneous noise that underlies ozone observations and simulations. This method allows for a selection of temporal and spatial averaging scales that match a particular signal strength (between 0.5 and 5 ppbv), and enables the identification of regions where an ozone signal can rise above the ozone noise over a given region and a given period of time. In conjunction, these two methods can be used to "scale down" chemical mechanism complexity and quantitatively determine spatial and temporal scales that could enable research communities to utilize simplified representations of atmospheric chemistry and thereby maximize their productivity and efficiency given computational constraints. While this framework is here applied to ozone data, it could also be applied to a broad range of geospatial data sets (observed or modeled) that have spatial and temporal coverage.

  2. Lead (Pb) Toxicity; Physio-Biochemical Mechanisms, Grain Yield, Quality, and Pb Distribution Proportions in Scented Rice.

    Science.gov (United States)

    Ashraf, Umair; Kanu, Adam S; Deng, Quanquan; Mo, Zhaowen; Pan, Shenggang; Tian, Hua; Tang, Xiangru

    2017-01-01

    Lead (Pb) caused interruptions with normal plant metabolism, crop yield losses and quality issues are of great concern. This study assessed the physio-biochemical responses, yield and grain quality traits and Pb distribution proportions in three different fragrant rice cultivars i.e., Meixiangzhan-2, Xinagyaxiangzhan and Basmati-385. Plants were exposed to 400, 800, and 1,200 ppm of Pb while pots without Pb were taken as control (0 ppm). Our results showed that Pb toxicity significantly ( P production of hydrogen peroxide (H 2 O 2 ), malanodialdehyde (MDA) and leaves leachates; while such effects were more apparent in Xinagyaxiangzhan than other two rice cultivars. Pb stress differentially affected the production protein, proline and soluble sugars; however the production rates were higher at heading stage (HS) than maturity stage (MS). Furthermore, Pb stress altered superoxide dismutase (SOD), peroxidases (POD), catalases (CAT) and ascorbate peroxidases (APX) activities and glutathione (GSH) and oxidized glutathione (GSSG) production in all rice cultivars at both HS and MS. All Pb levels reduced the yield and yield components of all rice cultivars; nonetheless such reductions were observed highest in Xinagyaxiangzhan (69.12%) than Meixiangzhan-2 (58.05%) and Basmati-385 (46.27%) and resulted in grain quality deterioration. Significant and positive correlations among rice yields with productive tillers/pot and grains per panicle while negative with sterility percentage were also observed. In addition, all rice cultivars readily taken up the Pb contents from soil to roots and transported upward in different proportions with maximum in roots followed by stemss, leaves, ears and grains. Higher proportions of Pb contents in above ground plant parts in Xinagyaxiangzhan possibly lead to maximum losses in this cultivar than other two cultivars; while less damage in Basmati-385 might be related to strong anti-oxidative defense system and lower proportions of Pb contents in

  3. Toxic effects of cadmium on flatworm stem cell dynamics: A transcriptomic and ultrastructural elucidation of underlying mechanisms.

    Science.gov (United States)

    Plusquin, Michelle; De Mulder, Katrien; Van Belleghem, Frank; DeGheselle, Olivier; Pirotte, Nicky; Willems, Maxime; Cuypers, Ann; Salvenmoser, Willi; Ladurner, Peter; Artois, Tom; Smeets, Karen

    2016-10-01

    Stem cells or undifferentiated cells can cope more easily with external stresses. To evaluate the impact of toxic compounds on stem cell dynamics in vivo, in relation to other biological responses, we use the carcinogenic element cadmium and the regenerating model organism Macrostomum lignano. Through both BrdU and anti-histone H3 immunostainings, cadmium-induced effects were investigated at different stages of the stem cell cycle. A 24-h exposure to 100 and 250 μM CdCl2 significantly decreased the number of stem cells (neoblasts) in mitosis, whereas the number of cells in the S phase remained unchanged. After this short-term exposure, the ultrastructure of the neoblasts was minimally affected in contrast to the epidermal tissues. These results were supported by gene expression data: transcripts of cdc2 and pig3 were significantly upregulated during all treatments. Both genes are involved in the cell cycle progression and are transcribed in the gonadal region, where stem cells are highly represented. Based on a substantial increase in gene expression of heat shock proteins (HSP) and their high activity in the gonadal region, we hypothesize that these proteins are key players in the protection of stem cells against external stresses. Apart from the strong HSP induction, other protective processes including cell division, apoptosis and anti-oxidative defence, were also activated. We, therefore, conclude that the protection of stem cells against external stressors may be based on the interplay between stem cell maintenance, i.e. repair and recovery through division, on one hand and apoptosis on the other hand. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1217-1228, 2016. © 2015 Wiley Periodicals, Inc.

  4. Toxic alcohol ingestion: prompt recognition and management in the emergency department [digest].

    Science.gov (United States)

    Beauchamp, Gillian A; Valento, Matthew; Kim, Jeremy

    2016-09-22

    Identifying patients with potential toxic alcohol exposure and initiating appropriate management is critical to avoid significant patient morbidity. Sources of toxic alcohol exposure include ethylene glycol, methanol, diethylene glycol, propylene glycol, and isopropanol. Treatment considerations include the antidotes fomepizole and ethanol, and hemodialysis for removal of the parent compound and its toxic metabolites. Additional interventions include adjunctive therapies that may improve acidosis and enhance clearance of the toxic alcohol or metabolites. This issue reviews common sources of alcohol exposure, basic mechanisms of toxicity, physical examination and laboratory findings that may guide rapid assessment and management, and indications for treatment. [Points & Pearls is a digest of Emergency Medicine Practice].

  5. Introducing Toxics

    OpenAIRE

    David C. Bellinger

    2013-01-01

    With this inaugural issue, Toxics begins its life as a peer-reviewed, open access journal focusing on all aspects of toxic chemicals. We are interested in publishing papers that present a wide range of perspectives on toxicants and naturally occurring toxins, including exposure, biomarkers, kinetics, biological effects, fate and transport, treatment, and remediation. Toxics differs from many other journals in the absence of a page or word limit on contributions, permitting authors to present ...

  6. Comparison of Toxicities to Vibrio fischeri and Fish Based on Discrimination of Excess Toxicity from Baseline Level

    Science.gov (United States)

    Wang, Xiao H.; Yu, Yang; Huang, Tao; Qin, Wei C.; Su, Li M.; Zhao, Yuan H.

    2016-01-01

    Investigations on the relationship of toxicities between species play an important role in the understanding of toxic mechanisms to environmental organisms. In this paper, the toxicity data of 949 chemicals to fish and 1470 chemicals to V. fischeri were used to investigate the modes of action (MOAs) between species. The results show that although there is a positive interspecies correlation, the relationship is poor. Analysis on the excess toxicity calculated from toxic ratios (TR) shows that many chemicals have close toxicities and share the same MOAs between the two species. Linear relationships between the toxicities and octanol/water partition coefficient (log KOW) for baseline and less inert compounds indicate that the internal critical concentrations (CBRs) approach a constant both to fish and V. fischeri for neutral hydrophobic compounds. These compounds share the same toxic mechanisms and bio-uptake processes between species. On the other hand, some hydrophilic compounds exhibit different toxic effects with greatly different log TR values between V. fischeri and fish species. These hydrophilic compounds were identified as reactive MOAs to V. fischeri, but not to fish. The interspecies correlation is improved by adding a hydrophobic descriptor into the correlation equation. This indicates that the differences in the toxic ratios between fish and V. fischeri for these hydrophilic compounds can be partly attributed to the differences of bioconcentration between the two species, rather than the differences of reactivity with the target macromolecules. These hydrophilic compounds may more easily pass through the cell membrane of V. fischeri than the gill and skin of fish, react with the target macromolecules and exhibit excess toxicity. The compounds with log KOW > 7 exhibiting very low toxicity (log TR toxicity and MOAs. PMID:26901437

  7. Applying genotoxicology tools to identify environmental stressors in support of river management

    CSIR Research Space (South Africa)

    Oberholster, Paul J

    2015-09-01

    Full Text Available Although bioassay approaches are useful for identifying chemicals of potential concern, they provide little understanding of the mechanisms of chemical toxicity. Without this understanding, it is difficult to address some of the key challenges...

  8. Bioaccumulation and subacute toxicity of mechanically and chemically dispersed heavy fuel oil in sea urchin (Glyptocidaris crenulari

    Directory of Open Access Journals (Sweden)

    Bailin Yang

    2015-12-01

    Full Text Available Oil spills have a disastrous ecological impact on ecosystems but few data are available for the effects of dispersed oil on benthic marine organisms. In order to provide information for assessment, we analysed the hydrocarbon compositions of the mechanically dispersed water accommodated fraction (MDWAF and the chemically dispersed water accommodated fraction (CDWAF of No. 120 fuel oil, their bioaccumulation, and DNA damage related to oil exposure, using the sea urchin as a sentinel organism. The results show that the concentration of polycyclic aromatic hydrocarbon in the tissues of sea urchin exposed to the CDWAF is higher than that of those exposed to the MDWAF. The single cell gel electrophoresis assay results also indicated higher DNA damage from exposure to the CDWAF of oil. Thus, dispersants should be applied with caution in oil spill accidents.

  9. Anaerobic biodegradability and methanogenic toxicity of key constituents in copper chemical mechanical planarization effluents of the semiconductor industry.

    Science.gov (United States)

    Hollingsworth, Jeremy; Sierra-Alvarez, Reyes; Zhou, Michael; Ogden, Kimberly L; Field, Jim A

    2005-06-01

    Copper chemical mechanical planarization (CMP) effluents can account for 30-40% of the water discharge in semiconductor manufacturing. CMP effluents contain high concentrations of soluble copper and a complex mixture of organic constituents. The aim of this study is to perform a preliminary assessment of the treatability of CMP effluents in anaerobic sulfidogenic bioreactors inoculated with anaerobic granular sludge by testing individual compounds expected in the CMP effluents. Of all the compounds tested (copper (II), benzotriazoles, polyethylene glycol (M(n) 300), polyethylene glycol (M(n) 860) monooleate, perfluoro-1-octane sulfonate, citric acid, oxalic acid and isopropanol) only copper was found to be inhibitory to methanogenic activity at the concentrations tested. Most of the organic compounds tested were biodegradable with the exception of perfluoro-1-octane sulfonate and benzotriazoles under sulfate reducing conditions and with the exception of the same compounds as well as Triton X-100 under methanogenic conditions. The susceptibility of key components in CMP effluents to anaerobic biodegradation combined with their low microbial inhibition suggest that CMP effluents should be amenable to biological treatment in sulfate reducing bioreactors.

  10. The Mechanism by Which Dodecyl Dimethyl Benzyl Ammonium Chloride Increased the Toxicity of Chlorpyrifos to Spodoptera exigua

    Directory of Open Access Journals (Sweden)

    Li Cui

    2017-07-01

    Full Text Available Beet armyworm, Spodoptera exigua (Hübner is one of the most destructive pests that causes significant losses in crops. Unfortunately, S. exigua have developed resistance toward the majority of insecticides. Synergists may provide an important choice to deal with the resistance problems. Dodecyl dimethyl benzyl ammonium chloride (DDBAC is a cationic surfactant, which displayed enhancement effect when combined with chlorpyrifos against S. exigua, giving enhancement factors of 1.50 and 1.57 at the concentrations of 90 and 810 mg L−1. In order to clarify the possible mechanisms, we investigate the effects of DDBAC on detoxification enzymes. However, DDBAC showed no inhibition on these enzymes activities. Meanwhile, scanning electron microscope images indicated DDBAC did not affect the cuticle super micro structure of S. exigua. The alterations in cuticular penetration rate have also been observed; indeed, it has been suggested that synergism is obtained by an acceleration of insecticide penetration through the cuticle. The chlorpyrifos penetration increased sharply when combined with 90 and 810 mg L−1 DDBAC, with only 12.6 and 8.5% of the initial chlorpyrifos recovered by external rinsing after 8 h. In contrast, when there was no DDBAC, more than 23.3% of the initial dose was recovered after 8 h.

  11. Toxic mechanisms of 3-monochloropropane-1,2-diol on progesterone production in R2C rat leydig cells.

    Science.gov (United States)

    Sun, Jianxia; Bai, Shun; Bai, Weibin; Zou, Feiyan; Zhang, Lei; Su, Zhijian; Zhang, Qihao; Ou, Shiyi; Huang, Yadong

    2013-10-16

    3-Monochloropropane-1,2-diol (3-MCPD) is a well-known food processing contaminant that has been shown to impede the male reproductive function. However, its mechanism of action remains to be elucidated. In this study, the effects of 3-MCPD on progesterone production were investigated using R2C Leydig cells. 3-MCPD caused concentration-dependent inhibition of cell viability at the IC25, IC50, and IC75 levels of 1.027, 1.802, and 3.160 mM, respectively. Single cell gel/comet assay and atomic force microscopy assay showed that 3-MCPD significantly induced early apoptosis. In addition, 3-MCPD significantly reduced progesterone production by reducing the expression of cytochrome P450 side-chain cleavage enzyme, steroidogenic acute regulatory protein, and 3β-hydroxysteroid dehydrogenase in R2C cells. The change in steroidogenic acute regulatory protein expression was highly consistent with progesterone production. Furthermore, the mitochondrial membrane potential and cAMP significantly decreased.

  12. Mechanisms of Action of (Methacrylates in Hemolytic Activity, in Vivo Toxicity and Dipalmitoylphosphatidylcholine (DPPC Liposomes Determined Using NMR Spectroscopy

    Directory of Open Access Journals (Sweden)

    Seiichiro Fujisawa

    2012-01-01

    Full Text Available We investigated the quantitative structure-activity relationships between hemolytic activity (log 1/H50 or in vivo mouse intraperitoneal (ip LD50 using reported data for α,β-unsaturated carbonyl compounds such as (methacrylate monomers and their 13C-NMR β-carbon chemical shift (δ. The log 1/H50 value for methacrylates was linearly correlated with the δCβ value. That for (methacrylates was linearly correlated with log P, an index of lipophilicity. The ipLD50 for (methacrylates was linearly correlated with δCβ but not with log P. For (methacrylates, the δCβ value, which is dependent on the π-electron density on the β-carbon, was linearly correlated with PM3-based theoretical parameters (chemical hardness, η; electronegativity, χ; electrophilicity, ω, whereas log P was linearly correlated with heat of formation (HF. Also, the interaction between (methacrylates and DPPC liposomes in cell membrane molecular models was investigated using 1H-NMR spectroscopy and differential scanning calorimetry (DSC. The log 1/H50 value was related to the difference in chemical shift (ΔδHa (Ha: H (trans attached to the β-carbon between the free monomer and the DPPC liposome-bound monomer. Monomer-induced DSC phase transition properties were related to HF for monomers. NMR chemical shifts may represent a valuable parameter for investigating the biological mechanisms of action of (methacrylates.

  13. Toxicological effects of multi-walled carbon nanotubes on Saccharomyces cerevisiae: The uptake kinetics and mechanisms and the toxic responses

    International Nuclear Information System (INIS)

    Zhu, Song; Zhu, Bin; Huang, Aiguo; Hu, Yang; Wang, Gaoxue; Ling, Fei

    2016-01-01

    Highlights: • MWCNTs ( 100 mg/L) had adverse effects on the cell proliferation. MWCNTs were clearly visible in lysosome, vacuole, endosome, mitochondria, multivesicular body and localization in the perinuclear region. The uptake kinetics data demonstrated that the maximum MWCNTs content (209.61 mg/g) was reached at 3 h, and a steady state was reached after 18 h. Based on the combined results of transmission electron microscope, endocytosis inhibition experiments and endocytosis-related genes (END3, END6, Sla2 and Rsp5) expression analysis, we elucidated MWCNTs uptake mechanism: (i) via a direct penetration of single MWCNTs; (ii) via endocytosis of single MWCNTs; and (iii) via endocytosis of MWCNTs aggregates. The percentage of apoptosis was significant increased at 600 mg/L. The decrease of mitochondrial transmembrane potential and the leakage of cytochrome c shown dose-dependent manners. Interestingly, there was no significant increase of reactive oxygen species (ROS). The apoptosis-related genes (SOD1, SOD2, Yca1, Nma111 and Nuc1) were significant changed. These results obtained in our study demonstrated that oxidized MWCNTs induce Saccharomyces cerevisiae apoptosis via mitochondrial impairment pathway.

  14. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases.

    Science.gov (United States)

    Al-Bari, Md Abdul Alim

    2015-01-01

    Antimalarial drugs (e.g. chloroquine and its close structural analogues) were developed primarily to treat malaria; however, they are beneficial for many dermatological, immunological, rheumatological and severe infectious diseases, for which they are used mostly today. Chloroquine and hydroxychloroquine, two of the most fascinating drugs developed in the last 50 years, are increasingly recognized for their effectiveness in myriad non-malarial diseases. In advanced research, chloroquine and hydroxychloroquine have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatic diseases, lupus erythematosus (different forms) and skin diseases, and in the treatment of different forms of cancer. Recently, chloroquine analogues have also been found to have metabolic, cardiovascular, antithrombotic and antineoplastic effects. This review is concerned with the lysosomotropic, anti-inflammatory and immunomodulatory mechanisms of chloroquine, hydroxychloroquine, quinacrine and related analogues, and the current evidence for both their beneficial effects and potential adverse manifestations in various diseases. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. Possible Mechanisms of Mercury Toxicity and Cancer Promotion: Involvement of Gap Junction Intercellular Communications and Inflammatory Cytokines

    Directory of Open Access Journals (Sweden)

    Roberto Zefferino

    2017-01-01

    Full Text Available A number of observations indicate that heavy metals are able to alter cellular metabolic pathways through induction of a prooxidative state. Nevertheless, the outcome of heavy metal-mediated effects in the development of human diseases is debated and needs further insights. Cancer is a well-established DNA mutation-linked disease; however, epigenetic events are perhaps more important and harmful than genetic alterations. Unfortunately, we do not have reliable screening methods to assess/validate the epigenetic (promoter effects of a physical or a chemical agent. We propose a mechanism of action whereby mercury acts as a possible promoter carcinogen. In the present contribution, we resume our previous studies on mercury tested at concentrations comparable with its occurrence as environmental pollutant. It is shown that Hg(II elicits a prooxidative state in keratinocytes linked to inhibition of gap junction-mediated intercellular communication and proinflammatory cytokine production. These combined effects may on one hand isolate cells from tissue-specific homeostasis promoting their proliferation and on the other hand tamper the immune system defense/surveillance checkmating the whole organism. Since Hg(II is not a mutagenic/genotoxic compound directly affecting gene expression, in a broader sense, mercury might be an example of an epigenetic tumor promoter or, further expanding this concept, a “metagenetic” effector.

  16. Using stable isotopes and functional wood anatomy to identify underlying mechanisms of drought tolerance in different provenances of lodgepole pine

    Science.gov (United States)

    Isaac-Renton, Miriam; Montwé, David; Hamann, Andreas; Spiecker, Heinrich; Cherubini, Paolo; Treydte, Kerstin

    2016-04-01

    Choosing drought-tolerant seed sources for reforestation may help adapt forests to climate change. By combining dendroecological growth analysis with a long-term provenance trial, we assessed growth and drought tolerance of different populations of a wide-ranging conifer, lodgepole pine (Pinus contorta). This experimental design simulated a climate warming scenario through southward seed transfer, and an exceptional drought also occurred in 2002. We felled over 500 trees, representing 23 seed sources, which were grown for 32 years at three warm, dry sites in southern British Columbia, Canada. Northern populations showed poor growth and drought tolerance. These seed sources therefore appear to be especially at risk under climate change. Before recommending assisted migration of southern seeds towards the north, however, it is important to understand the physiological mechanisms underlying these responses. We combine functional wood anatomy with a dual-isotope approach to evaluate these mechanisms to drought response.

  17. Toxic effects of male Perna viridis gonad exposed to BaP, DDT and their mixture: A metabolomic and proteomic study of the underlying mechanism.

    Science.gov (United States)

    Song, Qinqin; Zheng, Pengfei; Qiu, Liguo; Jiang, Xiu; Zhao, Hongwei; Zhou, Hailong; Han, Qian; Diao, Xiaoping

    2016-01-05

    Benzo(a)pyrene and dichlorodiphenyltrichloroethane are typical persistent organic pollutants, and also the widespread environmental estrogens with known toxicity towards green mussels Perna viridis. In this study, the toxicological effects of BaP and DDT and their mixture were assessed in green mussel gonads using proteomic and metabolomic approaches. Metabolomics by NMR spectroscopy revealed that BaP did not show obvious metabolite changes in the gonad of male green mussel. DDT mainly caused some disturbance of osmotic regulation and energy metabolism by changing BCAAs, alanine, threonine, arginine, etc., unknown metabolite (3.53 ppm), glycine, homarine and ATP at different levels. However, the mixture of BaP and DDT mainly caused some disturbance in osmotic regulation and energy metabolism by differentially altering branched chain amino acids, glutamate, alanine, arginine, unknown metabolite (3.53 ppm), glycine, 4-aminobutyrate, dimethylglycine, homarine and ATP. The results suggest that DDT alone may cause most of metabolites changes in the mixture exposed male mussel gonad, and the results also show that the male P. viridis gonad was more sensitive to DDT than BaP exposures. Proteomic study showed that BaP, DDT and their mixture may have different modes of action. Proteomic responses revealed that BaP induced signal transduction, oxidative stress, spermatogenesis, etc. in the male green mussel gonad; whereas DDT exposure altered proteins that were associated with signal transduction, oxidative stress, cytoskeleton and cell structure, cellular organization, energy metabolism, etc. However, the mixture of BaP and DDT affected proteins related to cytoskeleton and cell structure, oxidative stress, cellular organization, etc. This research demonstrated that metabolomic and proteomic approaches could better elucidate the underlying mechanism of environmental pollutants gonad toxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Toxicological effects, mechanisms, and implied toxicity thresholds in the roots of Vicia faba L. seedlings grown in copper-contaminated soil.

    Science.gov (United States)

    Xu, Xianghua; Huang, Zhicheng; Wang, Chengrun; Zhong, Li; Tian, Yuan; Li, Dongdong; Zhang, Gaojian; Shi, Jian

    2015-09-01

    Copper (Cu) contamination has become a global concern because of industrial, agricultural, and other anthropogenic activities. In the present experiments, the toxicological effects, mechanisms, and potential toxicity thresholds were investigated in the roots of Vicia faba L. seedlings that were cultivated in Cu-amended soils (0, 6.25, 12.5, 25, 50, 100, 200, 400, and 600 mg kg(-1)) for 20 days, based on an analysis of the soil physicochemical properties, native Cu, available Cu, and root-enriched Cu contents. The superoxide dismutase (SOD), ascorbate peroxidase (APX), and guaiacol peroxidase (POD) isozymes and activities, as well as glutathione (GSH) and heat shock protein 70 (HSP70), changed like biphasic dose-response curves, cooperating to control the redox homeostasis. The APX and POD enzymes exhibited enhanced activities and became H2O2 scavengers primarily when the catalase (CAT) activities tended to decrease. Endoprotease (EP) isozymes and activities might be enhanced to degrade carbonylated proteins and alleviate metabolic disturbance in the roots. Additionally, HSP70 may not be suitable as a biomarker for relatively higher soil Cu concentrations and relatively longer exposure times for the roots. As a result, the isozymes and activities of SOD, CAT, and EP, as well as GSH, can be adopted as the most sensitive biomarkers. The toxicity threshold is estimated as 0.76-1.21 mg kg(-1) of available Cu in the soils or 25.04-36.65 μg Cu g(-1) dry weights (DW) in the roots.

  19. Gene Expression Analysis Reveals New Possible Mechanisms of Vancomycin-Induced Nephrotoxicity and Identifies Gene Markers Candidates

    OpenAIRE

    Dieterich, Christine; Puey, Angela; Lyn, Sylvia; Swezey, Robert; Furimsky, Anna; Fairchild, David; Mirsalis, Jon C.; Ng, Hanna H.

    2008-01-01

    Vancomycin, one of few effective treatments against methicillin-resistant Staphylococcus aureus, is nephrotoxic. The goals of this study were to (1) gain insights into molecular mechanisms of nephrotoxicity at the genomic level, (2) evaluate gene markers of vancomycin-induced kidney injury, and (3) compare gene expression responses after iv and ip administration. Groups of six female BALB/c mice were treated with seven daily iv or ip doses of vancomycin (50, 200, and 400 mg/kg) or saline, and...

  20. Mechanisms of change in psychotherapy for depression : An empirical update and evaluation of research aimed at identifying psychological mediators

    NARCIS (Netherlands)

    Lemmens, L.H.J.M.; Müller, V.N.L.S.; Arntz, A.; Huibers, M.J.H.

    2016-01-01

    We present a systematic empirical update and critical evaluation of the current status of research aimed at identifying a variety of psychological mediators in various forms of psychotherapy for depression. We summarize study characteristics and results of 35 relevant studies, and discuss the extent

  1. Immunotoxicity, genotoxicity and epigenetic toxicity of nanomaterials: New strategies for toxicity testing?

    Science.gov (United States)

    Dusinska, Maria; Tulinska, Jana; El Yamani, Naouale; Kuricova, Miroslava; Liskova, Aurelia; Rollerova, Eva; Rundén-Pran, Elise; Smolkova, Bozena

    2017-11-01

    The unique properties of nanomaterials (NMs) are beneficial in numerous industrial and medical applications. However, they could also induce unintended effects. Thus, a proper strategy for toxicity testing is essential in human hazard and risk assessment. Toxicity can be tested in vivo and in vitro; in compliance with the 3Rs, alternative strategies for in vitro testing should be further developed for NMs. Robust, standardized methods are of great importance in nanotoxicology, with comprehensive material characterization and uptake as an integral part of the testing strategy. Oxidative stress has been shown to be an underlying mechanism of possible toxicity of NMs, causing both immunotoxicity and genotoxicity. For testing NMs in vitro, a battery of tests should be performed on cells of human origin, either cell lines or primary cells, in conditions as close as possible to an in vivo situation. Novel toxicity pathways, particularly epigenetic modification, should be assessed along with conventional toxicity testing methods. However, to initiate epigenetic toxicity screens for NM exposure, there is a need to better understand their adverse effects on the epigenome, to identify robust and reproducible causal links between exposure, epigenetic changes and adverse phenotypic endpoints, and to develop improved assays to monitor epigenetic toxicity. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Mechanisms of Silver Nanoparticle Release, Transformation and Toxicity: A Critical Review of Current Knowledge and Recommendations for Future Studies and Applications

    Directory of Open Access Journals (Sweden)

    Iseult Lynch

    2013-06-01

    Full Text Available Nanosilver, due to its small particle size and enormous specific surface area, facilitates more rapid dissolution of ions than the equivalent bulk material; potentially leading to increased toxicity of nanosilver. This, coupled with their capacity to adsorb biomolecules and interact with biological receptors can mean that nanoparticles can reach sub-cellular locations leading to potentially higher localized concentrations of ions once those particles start to dissolve or degrade in situ. Further complicating the story is the capacity for nanoparticles to generate reactive oxygen species, and to interact with, and potentially disturb the functioning of biomolecules such as proteins, enzymes and DNA. The fact that the nanoparticle size, shape, surface coating and a host of other factors contribute to these interactions, and that the particles themselves are evolving or ageing leads to further complications in terms of elucidating mechanisms of interaction and modes of action for silver nanoparticles, in contrast to dissolved silver species. This review aims to provide a critical assessment of the current understanding of silver nanoparticle toxicity, as well as to provide a set of pointers and guidelines for experimental design of future studies to assess the environmental and biological impacts of silver nanoparticles. In particular; in future we require a detailed description of the nanoparticles; their synthesis route and stabilisation mechanisms; their coating; and evolution and ageing under the exposure conditions of the assay. This would allow for comparison of data from different particles; different environmental or biological systems; and structure-activity or structure-property relationships to emerge as the basis for predictive toxicology. On the basis of currently available data; such comparisons or predictions are difficult; as the characterisation and time-resolved data is not available; and a full understanding of silver

  3. Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma.

    Science.gov (United States)

    Tonacchera, M; Chiovato, L; Pinchera, A; Agretti, P; Fiore, E; Cetani, F; Rocchi, R; Viacava, P; Miccoli, P; Vitti, P

    1998-02-01

    Toxic multinodular goiter is a cause of nonautoimmune hyperthyroidism and is believed to differ in its nature and pathogenesis from toxic adenoma. Gain-of-function mutations of the TSH receptor gene have been identified as a cause of toxic adenoma. The pathogenesis at the molecular level of hyperfunctioning nodules in toxic multinodular goiter has yet not been reported. Six patients with a single hot nodule within a multinodular goiter and 11 patients with toxic thyroid adenoma were enrolled in our study. At histology five hyperfunctioning nodules in multinodular goiters showed the features of adenomas, and one was identified as a hyperplastic nodule. The entire exon 10 of the TSH receptor gene was directly sequenced after PCR amplification from genomic DNA obtained from surgical specimens. Functional studies of mutated receptors were performed in COS-7 cells. Five out of 6 (83%) hyperfunctioning nodules within toxic multinodular goiters harbored a TSH receptor mutation. A TSH receptor mutation was also evident in the hyperfunctioning nodule that at histology had the features of noncapsulated hyperplastic nodule. Among toxic adenomas, 8 out of 11 (72%) nodules harbored a TSH receptor mutation. All the mutations were heterozygotic and somatic. Nonfunctioning nodules, whether adenomas or hyperplastic nodules present in association with hyperfunctioning nodules in the same multinodular goiters, had no TSH receptor mutation. All the mutations identified had constitutive activity as assessed by cAMP production after expression in COS-7 cells. Hyperfunctioning thyroid nodules in multinodular goiters recognize the same pathogenetic event (TSH receptor mutation) as toxic adenoma. Other mechanisms are implicated in the growth of nonfunctioning thyroid nodules coexistent in the same gland.

  4. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

    Science.gov (United States)

    Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I.; Taylor, Kent D.; Azziz, Ricardo; Goodarzi, Mark O.

    2015-01-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS. PMID:26305227

  5. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

    Directory of Open Access Journals (Sweden)

    Michelle R Jones

    2015-08-01

    Full Text Available Genome wide association studies (GWAS have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS, a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

  6. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity.

    Science.gov (United States)

    Jones, Michelle R; Brower, Meredith A; Xu, Ning; Cui, Jinrui; Mengesha, Emebet; Chen, Yii-Der I; Taylor, Kent D; Azziz, Ricardo; Goodarzi, Mark O

    2015-08-01

    Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the LHCGR region, STON1-GTF2A1L and LHCGR, were overexpressed in PCOS. In analysis stratified by obesity, LHCGR was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, INSR was underexpressed in obese PCOS subjects only. Alterations in gene expression in the LHCGR, RAB5B and INSR regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the LHCGR locus and increased methylation in the INSR locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.

  7. Quantitative proteomics as a tool to identify resistance mechanisms in erlotinib-resistant subclones of the non-small cell lung cancer cell line HCC827

    DEFF Research Database (Denmark)

    Jacobsen, Kirstine

    , which in 43-50% of cases are caused by a secondary mutation (T790M) in EGFR. Importantly, a majority of resistance cases are still unexplained (Lin & Bivona, 2012). Our aim is to identify novel resistance mechanisms – and potentially new drug targets - in erlotinib-resistant subclones of the NSCLC cell...... of erlotinib, and in biological triplicates on a Q-Exactive mass spectrometer. Only proteins identified with minimum 2 unique peptides and in minimum 2 of 3 replicates were accepted. Results: Importantly, the resistant clones did not acquire the T790M or other EGFR or KRAS mutations, potentiating...... the identification of novel resistance mechanisms. We identified 2875 cytoplasmic proteins present in all 4 cell lines. Of these 87, 56 and 23 are upregulated >1.5 fold; and 117, 72 and 32 are downregulated >1.5 fold, respectively, in the 3 resistant clones compared to the parental cell line. By network analysis, we...

  8. Children's Ability to Recognise Toxic and Non-Toxic Fruits

    Science.gov (United States)

    Fancovicova, Jana; Prokop, Pavol

    2011-01-01

    Children's ability to identify common plants is a necessary prerequisite for learning botany. However, recent work has shown that children lack positive attitudes toward plants and are unable to identify them. We examined children's (aged 10-17) ability to discriminate between common toxic and non-toxic plants and their mature fruits presented in…

  9. Toxic Elements

    DEFF Research Database (Denmark)

    Hajeb, Parvaneh; Shakibazadeh, Shahram; Sloth, Jens Jørgen

    2016-01-01

    Food is considered the main source of toxic element (arsenic, cadmium, lead, and mercury) exposure to humans, and they can cause major public health effects. In this chapter, we discuss the most important sources for toxic element in food and the foodstuffs which are significant contributors to h...

  10. DOE contractor's meeting on chemical toxicity

    International Nuclear Information System (INIS)

    1987-01-01

    The Office of Health and Environmental Research (OHER) is required to determine the potential health and environmental effects associated with energy production and use. To ensure appropriate communication among investigators and scientific disciplines that these research studies represent, OHER has sponsored workshops. This document provides a compilation of activities at the Third Annual DOE/OHER Workshop. This year's workshop was broadened to include all OHER activities identified as within the chemical effects area. The workshop consisted of eight sessions entitled Isolation and Detection of Toxic chemicals; Adduct Formation and Repair; Chemical Toxicity (Posters); Metabolism and Genotoxicity; Inhalation Toxicology; Gene Regulation; Metals Toxicity; and Biological Mechanisms. This document contains abstracts of the information presented by session

  11. Insight into particle production mechanisms from angular correlations of identified particles in pp collisions measured by ALICE

    CERN Multimedia

    CERN. Geneva

    2017-01-01

    Two-particle angular correlations are a robust tool which provide access to the underlying physics phenomena of particle production in collisions of both protons and heavy ions by studying distributions of particles in pseudorapidity and azimuthal angle difference. The correlation measurement is sensitive to several phenomena, including mini-jets, elliptic flow, Bose-Einstein correlations, resonance decays, conservation laws, which can be separated by selections of momentum, particle type and by analysing the shapes of the correlation structures. In this talk, we report measurements of the correlations of identified particles and their antiparticles (for pions, kaons, protons, and lambdas) at low transverse momenta in pp collisions at sqrt(s) = 7 TeV, recently submitted for publication by the ALICE Collaboration [arXiv:1612.08975]. The analysis reveals differences in particle production between baryons and mesons. The correlation functions for mesons exhibit the expected peak dominated by effects of mini-jet...

  12. Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders

    Science.gov (United States)

    Bukalo, Olena; Pinard, Courtney R; Holmes, Andrew

    2014-01-01

    The burden of anxiety disorders is growing, but the efficacy of available anxiolytic treatments remains inadequate. Cognitive behavioural therapy for anxiety disorders focuses on identifying and modifying maladaptive patterns of thinking and behaving, and has a testable analogue in rodents in the form of fear extinction. A large preclinical literature has amassed in recent years describing the neural and molecular basis of fear extinction in rodents. In this review, we discuss how this work is being harnessed to foster translational research on anxiety disorders and facilitate the search for new anxiolytic treatments. We begin by summarizing the anatomical and functional connectivity of a medial prefrontal cortex (mPFC)–amygdala circuit that subserves fear extinction, including new insights from optogenetics. We then cover some of the approaches that have been taken to model impaired fear extinction and associated impairments with mPFC–amygdala dysfunction. The principal goal of the review is to evaluate evidence that various neurotransmitter and neuromodulator systems mediate fear extinction by modulating the mPFC–amygdala circuitry. To that end, we describe studies that have tested how fear extinction is impaired or facilitated by pharmacological manipulations of dopamine, noradrenaline, 5-HT, GABA, glutamate, neuropeptides, endocannabinoids and various other systems, which either directly target the mPFC–amygdala circuit, or produce behavioural effects that are coincident with functional changes in the circuit. We conclude that there are good grounds to be optimistic that the progress in defining the molecular substrates of mPFC–amygdala circuit function can be effectively leveraged to identify plausible candidates for extinction-promoting therapies for anxiety disorders. Linked Articles This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014

  13. Analysis of copy number variations in Holstein cows identify potential mechanisms contributing to differences in residual feed intake.

    Science.gov (United States)

    Hou, Yali; Bickhart, Derek M; Chung, Hoyoung; Hutchison, Jana L; Norman, H Duane; Connor, Erin E; Liu, George E

    2012-11-01

    Genomic structural variation is an important and abundant source of genetic and phenotypic variation. In this study, we performed an initial analysis of copy number variations (CNVs) using BovineHD SNP genotyping data from 147 Holstein cows identified as having high or low feed efficiency as estimated by residual feed intake (RFI). We detected 443 candidate CNV regions (CNVRs) that represent 18.4 Mb (0.6 %) of the genome. To investigate the functional impacts of CNVs, we created two groups of 30 individual animals with extremely low or high estimated breeding values (EBVs) for RFI, and referred to these groups as low intake (LI; more efficient) or high intake (HI; less efficient), respectively. We identified 240 (~9.0 Mb) and 274 (~10.2 Mb) CNVRs from LI and HI groups, respectively. Approximately 30-40 % of the CNVRs were specific to the LI group or HI group of animals. The 240 LI CNVRs overlapped with 137 Ensembl genes. Network analyses indicated that the LI-specific genes were predominantly enriched for those functioning in the inflammatory response and immunity. By contrast, the 274 HI CNVRs contained 177 Ensembl genes. Network analyses indicated that the HI-specific genes were particularly involved in the cell cycle, and organ and bone development. These results relate CNVs to two key variables, namely immune response and organ and bone development. The data indicate that greater feed efficiency relates more closely to immune response, whereas cattle with reduced feed efficiency may have a greater capacity for organ and bone development.

  14. Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders.

    Science.gov (United States)

    Bukalo, Olena; Pinard, Courtney R; Holmes, Andrew

    2014-10-01

    The burden of anxiety disorders is growing, but the efficacy of available anxiolytic treatments remains inadequate. Cognitive behavioural therapy for anxiety disorders focuses on identifying and modifying maladaptive patterns of thinking and behaving, and has a testable analogue in rodents in the form of fear extinction. A large preclinical literature has amassed in recent years describing the neural and molecular basis of fear extinction in rodents. In this review, we discuss how this work is being harnessed to foster translational research on anxiety disorders and facilitate the search for new anxiolytic treatments. We begin by summarizing the anatomical and functional connectivity of a medial prefrontal cortex (mPFC)-amygdala circuit that subserves fear extinction, including new insights from optogenetics. We then cover some of the approaches that have been taken to model impaired fear extinction and associated impairments with mPFC-amygdala dysfunction. The principal goal of the review is to evaluate evidence that various neurotransmitter and neuromodulator systems mediate fear extinction by modulating the mPFC-amygdala circuitry. To that end, we describe studies that have tested how fear extinction is impaired or facilitated by pharmacological manipulations of dopamine, noradrenaline, 5-HT, GABA, glutamate, neuropeptides, endocannabinoids and various other systems, which either directly target the mPFC-amygdala circuit, or produce behavioural effects that are coincident with functional changes in the circuit. We conclude that there are good grounds to be optimistic that the progress in defining the molecular substrates of mPFC-amygdala circuit function can be effectively leveraged to identify plausible candidates for extinction-promoting therapies for anxiety disorders. © 2014 The British Pharmacological Society.

  15. Comparative analysis between identified injuries of victims of fall from height and other mechanisms of closed trauma

    Directory of Open Access Journals (Sweden)

    José Gustavo Parreira

    Full Text Available OBJECTIVE: To analyze the lesions diagnosed in victims of falls, comparing them with those diagnosed in other mechanisms of blunt trauma.METHODS: We conducted a retrospective study of trauma protocol charts (prospectively collected from 2008 to 2010, including victims of trauma over 13 years of age admitted to the emergency room. The severity of injuries was stratified by the Abbreviated Injury Scale (AIS and Injury Severity Score (ISS. Variables were compared between the group of victims of falls from height (Group 1 and the other victims of blunt trauma (Group 2. We used the Student t, chi-square and Fisher tests for comparison between groups, considering the value of p <0.05 as significant.RESULTS: The series comprised 4,532 cases of blunt trauma, of which 555 (12.2% were victims of falls from height. Severe lesions (AISe"3 were observed in the extremities (17.5%, in the cephalic segment (8.4%, chest (5.5% and the abdomen (2.9%. Victims of Group 1 had significantly higher mean age, AIS in extremities / pelvis, AIS in the thoracic segment and ISS (p <0.05. The group 1 had significantly (p <0.05 higher incidence of tracheal intubation on admission, pneumothorax, hemothorax, rib fractures, chest drainage, spinal trauma, pelvic fractures, complex pelvic fractures and fractures to the upper limbs.CONCLUSION: Victims of fall from height had greater anatomic injury severity, greater frequency and severity of lesions in the thoracic segment and extremities.

  16. Mechanisms for ITB formation and control in Alcator C-Mod identified through gyrokinetic simulations of TEM turbulence

    International Nuclear Information System (INIS)

    Ernst, D.R.; Basse, N.; Bonoli, P.T.; Catto, P.J.; Fiore, C.L.; Greenwald, M.; Hubbard, A.E.; Marmar, E.S.; Porkolab, M.; Rice, J.E.; Zeller, K.; Zhurovich, K.; Dorland, W.

    2005-01-01

    Internal particle and thermal energy transport barriers are produced in Alcator C-Mod with off-axis ICRF heating, with core densities exceeding 10 21 m -3 , without core fueling, and with little change in the temperature profile. Applying on-axis ICRF heating controls the core density gradient and rate of rise. The present study employs linear and nonlinear gyrokinetic simulations of trapped electron mode (TEM) turbulence to explore mechanisms for ITB formation and control in Alcator C-Mod ITB experiments. Anomalous pinches are found to be negligible in our simulations; further, the collisional Ware pinch is sufficient to account for the slow density rise, lasting many energy confinement times. The simulations have revealed new nonlinear physics of TEM turbulence. The critical density gradient for onset of TEM turbulent transport is nonlinearly up-shifted by zonal flows. As the density profile peaks, during ITB formation, this nonlinear critical gradient is eventually exceeded, and the turbulent particle diffusivity from GS2 gyrokinetic simulations matches the particle diffusivity from transport analysis, within experimental errors. A stable equilibrium is then established when the TEM turbulent diffusion balances the Ware pinch in the ITB. This equilibrium is sensitive to temperature through gyroBohm scaling of the TEM turbulent transport, and the collisionality dependence of the neoclassical pinch, providing for control of the density rate of rise with on-axis RF heating. With no core particle fueling, and ∼1 mm between density spatial channels, the C-Mod experiments provide a nearly ideal test bed for particle transport studies. The pure TEM is the only unstable drift mode in the ITB, producing particle transport driven by the density gradient. (author)

  17. A System-Wide Approach to Identify the Mechanisms of Barnacle Attachment: Toward the Discovery of New Antifouling Compounds

    KAUST Repository

    Al-Aqeel, Sarah

    2015-11-01

    Biofouling is a significant economic problem, particularly for marine and offshore oil industries. The acorn barnacle (Amphibalanus (Balanus) amphitrite) is the main biofouling organism in marine environments. Environmental conditions, the physiology of the biofouling organism, the surrounding microbial community, and the properties of the substratum can all influence the attachment of biofouling organisms to substrates. My dissertation investigated the biological processes involved in B. amphitrite development and attachment in the unique environment of the Red Sea, where the average water surface temperature is 34°C and the salinity reaches 41‰. I profiled the transcriptome and proteome of B. amphitrite at different life stages (nauplius II, nauplius VI, and cyprid) and identified 65,784 expressed contigs and 1387 expressed proteins by quantitative proteomics. During the planktonic stage, genes related to osmotic stress, salt stress, the hyperosmotic response, and the Wnt signaling pathway were strongly up-regulated, hereas genes related to the MAPK pathway, lipid metabolism, and cuticle development were down-regulated. In the transition from the nauplius VI to cyprid stages, there was up-regulation of genes involved in blood coagulation, cuticle development, and eggshell formation, and down-regulation of genes in the nitric oxide pathway, which stimulates the swimming and feeding responses of marine invertebrates. This system-wide integrated approach elucidated the development and attachment pathways important in B. amphitrite. Enzymes and metabolites in these pathways are potential molecular targets for the development of new antifouling compounds.

  18. Why are Functional Amyloids Non-Toxic in Humans?

    Directory of Open Access Journals (Sweden)

    Matthew P. Jackson

    2017-09-01

    Full Text Available Amyloids were first identified in association with amyloidoses, human diseases in which proteins and peptides misfold into amyloid fibrils. Subsequent studies have identified an array of functional amyloid fibrils that perform physiological roles in humans. Given the potential for the production of toxic species in amyloid assembly reactions, it is remarkable that cells can produce these functional amyloids without suffering any obvious ill effect. Although the precise mechanisms are unclear, there are a number of ways in which amyloid toxicity may be prevented. These include regulating the level of the amyloidogenic peptides and proteins, minimising the production of prefibrillar oligomers in amyloid assembly reactions, sequestrating amyloids within membrane bound organelles, controlling amyloid assembly by other molecules, and disassembling the fibrils under physiological conditions. Crucially, a better understanding of how toxicity is avoided in the production of functional amyloids may provide insights into the prevention of amyloid toxicity in amyloidoses.

  19. Introducing Toxics

    Directory of Open Access Journals (Sweden)

    David C. Bellinger

    2013-04-01

    Full Text Available With this inaugural issue, Toxics begins its life as a peer-reviewed, open access journal focusing on all aspects of toxic chemicals. We are interested in publishing papers that present a wide range of perspectives on toxicants and naturally occurring toxins, including exposure, biomarkers, kinetics, biological effects, fate and transport, treatment, and remediation. Toxics differs from many other journals in the absence of a page or word limit on contributions, permitting authors to present their work in as much detail as they wish. Toxics will publish original research papers, conventional reviews, meta-analyses, short communications, theoretical papers, case reports, commentaries and policy perspectives, and book reviews (Book reviews will be solicited and should not be submitted without invitation. Toxins and toxicants concern individuals from a wide range of disciplines, and Toxics is interested in receiving papers that represent the full range of approaches applied to their study, including in vitro studies, studies that use experimental animal or non-animal models, studies of humans or other biological populations, and mathematical modeling. We are excited to get underway and look forward to working with authors in the scientific and medical communities and providing them with a novel venue for sharing their work. [...

  20. Alternative splicing: a novel mechanism of regulation identified in the chorismate mutase gene of the potato cyst nematode Globodera rostochiensis.

    Science.gov (United States)

    Lu, Shun-Wen; Tian, Duanhua; Borchardt-Wier, Harmony B; Wang, Xiaohong

    2008-11-01

    Chorismate mutase (CM) secreted from the stylet of plant-parasitic nematodes plays an important role in plant parasitism. We isolated and characterized a new nematode CM gene (Gr-cm-1) from the potato cyst nematode, Globodera rostochiensis. The Gr-cm-1 gene was found to exist in the nematode genome as a single-copy gene that has two different alleles, Gr-cm-1A and Gr-cm-1B, both of which could give rise to two different mRNA transcripts of Gr-cm-1 and Gr-cm-1-IRII. In situ mRNA hybridization showed that the Gr-cm-1 gene was exclusively expressed within the subventral oesophageal gland cells of the nematode. Gr-cm-1 was demonstrated to encode a functional CM (GR-CM-1) potentially having a dimeric structure as the secreted bacterial *AroQ CMs. Gr-cm-1-IRII, generated by retention of intron 2 of the Gr-cm-1 pre-mRNA through alternative splicing (AS), would encode a truncated protein (GR-CM-1t) lacking the CM domain with no CM activity. The quantitative real-time reverse transcription-PCR assay revealed that splicing of the Gr-cm-1 gene was developmentally regulated; Gr-cm-1 was up-regulated whereas Gr-cm-1-IRII was down-regulated in early nematode parasitic stages compared to the preparasitic juvenile stage. Low-temperature SDS-PAGE analysis revealed that GR-CM-1 could form homodimers when expressed in Escherichia coli and the dimerization domain was retained in the truncated GR-CM-1t protein. The specific interaction between the two proteins was demonstrated in yeast. Our data suggested that the novel splice variant might function as a dominant negative isoform through heterodimerization with the full-length GR-CM-1 protein and that AS may represent an important mechanism for regulating CM activity during nematode parasitism.

  1. Ecological context, concentrated disadvantage, and youth reoffending: identifying the social mechanisms in a sample of serious adolescent offenders.

    Science.gov (United States)

    Wright, Kevin A; Kim, Byungbae; Chassin, Laurie; Losoya, Sandra H; Piquero, Alex R

    2014-10-01

    Serious youthful offenders are presented with a number of significant challenges when trying to make a successful transition from adolescence to adulthood. One of the biggest obstacles for these youth to overcome concerns their ability to desist from further antisocial behavior, and although an emerging body of research has documented important risk and protective factors associated with desistance, the importance of the neighborhoods within which these youth reside has been understudied. Guided by the larger neighborhood effects on crime literature, the current study examines the direct and indirect effects of concentrated disadvantage on youth reoffending among a sample of highly mobile, serious youthful offenders. We use data from Pathways to Desistance, a longitudinal study of serious youthful offenders (N = 1,354; 13.6% female; 41.4% African American, 33.5% Hispanic, 20.2% White), matched up with 2000 Census data on neighborhood conditions for youth's main residence location during waves 7 and 8 of the study. These waves represent the time period in which youth are navigating the transition to adulthood (aged 18-22; average age = 20). We estimate structural equation models to determine direct effects of concentrated disadvantage on youth reoffending and also to examine the possible indirect effects working through individual-level mechanisms as specified by theoretical perspectives including social control (e.g., unsupervised peer activities), strain (e.g., exposure to violence), and learning (e.g., exposure to antisocial peers). Additionally, we estimate models that take into account the impact that a change in neighborhood conditions may have on the behavior of youth who move to new residences during the study period. Our results show that concentrated disadvantage is indirectly associated with youth reoffending primarily through its association with exposure to deviant peers. Taking into account youth mobility during the study period produced an additional

  2. Antimony Toxicity

    Directory of Open Access Journals (Sweden)

    Shyam Sundar

    2010-12-01

    Full Text Available Antimony toxicity occurs either due to occupational exposure or during therapy. Occupational exposure may cause respiratory irritation, pneumoconiosis, antimony spots on the skin and gastrointestinal symptoms. In addition antimony trioxide is possibly carcinogenic to humans. Improvements in working conditions have remarkably decreased the incidence of antimony toxicity in the workplace. As a therapeutic, antimony has been mostly used for the treatment of leishmaniasis and schistosomiasis. The major toxic side-effects of antimonials as a result of therapy are cardiotoxicity (~9% of patients and pancreatitis, which is seen commonly in HIV and visceral leishmaniasis co-infections. Quality control of each batch of drugs produced and regular monitoring for toxicity is required when antimonials are used therapeutically.

  3. Supervision, support and mentoring interventions for health practitioners in rural and remote contexts: an integrative review and thematic synthesis of the literature to identify mechanisms for successful outcomes.

    Science.gov (United States)

    Moran, Anna M; Coyle, Julia; Pope, Rod; Boxall, Dianne; Nancarrow, Susan A; Young, Jennifer

    2014-02-13

    To identify mechanisms for the successful implementation of support strategies for health-care practitioners in rural and remote contexts. This is an integrative review and thematic synthesis of the empirical literature that examines support interventions for health-care practitioners in rural and remote contexts. This review includes 43 papers that evaluated support strategies for the rural and remote health workforce. Interventions were predominantly training and education programmes with limited evaluations of supervision and mentoring interventions. The mechanisms associated with successful outcomes included: access to appropriate and adequate training, skills and knowledge for the support intervention; accessible and adequate resources; active involvement of stakeholders in programme design, implementation and evaluation; a needs analysis prior to the intervention; external support, organisation, facilitation and/or coordination of the programme; marketing of the programme; organisational commitment; appropriate mode of delivery; leadership; and regular feedback and evaluation of the programme. Through a synthesis of the literature, this research has identified a number of mechanisms that are associated with successful support interventions for health-care practitioners in rural and remote contexts. This research utilised a methodology developed for studying complex interventions in response to the perceived limitations of traditional systematic reviews. This synthesis of the evidence will provide decision-makers at all levels with a collection of mechanisms that can assist the development and implementation of support strategies for staff in rural and remote contexts.

  4. Supervision, support and mentoring interventions for health practitioners in rural and remote contexts: an integrative review and thematic synthesis of the literature to identify mechanisms for successful outcomes

    Science.gov (United States)

    2014-01-01

    Objective To identify mechanisms for the successful implementation of support strategies for health-care practitioners in rural and remote contexts. Design This is an integrative review and thematic synthesis of the empirical literature that examines support interventions for health-care practitioners in rural and remote contexts. Results This review includes 43 papers that evaluated support strategies for the rural and remote health workforce. Interventions were predominantly training and education programmes with limited evaluations of supervision and mentoring interventions. The mechanisms associated with successful outcomes included: access to appropriate and adequate training, skills and knowledge for the support intervention; accessible and adequate resources; active involvement of stakeholders in programme design, implementation and evaluation; a needs analysis prior to the intervention; external support, organisation, facilitation and/or coordination of the programme; marketing of the programme; organisational commitment; appropriate mode of delivery; leadership; and regular feedback and evaluation of the programme. Conclusion Through a synthesis of the literature, this research has identified a number of mechanisms that are associated with successful support interventions for health-care practitioners in rural and remote contexts. This research utilised a methodology developed for studying complex interventions in response to the perceived limitations of traditional systematic reviews. This synthesis of the evidence will provide decision-makers at all levels with a collection of mechanisms that can assist the development and implementation of support strategies for staff in rural and remote contexts. PMID:24521004

  5. Antimony Toxicity

    OpenAIRE

    Sundar, Shyam; Chakravarty, Jaya

    2010-01-01

    Antimony toxicity occurs either due to occupational exposure or during therapy. Occupational exposure may cause respiratory irritation, pneumoconiosis, antimony spots on the skin and gastrointestinal symptoms. In addition antimony trioxide is possibly carcinogenic to humans. Improvements in working conditions have remarkably decreased the incidence of antimony toxicity in the workplace. As a therapeutic, antimony has been mostly used for the treatment of leishmaniasis and schistosomiasis. The...

  6. Oxygen toxicity

    Directory of Open Access Journals (Sweden)

    C. A. van der Westhuizen

    1990-07-01

    Full Text Available Oxygen has been discovered about 200 years ago. Since then the vital physiological involvement of oxygen in various biologi­cal processes, mainly energy production, has been established. However, in the body molecular oxygen can be converted to toxic oxygen metabolites such as superoxide anion, hydrogen peroxide, the hydroxyl radical and singlet oxygen. These toxic metabolites are produced mainly in the mitochondria, plasma membranes and endoplasmic reticulum.

  7. Transthyretin protects against A-beta peptide toxicity by proteolytic cleavage of the peptide: a mechanism sensitive to the Kunitz protease inhibitor.

    Directory of Open Access Journals (Sweden)

    Rita Costa

    Full Text Available Alzheimer's disease (AD is a neurodegenerative disorder characterized by the deposition of amyloid beta-peptide (A-Beta in the brain. Transthyretin (TTR is a tetrameric protein of about 55 kDa mainly produced in the liver and choroid plexus of the brain. The known physiological functions of TTR are the transport of thyroid hormone T(4 and retinol, through binding to the retinol binding protein. TTR has also been established as a cryptic protease able to cleave ApoA-I in vitro. It has been described that TTR is involved in preventing A-Beta fibrilization, both by inhibiting and disrupting A-Beta fibrils, with consequent abrogation of toxicity. We further characterized the nature of the TTR/A-Beta interaction and found that TTR, both recombinant or isolated from human sera, was able to proteolytically process A-Beta, cleaving the peptide after aminoacid residues 1, 2, 3, 10, 13, 14,16, 19 and 27, as determined by mass spectrometry, and reversed phase chromatography followed by N-terminal sequencing. A-Beta peptides (1-14 and (15-42 showed lower amyloidogenic potential than the full length counterpart, as assessed by thioflavin binding assay and ultrastructural analysis by transmission electron microscopy. A-Beta cleavage by TTR was inhibited in the presence of an alphaAPP peptide containing the Kunitz Protease Inhibitor (KPI domain but not in the presence of the secreted alphaAPP derived from the APP isoform 695 without the KPI domain. TTR was also able to degrade aggregated forms of A-Beta peptide. Our results confirmed TTR as a protective molecule in AD, and prompted A-Beta proteolysis by TTR as a protective mechanism in this disease. TTR may prove to be a useful therapeutic agent for preventing or retarding the cerebral amyloid plaque formation implicated in AD pathology.

  8. Mechanisms and manifestations of toxic actions at the bone tissue level; Mecanismes et manifestations de l'action des toxiques au niveau du tissu osseux

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-07-01

    The principal abnormalities determined by toxic at the bone level are: osteoporosis, osteomalacia, osteosclerosis or osteopetrosis. The principal toxics having a noxiousness at the bone level are: the fluorine, the phosphorus, the lead, the bismuth, the cadmium and the strontium. The strontium 90 has an important radioactivity that gives at the bone level osteosarcomas or at low doses, leukemoid reactions and marrow angiosarcoma. (N.C.)

  9. The study of the mechanism of arsenite toxicity in respiration-deficient cells reveals that NADPH oxidase-derived superoxide promotes the same downstream events mediated by mitochondrial superoxide in respiration-proficient cells

    Energy Technology Data Exchange (ETDEWEB)

    Guidarelli, Andrea; Fiorani, Mara; Carloni, Silvia; Cerioni, Liana; Balduini, Walter; Cantoni, Orazio, E-mail: orazio.cantoni@uniurb.it

    2016-09-15

    We herein report the results from a comparative study of arsenite toxicity in respiration-proficient (RP) and -deficient (RD) U937 cells. An initial characterization of these cells led to the demonstration that the respiration-deficient phenotype is not associated with apparent changes in mitochondrial mass and membrane potential. In addition, similar levels of superoxide (O{sub 2}{sup .-}) were generated by RP and RD cells in response to stimuli specifically triggering respiratory chain-independent mitochondrial mechanisms or extramitochondrial, NADPH-oxidase dependent, mechanisms. At the concentration of 2.5 μM, arsenite elicited selective formation of O{sub 2}{sup .-} in the respiratory chain of RP cells, with hardly any contribution of the above mechanisms. Under these conditions, O{sub 2}{sup .-} triggered downstream events leading to endoplasmic reticulum (ER) stress, autophagy and apoptosis. RD cells challenged with similar levels of arsenite failed to generate O{sub 2}{sup .-} because of the lack of a functional respiratory chain and were therefore resistant to the toxic effects mediated by the metalloid. Their resistance, however, was lost after exposure to four fold greater concentrations of arsenite, coincidentally with the release of O{sub 2}{sup .-} mediated by NADPH oxidase. Interestingly, extramitochondrial O{sub 2}{sup .-} triggered the same downstream events and an identical mode of death previously observed in RP cells. Taken together, the results obtained in this study indicate that arsenite toxicity is strictly dependent on O{sub 2}{sup .-} availability that, regardless of whether generated in the mitochondrial or extramitochondrial compartments, triggers similar downstream events leading to ER stress, autophagy and apoptosis. - Highlights: • Mitochondrial superoxide mediates arsenite toxicity in respiration-proficient cells. • NADPH-derived superoxide mediates arsenite toxicity in respiration-deficient cells. • Arsenite causes apoptosis

  10. Secretome Characterization and Correlation Analysis Reveal Putative Pathogenicity Mechanisms and Identify Candidate Avirulence Genes in the Wheat Stripe Rust Fungus Puccinia striiformis f. sp. tritici.

    Science.gov (United States)

    Xia, Chongjing; Wang, Meinan; Cornejo, Omar E; Jiwan, Derick A; See, Deven R; Chen, Xianming

    2017-01-01

    Stripe (yellow) rust, caused by Puccinia striiformis f. sp. tritici ( Pst ), is one of the most destructive diseases of wheat worldwide. Planting resistant cultivars is an effective way to control this disease, but race-specific resistance can be overcome quickly due to the rapid evolving Pst population. Studying the pathogenicity mechanisms is critical for understanding how Pst virulence changes and how to develop wheat cultivars with durable resistance to stripe rust. We re-sequenced 7 Pst isolates and included additional 7 previously sequenced isolates to represent balanced virulence/avirulence profiles for several avirulence loci in seretome analyses. We observed an uneven distribution of heterozygosity among the isolates. Secretome comparison of Pst with other rust fungi identified a large portion of species-specific secreted proteins, suggesting that they may have specific roles when interacting with the wheat host. Thirty-two effectors of Pst were identified from its secretome. We identified candidates for Avr genes corresponding to six Yr genes by correlating polymorphisms for effector genes to the virulence/avirulence profiles of the 14 Pst isolates. The putative AvYr76 was present in the avirulent isolates, but absent in the virulent isolates, suggesting that deleting the coding region of the candidate avirulence gene has produced races virulent to resistance gene Yr76 . We conclude that incorporating avirulence/virulence phenotypes into correlation analysis with variations in genomic structure and secretome, particularly presence/absence polymorphisms of effectors, is an efficient way to identify candidate Avr genes in Pst . The candidate effector genes provide a rich resource for further studies to determine the evolutionary history of Pst populations and the co-evolutionary arms race between Pst and wheat. The Avr candidates identified in this study will lead to cloning avirulence genes in Pst , which will enable us to understand molecular mechanisms

  11. Discriminating modes of toxic action in mice using toxicity in BALB/c mouse fibroblast (3T3) cells.

    Science.gov (United States)

    Huang, Tao; Yan, Lichen; Zheng, Shanshan; Wang, Yue; Wang, Xiaohong; Fan, Lingyun; Li, Chao; Zhao, Yuanhui; Martyniuk, Christopher J

    2017-12-01

    The objective of this study was to determine whether toxicity in mouse fibroblast cells (3T3 cells) could predict toxicity in mice. Synthesized data on toxicity was subjected to regression analysis and it was observed that relationship of toxicities between mice and 3T3 cells was not strong (R 2  = 0.41). Inclusion of molecular descriptors (e.g. ionization, pKa) improved the regression to R 2  = 0.56, indicating that this relationship is influenced by kinetic processes of chemicals or specific toxic mechanisms associated to the compounds. However, to determine if we were able to discriminate modes of action (MOAs) in mice using the toxicities generated from 3T3 cells, compounds were first classified into "baseline" and "reactive" guided by the toxic ratio (TR) for each compound in mice. Sequence, binomial and recursive partitioning analyses provided strong predictions of MOAs in mice based upon toxicities in 3T3 cells. The correct classification of MOAs based on these methods was 86%. Nearly all the baseline compounds predicted from toxicities in 3T3 cells were identified as baseline compounds from the TR in mice. The incorrect assignment of MOAs for some compounds is hypothesized to be due to experimental uncertainty that exists in toxicity assays for both mice and 3T3 cells. Conversely, lack of assignment can also arise because some reactive compounds have MOAs that are different in mice compared to 3T3 cells. The methods developed here are novel and contribute to efforts to reduce animal numbers in toxicity tests that are used to evaluate risks associated with organic pollutants in the environment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Common Mechanisms Underlying Refractive Error Identified in Functional Analysis of Gene Lists From Genome-Wide Association Study Results in 2 European British Cohorts

    Science.gov (United States)

    Hysi, Pirro G.; Mahroo, Omar A.; Cumberland, Phillippa; Wojciechowski, Robert; Williams, Katie M.; Young, Terri L.; Mackey, David A.; Rahi, Jugnoo S.; Hammond, Christopher J.

    2014-01-01

    IMPORTANCE To date, relatively few genes responsible for a fraction of heritability have been identified by means of large genetic association studies of refractive error. OBJECTIVE To explore the genetic mechanisms that lead to refractive error in the general population. DESIGN, SETTING, AND PARTICIPANTS Genome-wide association studies were carried out in 2 British population-based independent cohorts (N = 5928 participants) to identify genes moderately associated with refractive error. MAIN OUTCOMES AND MEASURES Enrichment analyses were used to identify sets of genes overrepresented in both cohorts. Enriched groups of genes were compared between both participating cohorts as a further measure against random noise. RESULTS Groups of genes enriched at highly significant statistical levels were remarkably consistent in both cohorts. In particular, these results indicated that plasma membrane (P = 7.64 × 10−30), cell-cell adhesion (P = 2.42 × 10−18), synaptic transmission (P = 2.70 × 10−14), calcium ion binding (P = 3.55 × 10−15), and cation channel activity (P = 2.77 × 10−14) were significantly overrepresented in relation to refractive error. CONCLUSIONS AND RELEVANCE These findings provide evidence that development of refractive error in the general population is related to the intensity of photosignal transduced from the retina, which may have implications for future interventions to minimize this disorder. Pathways connected to the procession of the nerve impulse are major mechanisms involved in the development of refractive error in populations of European origin. PMID:24264139

  13. Haloacetonitriles: metabolism and toxicity.

    Science.gov (United States)

    Lipscomb, John C; El-Demerdash, Ebtehal; Ahmed, Ahmed E

    2009-01-01

    The haloacetonitriles (HANs) exist in drinking water exclusively as byproducts of disinfection. HANs are found in drinking water more often, and in higher concentrations, when surface water is treated by chloramination. Human exposure occurs through consumption of finished drinking water; oral and dermal contact also occurs, and results from showering, swimming and other activities. HANs are reactive and are toxic to gastrointestinal tissues following oral administration. Such toxicity is characterized by GSH depletion, increased lipid peroxidation, and covalent binding of HAN-associated radioactivity to gut tissues. The presence of GSH in cells is an important protective mechanism against HAN toxicity; depletion of cellular GSH results in increased toxicity. Some studies have demonstrated an apparently synergistic effect between ROS and HAN administration, that may help explain effects observed in GI tissues. ROS are produced in gut tissues, and in vitro evidence indicates that ROS may contribute to the degradation and formation of reactive intermediates from HANs. The rationale for ROS involvement may involve HAN-induced depletion of GSH and the role of GSH in scavenging ROS. In addition to effects on GI tissues, studies show that HAN-derived radiolabel is found covalently bound to proteins and DNA in several organs and tissues. The addition of antioxidants to biologic systems protects against HAN-induced DNA damage. The protection offered by antioxidants supports the role of oxidative stress and the potential for a threshold in han-induced toxicity. However, additional data are needed to substantiate evidence for such a threshold. HANs are readily absorbed from the GI tract and are extensively metabolized. Elimination occurs primarily in urine, as unconjugated one-carbon metabolites. Evidence supports the involvement of mixed function oxidases, the cytochrome P450 enzyme family and GST, in HAN metabolism. Metabolism represents either a detoxification or

  14. Radionuclide toxicity

    International Nuclear Information System (INIS)

    Galle, P.

    1982-01-01

    The aim of this symposium was to review the radionuclide toxicity problems. Five topics were discussed: (1) natural and artificial radionuclides (origin, presence or emission in the environment, human irradiation); (2) environmental behaviour of radionuclides and transfer to man; (3) metabolism and toxicity of radionuclides (radioiodine, strontium, rare gas released from nuclear power plants, ruthenium-activation metals, rare earths, tritium, carbon 14, plutonium, americium, curium and einsteinium, neptunium, californium, uranium) cancerogenous effects of radon 222 and of its danghter products; (4) comparison of the hazards of various types of energy; (5) human epidemiology of radionuclide toxicity (bone cancer induction by radium, lung cancer induction by radon daughter products, liver cancer and leukaemia following the use of Thorotrast, thyroid cancer; other site of cancer induction by radionuclides) [fr

  15. Thyroid cancer in toxic and non-toxic multinodular goiter

    Directory of Open Access Journals (Sweden)

    Cerci C

    2007-01-01

    Full Text Available Background : Many authors have claimed that hyperthyroidism protects against thyroid cancer and believed that the incidence of malignancy is lower in patients with toxic multinodular goiter (TMG than in those with non-toxic multinodular goiter. But in recent studies, it was reported that the incidence of malignancy with TMG is not as low as previously thought. Aim : To compare the thyroid cancer incidence in patients with toxic and non-toxic multinodular goiter. Settings and Design : Histology reports of patients treated surgically with a preoperative diagnosis of toxic and non-toxic multinodular goiter were reviewed to identify the thyroid cancer incidence. Patients having a history of neck irradiation or radioactive iodine therapy were excluded from the study. Materials and Methods : We reviewed 294 patients operated between 2001-2005 from toxic and non-toxic multinodular goiter. One hundred and twenty-four of them were toxic and 170 were non-toxic. Hyperthyroidism was diagnosed by elevated tri-iodothyroinine / thyroxine ratios and low thyroid-stimulating hormone with clinical signs and symptoms. All patients were evaluated with ultrasonography and scintigraphy and fine needle aspiration biopsy. Statistical Analysis Used : Significance of the various parameters was calculated by using ANOVA test. Results : The incidence of malignancy was 9% in the toxic and 10.58% in the non-toxic multinodular goiter group. Any significant difference in the incidence of cancer and tumor size between the two groups could not be detected. Conclusions : The incidence of malignancy in toxic multinodular goiter is not very low as thought earlier and is nearly the same in non-toxic multinodular goiter.

  16. Molecular mechanisms of the epithelial transport of toxic metal ions, particularly mercury, cadmium, lead, arsenic, zinc, and copper. Comprehensive progress report, October 1, 1975--December 31, 1978

    International Nuclear Information System (INIS)

    Wasserman, R.H.

    1978-10-01

    Investigations were undertaken to elucidate the mode of transepithelial transport of potentially toxic metal ions across the gastrointestinal tract, with primary attention given to cadmium, zinc, and arsenic. In addition, the toxic effects of cadmium on the metabolism of vitamin D and calcium have been investigated in some detail. Several approaches have been taken, including studies on the localization of heavy metals in the intestinal mucosa, the effects of cadmium on various parameters of calcium metabolism, the modes of intestinal absorption of cadmium, arsenate, and zinc, and the interactions of heavy metals with each other and with calcium, phosphorus, and vitamin D. Details of these experiments are attached in the Comprehensive Progress Report

  17. Retrospective analysis of associations between water quality and toxic blooms of golden alga (Prymnesium parvum) in Texas reservoirs: Implications for understanding dispersal mechanisms and impacts of climate change

    Science.gov (United States)

    Patino, Reynaldo; Dawson, D.; VanLandeghem, Matthew M.

    2014-01-01

    Toxic blooms of golden alga (GA, Prymnesium parvum) in Texas typically occur in winter or early spring. In North America, they were first reported in Texas in the 1980s, and a marked range expansion occurred in 2001. Although there is concern about the influence of climate change on the future distribution of GA, factors responsible for past dispersals remain uncertain. To better understand the factors that influence toxic bloom dispersal in reservoirs, this study characterized reservoir water quality associated with toxic GA blooms since 2001, and examined trends in water quality during a 20-year period bracketing the 2001 expansion. Archived data were analyzed for six impacted and six nonimpacted reservoirs from two major Texas basins: Brazos River and Colorado River. Data were simplified for analysis by pooling spatially (across sampling stations) and temporally (winter, December-February) within reservoirs and generating depth-corrected (1 m) monthly values. Classification tree analysis [period of record (POR), 2001-2010] using salinity-associated variables (specific conductance, chloride, sulfate), dissolved oxygen (DO), pH, temperature, total hardness, potassium, nitrate+nitrite, and total phosphorus indicated that salinity best predicts the toxic bloom occurrence. Minimum estimated salinities for toxic bloom formation were 0.59 and 1.02 psu in Brazos and Colorado River reservoirs, respectively. Principal component analysis (POR, 2001-2010) indicated that GA habitat is best defined by higher salinity relative to nonimpacted reservoirs, with winter DO and pH also being slightly higher and winter temperature slightly lower in impacted reservoirs. Trend analysis, however, did not reveal monotonic changes in winter water quality of GA-impacted reservoirs during the 20-year period (1991-2010) bracketing the 2001 dispersal. Therefore, whereas minimum levels of salinity are required for GA establishment and toxic blooms in Texas reservoirs, the lack of trends in

  18. Molecular mechanisms of the epithelial transport of toxic metal ions, particularly mercury, cadmium, lead, arsenic, zinc, and copper. Comprehensive progress report, October 1, 1975--December 31, 1978

    Energy Technology Data Exchange (ETDEWEB)

    Wasserman, R. H.

    1978-10-01

    Investigations were undertaken to elucidate the mode of transepithelial transport of potentially toxic metal ions across the gastrointestinal tract, with primary attention given to cadmium, zinc, and arsenic. In addition, the toxic effects of cadmium on the metabolism of vitamin D and calcium have been investigated in some detail. Several approaches have been taken, including studies on the localization of heavy metals in the intestinal mucosa, the effects of cadmium on various parameters of calcium metabolism, the modes of intestinal absorption of cadmium, arsenate, and zinc, and the interactions of heavy metals with each other and with calcium, phosphorus, and vitamin D. Details of these experiments are attached in the Comprehensive Progress Report.

  19. Degradation of lipid regulators by the UV/chlorine process: Radical mechanisms, chlorine oxide radical (ClO•)-mediated transformation pathways and toxicity changes.

    Science.gov (United States)

    Kong, Xiujuan; Wu, Zihao; Ren, Ziran; Guo, Kaiheng; Hou, Shaodong; Hua, Zhechao; Li, Xuchun; Fang, Jingyun

    2018-06-15

    Degradation of three lipid regulators, i.e., gemfibrozil, bezafibrate and clofibric acid, by a UV/chlorine treatment was systematically investigated. The chlorine oxide radical (ClO • ) played an important role in the degradation of gemfibrozil and bezafibrate with second-order rate constants of 4.2 (±0.3) × 10 8  M -1  s -1 and 3.6 (±0.1) × 10 7  M -1  s -1 , respectively, whereas UV photolysis and the hydroxyl radical (HO • ) mainly contributed to the degradation of clofibric acid. The first-order rate constants (k') for the degradation of gemfibrozil and bezafibrate increased linearly with increasing chlorine dosage, primarily due to the linear increase in the ClO • concentration. The k' values for gemfibrozil, bezafibrate, and clofibric acid degradation decreased with increasing pH from 5.0 to 8.4; however, the contribution of the reactive chlorine species (RCS) increased. Degradation of gemfibrozil and bezafibrate was enhanced in the presence of Br - , whereas it was inhibited in the presence of natural organic matter (NOM). The presence of ammonia at a chlorine: ammonia molar ratio of 1:1 resulted in decreases in the k' values for gemfibrozil and bezafibrate of 69.7% and 7%, respectively, but led to an increase in that for clofibric acid of 61.8%. Degradation of gemfibrozil by ClO • was initiated by hydroxylation and chlorine substitution on the benzene ring. Then, subsequent hydroxylation, bond cleavage and chlorination reactions led to the formation of more stable products. Three chlorinated intermediates were identified during ClO • oxidation process. Formation of the chlorinated disinfection by-products chloral hydrate and 1,1,1-trichloropropanone was enhanced relative to that of other by-products. The acute toxicity of gemfibrozil to Vibrio fischeri increased significantly when subjected to direct UV photolysis, whereas it decreased when oxidized by ClO • . This study is the first to report the transformation pathway of a

  20. High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.

    Science.gov (United States)

    Zeng, Zhihong; Liu, Wenbin; Tsao, Twee; Qiu, YiHua; Zhao, Yang; Samudio, Ismael; Sarbassov, Dos D; Kornblau, Steven M; Baggerly, Keith A; Kantarjian, Hagop M; Konopleva, Marina; Andreeff, Michael

    2017-09-01

    The bone marrow microenvironment is known to provide a survival advantage to residual acute myeloid leukemia cells, possibly contributing to disease recurrence. The mechanisms by which stroma in the microenvironment regulates leukemia survival remain largely unknown. Using reverse-phase protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation in response to the targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), and Nutlin-3a (MDM2), and to identify the effective combination therapy targeting acute myeloid leukemia in the context of the leukemia microenvironment. Stroma reprogrammed signaling networks and modified the sensitivity of acute myeloid leukemia samples to all three targeted inhibitors. Stroma activated AKT at Ser473 in the majority of samples treated with single-agent ABT737 or Nutlin-3a. This survival mechanism was partially abrogated by concomitant treatment with temsirolimus plus ABT737 or Nutlin-3a. Mapping the signaling networks revealed that combinations of two inhibitors increased the number of affected proteins in the targeted pathways and in multiple parallel signaling, translating into facilitated cell death. These results demonstrated that a mechanism-based selection of combined inhibitors can be used to guide clinical drug selection and tailor treatment regimens to eliminate microenvironment-mediated resistance in acute myeloid leukemia. Copyright© 2017 Ferrata Storti Foundation.

  1. Integrative Analysis of Genetic, Genomic, and Phenotypic Data for Ethanol Behaviors: A Network-Based Pipeline for Identifying Mechanisms and Potential Drug Targets.

    Science.gov (United States)

    Bogenpohl, James W; Mignogna, Kristin M; Smith, Maren L; Miles, Michael F

    2017-01-01

    Complex behavioral traits, such as alcohol abuse, are caused by an interplay of genetic and environmental factors, producing deleterious functional adaptations in the central nervous system. The long-term behavioral consequences of such changes are of substantial cost to both the individual and society. Substantial progress has been made in the last two decades in understanding elements of brain mechanisms underlying responses to ethanol in animal models and risk factors for alcohol use disorder (AUD) in humans. However, treatments for AUD remain largely ineffective and few medications for this disease state have been licensed. Genome-wide genetic polymorphism analysis (GWAS) in humans, behavioral genetic studies in animal models and brain gene expression studies produced by microarrays or RNA-seq have the potential to produce nonbiased and novel insight into the underlying neurobiology of AUD. However, the complexity of such information, both statistical and informational, has slowed progress toward identifying new targets for intervention in AUD. This chapter describes one approach for integrating behavioral, genetic, and genomic information across animal model and human studies. The goal of this approach is to identify networks of genes functioning in the brain that are most relevant to the underlying mechanisms of a complex disease such as AUD. We illustrate an example of how genomic studies in animal models can be used to produce robust gene networks that have functional implications, and to integrate such animal model genomic data with human genetic studies such as GWAS for AUD. We describe several useful analysis tools for such studies: ComBAT, WGCNA, and EW_dmGWAS. The end result of this analysis is a ranking of gene networks and identification of their cognate hub genes, which might provide eventual targets for future therapeutic development. Furthermore, this combined approach may also improve our understanding of basic mechanisms underlying gene x

  2. Comparative proteomic analysis of the molecular responses of mouse macrophages to titanium dioxide and copper oxide nanoparticles unravels some toxic mechanisms for copper oxide nanoparticles in macrophages.

    Directory of Open Access Journals (Sweden)

    Sarah Triboulet

    Full Text Available Titanium dioxide and copper oxide nanoparticles are more and more widely used because of their catalytic properties, of their light absorbing properties (titanium dioxide or of their biocidal properties (copper oxide, increasing the risk of adverse health effects. In this frame, the responses of mouse macrophages were studied. Both proteomic and targeted analyses were performed to investigate several parameters, such as phagocytic capacity, cytokine release, copper release, and response at sub toxic doses. Besides titanium dioxide and copper oxide nanoparticles, copper ions were used as controls. We also showed that the overall copper release in the cell does not explain per se the toxicity observed with copper oxide nanoparticles. In addition, both copper ion and copper oxide nanoparticles, but not titanium oxide, induced DNA strands breaks in macrophages. As to functional responses, the phagocytic capacity was not hampered by any of the treatments at non-toxic doses, while copper ion decreased the lipopolysaccharide-induced cytokine and nitric oxide productions. The proteomic analyses highlighted very few changes induced by titanium dioxide nanoparticles, but an induction of heme oxygenase, an increase of glutathione synthesis and a decrease of tetrahydrobiopterin in response to copper oxide nanoparticles. Subsequent targeted analyses demonstrated that the increase in glutathione biosynthesis and the induction of heme oxygenase (e.g. by lovastatin/monacolin K are critical for macrophages to survive a copper challenge, and that the intermediates of the catecholamine pathway induce a strong cross toxicity with copper oxide nanoparticles and copper ions.

  3. Effect of type of explosives and physical-mechanical properties of explosive rock on formation of toxic gases in atmosphere of shafts

    Science.gov (United States)

    Mindeli, E. O.; Khudyakov, M. Y.

    1981-01-01

    The quality of toxic gases formed during explosive work in underground shafts depends upon the type of explosives and the conditions of explosion. Several types of explosives and rocks were examined. All remaining conditions were maintained the same (sandy-argillaceous stemming, electrical method of explosions, diameter of blast holes, and the direct triggering of charges).

  4. Comparative proteomic analysis of the molecular responses of mouse macrophages to titanium dioxide and copper oxide nanoparticles unravels some toxic mechanisms for copper oxide nanoparticles in macrophages.

    Science.gov (United States)

    Triboulet, Sarah; Aude-Garcia, Catherine; Armand, Lucie; Collin-Faure, Véronique; Chevallet, Mireille; Diemer, Hélène; Gerdil, Adèle; Proamer, Fabienne; Strub, Jean-Marc; Habert, Aurélie; Herlin, Nathalie; Van Dorsselaer, Alain; Carrière, Marie; Rabilloud, Thierry

    2015-01-01

    Titanium dioxide and copper oxide nanoparticles are more and more widely used because of their catalytic properties, of their light absorbing properties (titanium dioxide) or of their biocidal properties (copper oxide), increasing the risk of adverse health effects. In this frame, the responses of mouse macrophages were studied. Both proteomic and targeted analyses were performed to investigate several parameters, such as phagocytic capacity, cytokine release, copper release, and response at sub toxic doses. Besides titanium dioxide and copper oxide nanoparticles, copper ions were used as controls. We also showed that the overall copper release in the cell does not explain per se the toxicity observed with copper oxide nanoparticles. In addition, both copper ion and copper oxide nanoparticles, but not titanium oxide, induced DNA strands breaks in macrophages. As to functional responses, the phagocytic capacity was not hampered by any of the treatments at non-toxic doses, while copper ion decreased the lipopolysaccharide-induced cytokine and nitric oxide productions. The proteomic analyses highlighted very few changes induced by titanium dioxide nanoparticles, but an induction of heme oxygenase, an increase of glutathione synthesis and a decrease of tetrahydrobiopterin in response to copper oxide nanoparticles. Subsequent targeted analyses demonstrated that the increase in glutathione biosynthesis and the induction of heme oxygenase (e.g. by lovastatin/monacolin K) are critical for macrophages to survive a copper challenge, and that the intermediates of the catecholamine pathway induce a strong cross toxicity with copper oxide nanoparticles and copper ions.

  5. An integrated (electro- and bio-oxidation) approach for remediation of industrial wastewater containing azo-dyes: Understanding the degradation mechanism and toxicity assessment

    International Nuclear Information System (INIS)

    Aravind, Priyadharshini; Selvaraj, Hosimin; Ferro, Sergio; Sundaram, Maruthamuthu

    2016-01-01

    Highlights: • Firstly, the mediated electro-oxidation allows rapid discoloration of the effluent. • Cost effective sunlight-mediated removal of bio-toxic active chlorine species. • Electrochemical pretreatment enhances the biodegradability of textile wastewater. • About 90% COD removal was achieved by a subsequent biodegradation. • By-products from degradation of dyes have shown to be ecofriendly and non-toxic. - Abstract: A hybrid approach for the remediation of recalcitrant dye wastewater is proposed. The chlorine-mediated electrochemical oxidation of real textile effluents and synthetic samples (using Ti/IrO_2-RuO_2-TiO_2 anodes), lead to discoloration by 92% and 89%, respectively, in 100 min, without significant mineralization. The remediation was obtained through biodegradation, after removing the residual bio-toxic active chlorine species via sunlight exposition. Results show that the electrochemical discoloration enhances the effluent biodegradability with about 90% COD removal employing acclimatized naphthalene-degrading bacterial consortia, within 144 h. Based on results obtained through FT-IR and GC–MS, it is likely that azo group stripping and oxidative cleavage of dyes occur due to the nucleophilic attack of active chlorine species during electro-oxidation. This leads to generation of aromatic intermediates which are further desulfonated, deaminated or oxidized only at their functional groups. These aromatic intermediates were mineralized into simpler organic acids and aldehydes by bacterial consortia. Phyto-toxicity trials on Vigna radiata confirmed the toxic nature of the untreated dye solutions. An increase in root and shoot development was observed with the electrochemically treated solutions, the same was higher in case of bio-treated solutions. Overall, obtained results confirm the capability of the proposed hybrid oxidation scheme for the remediation of textile wastewater.

  6. An integrated (electro- and bio-oxidation) approach for remediation of industrial wastewater containing azo-dyes: Understanding the degradation mechanism and toxicity assessment

    Energy Technology Data Exchange (ETDEWEB)

    Aravind, Priyadharshini, E-mail: priya.bdu07@gmail.com [Corrosion and Materials Protection Division (CMPD), CSIR—Central electrochemical research institute (CECRI), Karaikudi 630 003 (India); Selvaraj, Hosimin [Corrosion and Materials Protection Division (CMPD), CSIR—Central electrochemical research institute (CECRI), Karaikudi 630 003 (India); Ferro, Sergio [Ecas4 Australia, Unit 8, 1 London Road, Mile End, South Australia 5031 (Australia); Sundaram, Maruthamuthu [Corrosion and Materials Protection Division (CMPD), CSIR—Central electrochemical research institute (CECRI), Karaikudi 630 003 (India)

    2016-11-15

    Highlights: • Firstly, the mediated electro-oxidation allows rapid discoloration of the effluent. • Cost effective sunlight-mediated removal of bio-toxic active chlorine species. • Electrochemical pretreatment enhances the biodegradability of textile wastewater. • About 90% COD removal was achieved by a subsequent biodegradation. • By-products from degradation of dyes have shown to be ecofriendly and non-toxic. - Abstract: A hybrid approach for the remediation of recalcitrant dye wastewater is proposed. The chlorine-mediated electrochemical oxidation of real textile effluents and synthetic samples (using Ti/IrO{sub 2}-RuO{sub 2}-TiO{sub 2} anodes), lead to discoloration by 92% and 89%, respectively, in 100 min, without significant mineralization. The remediation was obtained through biodegradation, after removing the residual bio-toxic active chlorine species via sunlight exposition. Results show that the electrochemical discoloration enhances the effluent biodegradability with about 90% COD removal employing acclimatized naphthalene-degrading bacterial consortia, within 144 h. Based on results obtained through FT-IR and GC–MS, it is likely that azo group stripping and oxidative cleavage of dyes occur due to the nucleophilic attack of active chlorine species during electro-oxidation. This leads to generation of aromatic intermediates which are further desulfonated, deaminated or oxidized only at their functional groups. These aromatic intermediates were mineralized into simpler organic acids and aldehydes by bacterial consortia. Phyto-toxicity trials on Vigna radiata confirmed the toxic nature of the untreated dye solutions. An increase in root and shoot development was observed with the electrochemically treated solutions, the same was higher in case of bio-treated solutions. Overall, obtained results confirm the capability of the proposed hybrid oxidation scheme for the remediation of textile wastewater.

  7. Mechanics

    CERN Document Server

    Hartog, J P Den

    1961-01-01

    First published over 40 years ago, this work has achieved the status of a classic among introductory texts on mechanics. Den Hartog is known for his lively, discursive and often witty presentations of all the fundamental material of both statics and dynamics (and considerable more advanced material) in new, original ways that provide students with insights into mechanical relationships that other books do not always succeed in conveying. On the other hand, the work is so replete with engineering applications and actual design problems that it is as valuable as a reference to the practicing e

  8. The Interferon-signature of Sjögren’s Syndrome: How Unique Biomarkers Can Identify Underlying Inflammatory and Immunopathological Mechanisms of Specific Diseases

    Directory of Open Access Journals (Sweden)

    Cuong eNguyen

    2013-07-01

    Full Text Available Innate immune responses direct the nature and specificity of downstream adaptive responses in autoimmune diseases. One of the strongest markers of innate immunity is the up-regulated expression of interferon (IFN and IFN-responsive/stimulated genes (IRGs/ISGs. While multiple IRGs are induced during the innate phase of host responses, transcriptome data suggest unique IRG-signatures for different diseases. Sjögren’s syndrome (SjS is characterized by chronic immune attacks against exocrine glands leading to exocrine dysfunction, plus strong up-regulated expressions of IFN IRG transcripts. Genome-wide transcriptome analyses indicate that differentially-expressed IRGs are restricted during disease development and therefore define underlying etiopathological mechanisms. Here we review the innate immune-associated IFN-signature of SjS and show how differential gene expressions of IRG/ISG sets interact molecularly and biologically to identify critical details of SjS etiopathogenesis.

  9. Spontaneous bacteriocin resistance in Listeria monocytogenes as a susceptibility screen for identifying different mechanisms of resistance and modes of action by bacteriocins of lactic acid bacteria.

    Science.gov (United States)

    Macwana, Sunita; Muriana, Peter M

    2012-01-01

    A practical system was devised for grouping bacteriocins of lactic acid bacteria (LAB) based on mode of action as determined by changes in inhibitory activity to spontaneously-acquired bacteriocin resistance (Bac(R)). Wild type Listeria monocytogenes 39-2 was sensitive to five bacteriocins produced by 3 genera of LAB: pediocin PA-1 and pediocin Bac3 (Pediococcus), lacticin FS97 and lacticin FS56 (Lactococcus), and curvaticin FS47 (Lactobacillus). A spontaneous Bac(R) derivative of L. monocytogenes 39-2 obtained by selective recovery against lacticin FS56 provided complete resistance to the bacteriocin made by Lactococcus lactis FS56. The lacticin FS56-resistant strain of L. monocyotgenes 39-2 was also cross-resistant to curvaticin FS47 and pediocin PA-1, but not to lacticin FS97 or pediocin Bac3. The same pattern of cross-resistance was also observed with Bac(R) isolates obtained with L. monocytogenes Scott A-2. A spontaneous mutation that renders a strain cross-resistant to different bacteriocins indicates that they share a common mechanism of resistance due to similar modes of action of the bacteriocins. Spontaneous resistance was acquired to other bacteriocins (in aggregate) by following the same procedure against which the Bac(R) strain was still sensitive. In subsequent challenge assays, mixtures of bacteriocins of different modes of action provided greater inhibition than mixtures of bacteriocins of the same mode of action (as determined by our screening method). This study identifies a methodical approach to classify bacteriocins into functional groups based on mechanism of resistance (i.e., mode of action) that could be used for identifying the best mixture of bacteriocins for use as biopreservatives. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Molecular mechanisms of the epithelial transport of toxic metal ions, particularly mercury, cadmium, lead, arsenic, zinc and copper. Progress report, January 1, 1980-December 31, 1980

    International Nuclear Information System (INIS)

    Wasserman, R.H.

    1980-01-01

    Investigations were continued to elucidate the mode of transepithelial transport of toxic metal ions across the gastrointestinal tract, as well as their interactions with biological processes and other metal ions. All experimental details that are either published, submitted for publication or in press during this report period are included in the Appendix. Primary attention for this report has been given to the intestinal absorption of lead and its interaction with other biological moieties

  11. Investigating the mechanisms of Ni uptake and sub-lethal toxicity in the Atlantic killifish Fundulus heteroclitus in relation to salinity

    International Nuclear Information System (INIS)

    Blewett, Tamzin A.; Ransberry, Victoria E.; McClelland, Grant B.; Wood, Chris M.

    2016-01-01

    The Atlantic killifish (Fundulus heteroclitus) is a resilient estuarine species that may be subjected to anthropogenic contamination of its natural habitat, by toxicants such as nickel (Ni). We investigated Ni accumulation and potential modes of Ni toxicity, in killifish, as a function of environmental salinity. Killifish were acclimated to 4 different salinities [0 freshwater (FW), 10, 30 and 100% seawater (SW)] and exposed to 5 mg/L of Ni for 96 h. Tissue Ni accumulation, whole body ions, critical swim speed and oxidative stress parameters were examined. SW was protective against Ni accumulation in the gills and kidney. Addition of Mg and Ca to FW protected against gill Ni accumulation, suggesting competition with Ni for uptake. Concentration-dependent Ni accumulation in the gill exhibited saturable relationships in both FW- and SW-acclimated fish. However SW fish displayed a lower B_m_a_x (i.e. lower number of Ni binding sites) and a lower K_m (i.e. higher affinity for Ni binding). No effect of Ni exposure was observed on critical swim speed (U_c_r_i_t) or maximum rate of oxygen consumption (MO_2_m_a_x). Markers of oxidative stress showed either no effect (e.g. protein carbonyl formation), or variable effects that appeared to depend more on salinity than on Ni exposure. These data indicate that the killifish is very tolerant to Ni toxicity, a characteristic that may facilitate the use of this species as a site-specific biomonitor of contaminated estuaries. - Highlights: • SW was protective against Ni accumulation in the gills and kidney only. • Mg and Ca in FW protected against Ni accumulation, suggesting competition with Ni. • No effect of Ni exposure was observed on critical swim speed or oxygen consumption. - Marine vertebrates do not have the same response to Ni toxicity as freshwater vertebrates and as such. Euryhaline killifish may be very useful as site-specific biomonitors.

  12. The Study of Compound Quality of various Siam Weed (Eupatorium odoratum) Extracts and Toxicity Detoxification mechanisms Against 3rd Instar Larvae of Fruit Fly (Dacus dorsalis)

    International Nuclear Information System (INIS)

    Sutthivaiyakit, Pakawadee; Visetson, Suraphon; Sutthivaiyakit, Somyote; Patharakorn, Thipamon; Patharakorn, Surapol; Piadang, Patharakorn

    2006-09-01

    The 1H-NMR spectroscopy showed signals of DeltaH tild0.71.6 from hexane-leaf extracts from Siam weed (Eupatorium odoratum) These signals derive from protons of non-polar compounds which include fatty acid residues and terpinoids. In addition, the amplification of the signals indicated of some minor DeltaH tild6.2-7.7. This revealed protons from aromatic rings possibly involving in flavonoids from 1H-NMR spectrum. This is a believe that is a believe that these compounds could be varied from slightly polar compounds to moderately polar compounds. Furthermore, the Thin Layer Chromatography (TLC) of hexane, chloroform and methanol fractions showed the extracts composed of majority of less polar. It is and indication of the method of separation is quite food for separation of polarity basis from these extracts. Finally, the TLC of hexane fraction distinctively produced 7-8 compounds from the extracts. Toxicity testing using topical spray method showed that methnoloc extracts gave highest toxicity against 3rd instar larvae of fruit fly (Darcus dorsalis). The root extracts produced ca. 5 fold mohile GSH-S-transferase ws elevated 2-3 fold. The addition of dimethyl maleate into the extraccts increased their toxicity. The persistent experiment of eupathal from the extracts showed that the extracts can be stabilixed under aqueous solution upto 1 month with losing the compound. Finally, the Siam weed extracts prosuced non toxic to non-target organisms such as gabbies, bee, and mouse. The results of LC50 showed 15,000-26,000 mg/L 6,000-15,000 mg/L and 3,000-10,000 mg/L from hexane, chloroform and methanol extracts, respectively.

  13. An integrated (electro- and bio-oxidation) approach for remediation of industrial wastewater containing azo-dyes: Understanding the degradation mechanism and toxicity assessment.

    Science.gov (United States)

    Aravind, Priyadharshini; Selvaraj, Hosimin; Ferro, Sergio; Sundaram, Maruthamuthu

    2016-11-15

    A hybrid approach for the remediation of recalcitrant dye wastewater is proposed. The chlorine-mediated electrochemical oxidation of real textile effluents and synthetic samples (using Ti/IrO2-RuO2-TiO2 anodes), lead to discoloration by 92% and 89%, respectively, in 100min, without significant mineralization. The remediation was obtained through biodegradation, after removing the residual bio-toxic active chlorine species via sunlight exposition. Results show that the electrochemical discoloration enhances the effluent biodegradability with about 90% COD removal employing acclimatized naphthalene-degrading bacterial consortia, within 144h. Based on results obtained through FT-IR and GC-MS, it is likely that azo group stripping and oxidative cleavage of dyes occur due to the nucleophilic attack of active chlorine species during electro-oxidation. This leads to generation of aromatic intermediates which are further desulfonated, deaminated or oxidized only at their functional groups. These aromatic intermediates were mineralized into simpler organic acids and aldehydes by bacterial consortia. Phyto-toxicity trials on Vigna radiata confirmed the toxic nature of the untreated dye solutions. An increase in root and shoot development was observed with the electrochemically treated solutions, the same was higher in case of bio-treated solutions. Overall, obtained results confirm the capability of the proposed hybrid oxidation scheme for the remediation of textile wastewater. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. miR Profiling Identifies Cyclin-Dependent Kinase 6 Downregulation as a Potential Mechanism of Acquired Cisplatin Resistance in Non-Small-Cell Lung Carcinoma.

    Science.gov (United States)

    Bar, Jair; Gorn-Hondermann, Ivan; Moretto, Patricia; Perkins, Theodore J; Niknejad, Nima; Stewart, David J; Goss, Glenwood D; Dimitroulakos, Jim

    2015-11-01

    To identify the mechanisms of cisplatin resistance, global microRNA (miR) expression was tested. The expression of miR-145 was consistently higher in resistant cells. The expression of cyclin-dependent kinase 6 (CDK6), a potential target of miR-145, was lower in resistant cells, and inhibition of CDK4/6 protected cells from cisplatin. Cell cycle inhibition, currently being tested in clinical trials, might be antagonistic to cisplatin and other cytotoxic drugs. Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death. Platinum-based chemotherapeutic drugs are the most active agents in treating advanced disease. Resistance to these drugs is common and multifactorial; insight into the molecular mechanisms involved will likely enhance efficacy. A set of NSCLC platinum-resistant sublines was created from the Calu6 cell line. Cell viability was quantified using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Differentially expressed microRNAs (miRs) in these lines were identified using Affymetrix miR arrays. The potential genes targeted by these miRs were searched using the TargetScan algorithm. The expression levels of miRs and mRNA were tested using real-time polymerase chain reaction. miR-145 was reproducibly elevated in all the resistant sublines tested; however, modulation of miR-145 levels alone in these cells did not affect their response to cisplatin. A potential target of miR-145 is cyclin-dependent kinase 6 (CDK6), an important regulator of cell proliferation. The mRNA and protein levels of CDK6 were both downregulated in the resistant sublines. An inhibitor of CDK4/6 (PD0332991) protected parental NSCLC cells from cisplatin cytotoxicity. In the present study, we identified miRs differentially expressed in cisplatin-resistant cell lines, including miR-145. A predicted target of miR-145 is CDK6, and its expression was found to be downregulated in the resistant sublines, although not directly by miR-145. Inhibition

  15. Toxic shock syndrome

    Science.gov (United States)

    Staphylococcal toxic shock syndrome; Toxic shock-like syndrome; TSLS ... Toxic shock syndrome is caused by a toxin produced by some types of staphylococcus bacteria. A similar problem, called toxic shock- ...

  16. Human Toxicity

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Fantke, Peter

    2015-01-01

    all chemicals and impact pathways characterizes the contribution of each factor to the total variation of 10–12 orders of magnitude in impacts per kg across all chemicals. This large variation between characterisation factors for different chemicals as well as the 3 orders of magnitude uncertainty....... As a whole, the assessment of toxicity in LCA has progressed on a very sharp learning curve during the past 20 years. This rapid progression is expected to continue in the coming years, focusing more on direct exposure of workers to chemicals during manufacturing and of consumers during product use...

  17. Una red neuronal binaria para la identificación de mecanismos isomorfos. // A binary Neural network for identifying isomorphic mechanisms.

    Directory of Open Access Journals (Sweden)

    G. Galán Marín

    2002-05-01

    Full Text Available Un problema de importancia primordial en el diseño mecánico es identificar los mecanismos isomorfos, puesto que los isomorfismos nodetectados generan soluciones duplicadas y por tanto suponen un esfuerzo innecesario en el proceso de diseño. Desde 1960, una grancantidad de métodos han sido propuestos para la detección de mecanismos isomorfos. Sin embargo, diversos trabajos han mostrado queaunque pueden existir algoritmos eficaces para casos particulares, en el caso general los métodos tradicionales para la detección deisomorfismos en cadenas cinemáticas no proporcionan usualmente soluciones eficientes para este problema, que ha sido clasificado comoNP-duro. Un eficaz método alternativo para la resolución de problemas NP-duros ha surgido recientemente con las redes neuronales. Eneste trabajo proponemos un nuevo modelo de red neuronal binaria diseñado para la resolución del problema de detección de mecanismosisomorfos. El modelo propuesto se halla basado en unas dinámicas discretas que garantizan una rápida y correcta convergencia de la redhacia soluciones aceptables. Las simulaciones numéricas muestran en los mecanismos analizados que la red neuronal propuestaproporciona excelentes resultados, mostrándose además muy superior a la red de Hopfield continua tradicional en lo que respecta al tiempode computación y en la facilidad de su implementación.Palabras claves: Mecanismos isomorfos, síntesis de mecanismos, isomorfismo de grafos, red neuronal binaria,redes de Hopfield.____________________________________________________________________________AbstractAn important step in the kinematic mechanism synthesis process is to identify graph isomorphism whilegenerating new mechanisms. Undetected isomorphisms result in duplicate solutions and unnecessary effort.Since 1960, a lot of methods have been proposed for the graph isomorphism identification. Some authors haveconcluded that, in the general case, the traditional methods of

  18. Lead toxicity: current concerns.

    OpenAIRE

    Goyer, R A

    1993-01-01

    Over the 20-year period since the first issue of Environmental Health Perspectives was published, there has been considerable progress in the understanding of the potential toxicity of exposure to lead. Many of these advances have been reviewed in published symposia, conferences, and review papers in EHP. This brief review identifies major advances as well as a number of current concerns that present opportunities for prevention and intervention strategies. The major scientific advance has be...

  19. Toxic releases from power plants

    International Nuclear Information System (INIS)

    Rubin, E.S.

    1999-01-01

    Beginning in 1998, electric power plants burning coal or oil must estimate and report their annual releases of toxic chemicals listed in the Toxics Release Inventory (TRI) published by the US Environmental Protection Agency (EPA). This paper identifies the toxic chemicals of greatest significance for the electric utility sector and develops quantitative estimates of the toxic releases reportable to the TRI for a representative coal-fired power plant. Key factors affecting the magnitude and types of toxic releases for individual power plants also are discussed. A national projection suggests that the magnitude of electric utility industry releases will surpass those of the manufacturing industries which current report to the TRI. Risk communication activities at the community level will be essential to interpret and provide context for the new TRI results

  20. Metaproteomics Identifies the Protein Machinery Involved in Metal and Radionuclide Reduction in Subsurface Microbiomes and Elucidates Mechanisms and U(VI) Reduction Immobilization

    Energy Technology Data Exchange (ETDEWEB)

    Pfiffner, Susan M. [Univ. of Tennessee, Knoxville, TN (United States); Löffler, Frank [Univ. of Tennessee, Knoxville, TN (United States); Ritalahti, Kirsti [Univ. of Tennessee, Knoxville, TN (United States); Sayler, Gary [Univ. of Tennessee, Knoxville, TN (United States); Layton, Alice [Univ. of Tennessee, Knoxville, TN (United States); Hettich, Robert [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-08-31

    The overall goal for this funded project was to develop and exploit environmental metaproteomics tools to identify biomarkers for monitoring microbial activity affecting U speciation at U-contaminated sites, correlate metaproteomics profiles with geochemical parameters and U(VI) reduction activity (or lack thereof), elucidate mechanisms contributing to U(VI) reduction, and provide remediation project managers with additional information to make science-based site management decisions for achieving cleanup goals more efficiently. Although significant progress has been made in elucidating the microbiology contribution to metal and radionuclide reduction, the cellular components, pathway(s), and mechanisms involved in U trans-formation remain poorly understood. Recent advances in (meta)proteomics technology enable detailed studies of complex samples, including environmental samples, which differ between sites and even show considerable variability within the same site (e.g., the Oak Ridge IFRC site). Additionally, site-specific geochemical conditions affect microbial activity and function, suggesting generalized assessment and interpretations may not suffice. This research effort integrated current understanding of the microbiology and biochemistry of U(VI) reduction and capitalize on advances in proteomics technology made over the past few years. Field-related analyses used Oak Ridge IFRC field ground water samples from locations where slow-release substrate biostimulation has been implemented to accelerate in situ U(VI) reduction rates. Our overarching hypothesis was that the metabolic signature in environmental samples, as deciphered by the metaproteome measurements, would show a relationship with U(VI) reduction activity. Since metaproteomic and metagenomic characterizations were computationally challenging and time-consuming, we used a tiered approach that combines database mining, controlled laboratory studies, U(VI) reduction activity measurements, phylogenetic

  1. How cannabis causes paranoia: using the intravenous administration of ∆9-tetrahydrocannabinol (THC) to identify key cognitive mechanisms leading to paranoia.

    Science.gov (United States)

    Freeman, Daniel; Dunn, Graham; Murray, Robin M; Evans, Nicole; Lister, Rachel; Antley, Angus; Slater, Mel; Godlewska, Beata; Cornish, Robert; Williams, Jonathan; Di Simplicio, Martina; Igoumenou, Artemis; Brenneisen, Rudolf; Tunbridge, Elizabeth M; Harrison, Paul J; Harmer, Catherine J; Cowen, Philip; Morrison, Paul D

    2015-03-01

    Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis-∆(9)-tetrahydrocannabinol (THC)-causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

  2. Synthesized TiO{sub 2}/ZSM-5 composites used for the photocatalytic degradation of azo dye: Intermediates, reaction pathway, mechanism and bio-toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Kefu; Hu, Xin-Yan [College of the Environment and Ecology, Xiamen University, Xiamen (China); Chen, Bor-Yann; Hsueh, Chung-Chuan [Department of Chemical and Materials Engineering, National I-Lan University, I-Lan, Taiwan (China); Zhang, Qian [Department of Environmental Engineering, National Taiwan University, Taipei, Taiwan (China); Wang, Jiajie; Lin, Yu-Jung [College of the Environment and Ecology, Xiamen University, Xiamen (China); Chang, Chang-Tang, E-mail: ctchang73222@gmail.com [Department of Environmental Engineering, National I-Lan University, I-Lan, Taiwan (China)

    2016-10-15

    Highlights: • The major photo-catalytic degradation pathway of azo-dye was elaborated according to the identification of by-products from GC–MS and IC analysis. • Comparative assessment on characteristics of abiotic and biotic dye decolorization was analyzed. • EDTA (hole scavengers) and t-BuOH (radical scavengers) were used to determine the main active oxidative species in the system. • The toxicity effects of degradation intermediates of Reactive Black 5 (RB5) on the cellular respiratory activity were assessed. - Abstract: In this study, a one-step solid dispersion method was used to synthesize titanium dioxide (TiO{sub 2})/Zeolite Socony Mobil-5 (ZSM-5) composites with substantially reduced time and energy consumption. A degradation efficiency of more than 95% was achieved within 10 min using 50% PTZ (synthesized TiO{sub 2}/ZSM-5 composites with TiO{sub 2} contents of 50 wt% loaded on ZSM-5) at pH 7 and 25 °C. The possible degradation pathway of azo-dye Reactive Black 5 (RB5) was investigated using gas chromatography–mass spectrometry and ion chromatography (IC). The bonds between the N atoms and naphthalene groups are likely attacked first and cleaved by hydroxyl radicals, ultimately resulting in the decolorization and mineralization of the azo dye. A comparative assessment of the characteristics of abiotic and biotic dye decolorization was completed. In addition, the toxicity effects of the degradation intermediates of azo-dye RB5 on cellular respiratory activity were analyzed. The bio-toxicity results showed that the decay rate constants of CO{sub 2} production from the azo-dye RB5 samples at different degradation times increased initially and subsequently decreased, indicating that intermediates of higher toxicity could adhere to the catalyst surface and gradually destroyed by further photocatalytic oxidation. Additionally, EDTA (hole scavengers) and t-BuOH (radical scavengers) were used to detect the main active oxidative species in the system

  3. Toxicity of Uranium Adsorbent Materials using the Microtox Toxicity Test

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jiyeon [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Jeters, Robert T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Gill, Gary A. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Kuo, Li-Jung [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Bonheyo, George T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2015-10-01

    The Marine Sciences Laboratory at the Pacific Northwest National Laboratory evaluated the toxicity of a diverse range of natural and synthetic materials used to extract uranium from seawater. The uranium adsorbent materials are being developed as part of the U. S. Department of Energy, Office of Nuclear Energy, Fuel Resources Program. The goal of this effort was to identify whether deployment of a farm of these materials into the marine environment would have any toxic effects on marine organisms.

  4. Mechanics

    CERN Document Server

    Chester, W

    1979-01-01

    When I began to write this book, I originally had in mind the needs of university students in their first year. May aim was to keep the mathematics simple. No advanced techniques are used and there are no complicated applications. The emphasis is on an understanding of the basic ideas and problems which require expertise but do not contribute to this understanding are not discussed. How­ ever, the presentation is more sophisticated than might be considered appropri­ ate for someone with no previous knowledge of the subject so that, although it is developed from the beginning, some previous acquaintance with the elements of the subject would be an advantage. In addition, some familiarity with element­ ary calculus is assumed but not with the elementary theory of differential equations, although knowledge of the latter would again be an advantage. It is my opinion that mechanics is best introduced through the motion of a particle, with rigid body problems left until the subject is more fully developed. Howev...

  5. Cobalt toxicity: Chemical and radiological combined effects on HaCaT keratinocyte cell line

    International Nuclear Information System (INIS)

    Sandre, C.; Moulin, C.; Bresson, C.; Gault, N.; Poncy, J. L.; Lefaix, J. L.

    2010-01-01

    Cobalt (Co) is an essential trace element well known as a constituent of vitamin B 12 , but different compounds of Co are also described as highly toxic and/or radio-toxic for individuals or the environment. In nuclear power plants, 58 Co and 60 Co are radioactive isotopes of cobalt present as activation products of stable Co and Ni used in alloys. Skin exposure is a current occupational risk in the hard metal and nuclear industries. As biochemical and molecular cobalt-induced toxicological mechanisms are not fully identified, we investigated cobalt toxicity in a model human keratinocyte cell line, HaCaT. In this study, we propose a model to determine the in vitro chemical impact on cell viability of a soluble form of cobalt (CoCl 2 ) with or without gamma-ray doses to mimic contamination by 60 Co, to elucidate the mechanisms of cobalt intracellular chemical and radiological toxicity. Intracellular cobalt concentration was determined after HaCaT cell contamination and chemical toxicity was evaluated in terms of cellular viability and clonogenic survival. We investigated damage to DNA in HaCaT cells by combined treatment with chemical cobalt and a moderate gamma-ray dose. Additive effects of cobalt and irradiation were demonstrated. The underlying mechanism of cobalt toxicity is not clearly established, but our results seem to indicate that the toxicity of Co(II) and of irradiation arises from production of reactive oxygen species. (authors)

  6. Cobalt toxicity: Chemical and radiological combined effects on HaCaT keratinocyte cell line

    Energy Technology Data Exchange (ETDEWEB)

    Gault, N. [CEA Fontenay aux Roses, DSV/IRCM/SCSR/LRTS, 92265 Fontenay aux Rose (France); Sandre, C.; Moulin, B.; Bresson, C. [CEA, DEN, SECR, Laboratoire de Speciation des Radionucleides et des Molecules, F-91191 Gif-sur-Yvette (France); Poncy, J.L. [CEA Bruyeres Le Chatel, DSV/IRCM/SREIT/LRT, 91680 Bruyeres Le Chatel (France); Lefaix, J.L. [CEA Caen, DSV/IRCM/SRO/LARIA, 14070 Caen (France)

    2010-07-01

    Cobalt (Co) is an essential trace element well known as a constituent of vitamin B12, but different compounds of Co are also described as highly toxic and/or radio-toxic for individuals or the environment. In nuclear power plants, {sup 58}Co and {sup 60}Co are radioactive isotopes of cobalt present as activation products of stable Co and Ni used in alloys. Skin exposure is a current occupational risk in the hard metal and nuclear industries. As biochemical and molecular cobalt-induced toxicological mechanisms are not fully identified, we investigated cobalt toxicity in a model human keratinocyte cell line, HaCaT. In this study, we propose a model to determine the in vitro chemical impact on cell viability of a soluble form of cobalt (CoCl{sub 2}) with or without {gamma}-ray doses to mimic contamination by {sup 60}Co, to elucidate the mechanisms of cobalt intracellular chemical and radiological toxicity. Intracellular cobalt concentration was determined after HaCaT cell contamination and chemical toxicity was evaluated in terms of cellular viability and clonogenic survival. We investigated damage to DNA in HaCaT cells by combined treatment with chemical cobalt and a moderate {gamma}-ray dose. Additive effects of cobalt and irradiation were demonstrated. The underlying mechanism of cobalt toxicity is not clearly established, but our results seem to indicate that the toxicity of Co(II) and of irradiation arises from production of reactive oxygen species. (authors)

  7. Cobalt toxicity: Chemical and radiological combined effects on HaCaT keratinocyte cell line

    Energy Technology Data Exchange (ETDEWEB)

    Sandre, C.; Moulin, C.; Bresson, C. [CEA Saclay, DEN, SECR, Lab Speciat Radionucleides and Mol, F-91191 Gif Sur Yvette (France); Gault, N. [CEA Fontenay Roses, DSV IRCM SCSR LRTS, F-92265 Fontenay Aux Roses (France); Poncy, J. L. [CEA Bruyeres Le Chatel, DSV IRCM SREIT LRT, F-91680 Bruyeres Le Chatel (France); Lefaix, J. L. [CEA Caen, DSV IRCM SRO LARIA, F-14070 Caen (France)

    2010-07-01

    Cobalt (Co) is an essential trace element well known as a constituent of vitamin B{sub 12}, but different compounds of Co are also described as highly toxic and/or radio-toxic for individuals or the environment. In nuclear power plants, {sup 58}Co and {sup 60}Co are radioactive isotopes of cobalt present as activation products of stable Co and Ni used in alloys. Skin exposure is a current occupational risk in the hard metal and nuclear industries. As biochemical and molecular cobalt-induced toxicological mechanisms are not fully identified, we investigated cobalt toxicity in a model human keratinocyte cell line, HaCaT. In this study, we propose a model to determine the in vitro chemical impact on cell viability of a soluble form of cobalt (CoCl{sub 2}) with or without gamma-ray doses to mimic contamination by {sup 60}Co, to elucidate the mechanisms of cobalt intracellular chemical and radiological toxicity. Intracellular cobalt concentration was determined after HaCaT cell contamination and chemical toxicity was evaluated in terms of cellular viability and clonogenic survival. We investigated damage to DNA in HaCaT cells by combined treatment with chemical cobalt and a moderate gamma-ray dose. Additive effects of cobalt and irradiation were demonstrated. The underlying mechanism of cobalt toxicity is not clearly established, but our results seem to indicate that the toxicity of Co(II) and of irradiation arises from production of reactive oxygen species. (authors)

  8. Toxic pollutants emitted from thermal decomposition of phthalimide compounds

    Energy Technology Data Exchange (ETDEWEB)

    Chen Kai; Mackie, John C.; Wojtalewicz, Dominika; Kennedy, Eric M. [Process Safety and Environmental Protection Research Group, School of Engineering, The University of Newcastle, Callaghan, New South Wales 2308 (Australia); Dlugogorski, Bogdan Z., E-mail: Bogdan.Dlugogorski@newcastle.edu.au [Process Safety and Environmental Protection Research Group, School of Engineering, University of Newcastle, Callaghan, New South Wales 2308 (Australia)

    2011-03-15

    Phthalimide (PI) and tetrahydrophthalimide (THPI) are two structurally similar compounds extensively used as intermediates for the synthesis of variety of industrial chemicals. This paper investigates the thermal decomposition of PI and THPI under oxygen rich to oxygen lean conditions, quantifying the production of toxicants and explaining their formation pathways. The experiments involved a plug flow reactor followed by silica cartridges, activated charcoal trap and a condenser, with the decomposition products identified and quantified by Fourier transform infrared spectroscopy (FTIR), gas chromatography-mass spectrometry (GC-MS) and micro gas chromatography ({mu}GC). The density functional theory (DFT) calculations served to obtain dissociation energies and reaction pathways, to elucidate the reaction mechanism. The oxidation of PI and THPI produced several toxic nitrogen-containing gases and volatile organic compounds, including hydrogen cyanide, isocyanic acid, nitrogen oxides, benzonitrile, maleimide and tentatively identified benzenemethanimine. The detection of dibenzo-p-dioxin (DD) and dibenzofuran (DF) suggests potential formation of the toxic persistent organic pollutants (POPs) in fires involving PI and THPI, in presence of a chlorine source. The oxidation of THPI produced 2-cyclohexen-1-one, a toxic unsaturated ketone. The results of the present study provide the data for quantitative risk assessments of emissions of toxicants in combustion processes involving PI and THPI.

  9. Toxic pollutants emitted from thermal decomposition of phthalimide compounds

    International Nuclear Information System (INIS)

    Chen Kai; Mackie, John C.; Wojtalewicz, Dominika; Kennedy, Eric M.; Dlugogorski, Bogdan Z.

    2011-01-01

    Phthalimide (PI) and tetrahydrophthalimide (THPI) are two structurally similar compounds extensively used as intermediates for the synthesis of variety of industrial chemicals. This paper investigates the thermal decomposition of PI and THPI under oxygen rich to oxygen lean conditions, quantifying the production of toxicants and explaining their formation pathways. The experiments involved a plug flow reactor followed by silica cartridges, activated charcoal trap and a condenser, with the decomposition products identified and quantified by Fourier transform infrared spectroscopy (FTIR), gas chromatography-mass spectrometry (GC-MS) and micro gas chromatography (μGC). The density functional theory (DFT) calculations served to obtain dissociation energies and reaction pathways, to elucidate the reaction mechanism. The oxidation of PI and THPI produced several toxic nitrogen-containing gases and volatile organic compounds, including hydrogen cyanide, isocyanic acid, nitrogen oxides, benzonitrile, maleimide and tentatively identified benzenemethanimine. The detection of dibenzo-p-dioxin (DD) and dibenzofuran (DF) suggests potential formation of the toxic persistent organic pollutants (POPs) in fires involving PI and THPI, in presence of a chlorine source. The oxidation of THPI produced 2-cyclohexen-1-one, a toxic unsaturated ketone. The results of the present study provide the data for quantitative risk assessments of emissions of toxicants in combustion processes involving PI and THPI.

  10. Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling.

    Science.gov (United States)

    Stockwell, Simon R; Platt, Georgina; Barrie, S Elaine; Zoumpoulidou, Georgia; Te Poele, Robert H; Aherne, G Wynne; Wilson, Stuart C; Sheldrake, Peter; McDonald, Edward; Venet, Mathilde; Soudy, Christelle; Elustondo, Frédéric; Rigoreau, Laurent; Blagg, Julian; Workman, Paul; Garrett, Michelle D; Mittnacht, Sibylle

    2012-01-01

    Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for

  11. Differential sensitivity of five cyanobacterial strains to ammonium toxicity and its inhibitory mechanism on the photosynthesis of rice-field cyanobacterium Ge-Xian-Mi (Nostoc)

    International Nuclear Information System (INIS)

    Dai Guozheng; Deblois, Charles P.; Liu Shuwen; Juneau, Philippe; Qiu Baosheng

    2008-01-01

    Effects of two fertilizers, NH 4 Cl and KCl, on the growth of the edible cyanobacterium Ge-Xian-Mi (Nostoc) and four other cyanobacterial strains were compared at pH 8.3 ± 0.2 and 25 deg. C. Their growth was decreased by at least 65% at 10 mmol L -1 NH 4 Cl but no inhibitory effect was observed at the same level of KCl. Meanwhile, the strains exhibited a great variation of sensitivity to NH 4 + toxicity in the order: Ge-Xian-Mi > Anabaena azotica FACHB 118 > Microcystis aeruginosa FACHB 905 > M. aeruginosa FACHB 315 > Synechococcus FACHB 805. The 96-h EC 50 value for relative growth rate with regard to NH 4 + for Ge-Xian-Mi was 1.105 mmol L -1 , which was much less than the NH 4 + concentration in many agricultural soils (2-20 mmol L -1 ). This indicated that the use of ammonium as nitrogen fertilizer was responsible for the reduced resource of Ge-Xian-Mi in the paddy field. After 96 h exposure to 1 mmol L -1 NH 4 Cl, the photosynthetic rate, F v /F m value, saturating irradiance for photosynthesis and PSII activity of Ge-Xian-Mi colonies were remarkably decreased. The chlorophyll synthesis of Ge-Xian-Mi was more sensitive to NH 4 + toxicity than phycobiliproteins. Thus, the functional absorption cross section of Ge-Xian-Mi PSII was increased markedly at NH 4 Cl levels ≥1 mmol L -1 and the electron transport on the acceptor side of PSII was significantly accelerated by NH 4 Cl addition ≥3 mmol L -1 . Dark respiration of Ge-Xian-Mi was significantly increased by 246% and 384% at 5 and 10 mmol L -1 NH 4 Cl, respectively. The rapid fluorescence rise kinetics indicated that the oxygen-evolving complex of PSII was the inhibitory site of NH 4 +

  12. Mechanisms Involved in Toxicity of Liver Caused by Piroxicam in Mice and Protective Effects of Leaf Extract of Hibiscus Rosa-Sinensis L.

    Directory of Open Access Journals (Sweden)

    C. R. Sahu

    2016-01-01

    Full Text Available Piroxicam is one of the important therapeutic nonsteroidal anti-inflammatory class of drugs used mainly to suppress pain and inflammation in arthritis and other musculoskeletal disorders. Besides being anti-inflammatory, these drugs are analgesic and antipyretic often used for the relief of nonspecific fever condition. Recently, piroxicam has also gained attention as an effective therapy for tumors, colorectal, and invasive bladder cancers. The objective of the current study is to evaluate the protective effects of the alcoholic leaf extract of Hibiscus rosa-sinensis (AEH, Malvaceae, against piroxicam-induced toxicity in mice. Sixty adult Swiss albino mice ( Mus musculus were divided into four groups ( n = 10, which included a control group, a group treated orally with AEH (30 mg kg –1 b.w. for 15 days, a group treated orally with piroxicam (6.6 mg kg –1 b.w. for 15 days, and another group treated orally with piroxicam and AEH for 15 days. The results indicated that treatment with piroxicam alone resulted in a significant increase in the activities of serum marker enzymes, namely, aspartate transaminase, alanine transaminase, and alkaline phosphatase with profound hepatic lipid peroxidation as evidenced by a marked increment in the level of thoibarbituric acid reactive substances along with a distinct diminution in reduced glutathoine content and various antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase in the liver. However, treatment with AEH during piroxicam treatment retrieved or partially antagonized the effects induced by piroxicam toward the normal values of controls. Histopathological observations also corroborate with the above findings. It can be concluded that AEH exhibited a protective action against piroxicam toxicity and effective in combating oxidative stress-induced hepatic damage.

  13. DOE contractor's meeting on chemical toxicity

    Energy Technology Data Exchange (ETDEWEB)

    1987-01-01

    The Office of Health and Environmental Research (OHER) is required to determine the potential health and environmental effects associated with energy production and use. To ensure appropriate communication among investigators and scientific disciplines that these research studies represent, OHER has sponsored workshops. This document provides a compilation of activities at the Third Annual DOE/OHER Workshop. This year's workshop was broadened to include all OHER activities identified as within the chemical effects area. The workshop consisted of eight sessions entitled Isolation and Detection of Toxic chemicals; Adduct Formation and Repair; Chemical Toxicity (Posters); Metabolism and Genotoxicity; Inhalation Toxicology; Gene Regulation; Metals Toxicity; and Biological Mechanisms. This document contains abstracts of the information presented by session.

  14. Toxic potential of palytoxin.

    Science.gov (United States)

    Patocka, Jiří; Gupta, Ramesh C; Wu, Qing-hua; Kuca, Kamil

    2015-10-01

    This review briefly describes the origin, chemistry, molecular mechanism of action, pharmacology, toxicology, and ecotoxicology of palytoxin and its analogues. Palytoxin and its analogues are produced by marine dinoflagellates. Palytoxin is also produced by Zoanthids (i.e. Palythoa), and Cyanobacteria (Trichodesmium). Palytoxin is a very large, non-proteinaceous molecule with a complex chemical structure having both lipophilic and hydrophilic moieties. Palytoxin is one of the most potent marine toxins with an LD50 of 150 ng/kg body weight in mice exposed intravenously. Pharmacological and electrophysiological studies have demonstrated that palytoxin acts as a hemolysin and alters the function of excitable cells through multiple mechanisms of action. Palytoxin selectively binds to Na(+)/K(+)-ATPase with a Kd of 20 pM and transforms the pump into a channel permeable to monovalent cations with a single-channel conductance of 10 pS. This mechanism of action could have multiple effects on cells. Evaluation of palytoxin toxicity using various animal models revealed that palytoxin is an extremely potent neurotoxin following an intravenous, intraperitoneal, intramuscular, subcutaneous or intratracheal route of exposure. Palytoxin also causes non-lethal, yet serious toxic effects following dermal or ocular exposure. Most incidents of palytoxin poisoning have manifested after oral intake of contaminated seafood. Poisonings in humans have also been noted after inhalation, cutaneous/systemic exposures with direct contact of aerosolized seawater during Ostreopsis blooms and/or through maintaining aquaria containing Cnidarian zoanthids. Palytoxin has a strong potential for toxicity in humans and animals, and currently this toxin is of great concern worldwide.

  15. Differential sensitivity of five cyanobacterial strains to ammonium toxicity and its inhibitory mechanism on the photosynthesis of rice-field cyanobacterium Ge-Xian-Mi (Nostoc)

    Energy Technology Data Exchange (ETDEWEB)

    Dai Guozheng [College of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China); Hubei Key Laboratory of Genetic Regulation and Integrative Biology, Central China Normal University, Wuhan 430079, Hubei (China); Deblois, Charles P. [Department des Sciences Biologiques, TOXEN, Canada Research Chair on Ecotoxicology of Aquatic Microorganisms, Universite du Quebec a Montreal, Succursale Centre-ville, C.P. 8888 Montreal, Quebec H3C 3P8 (Canada); Liu Shuwen [College of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China); Hubei Key Laboratory of Genetic Regulation and Integrative Biology, Central China Normal University, Wuhan 430079, Hubei (China); Juneau, Philippe [Department des Sciences Biologiques, TOXEN, Canada Research Chair on Ecotoxicology of Aquatic Microorganisms, Universite du Quebec a Montreal, Succursale Centre-ville, C.P. 8888 Montreal, Quebec H3C 3P8 (Canada); Qiu Baosheng [College of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China); Hubei Key Laboratory of Genetic Regulation and Integrative Biology, Central China Normal University, Wuhan 430079, Hubei (China)], E-mail: bsqiu@public.wh.hb.cn

    2008-08-29

    Effects of two fertilizers, NH{sub 4}Cl and KCl, on the growth of the edible cyanobacterium Ge-Xian-Mi (Nostoc) and four other cyanobacterial strains were compared at pH 8.3 {+-} 0.2 and 25 deg. C. Their growth was decreased by at least 65% at 10 mmol L{sup -1} NH{sub 4}Cl but no inhibitory effect was observed at the same level of KCl. Meanwhile, the strains exhibited a great variation of sensitivity to NH{sub 4}{sup +} toxicity in the order: Ge-Xian-Mi > Anabaena azotica FACHB 118 > Microcystis aeruginosa FACHB 905 > M. aeruginosa FACHB 315 > Synechococcus FACHB 805. The 96-h EC{sub 50} value for relative growth rate with regard to NH{sub 4}{sup +} for Ge-Xian-Mi was 1.105 mmol L{sup -1}, which was much less than the NH{sub 4}{sup +} concentration in many agricultural soils (2-20 mmol L{sup -1}). This indicated that the use of ammonium as nitrogen fertilizer was responsible for the reduced resource of Ge-Xian-Mi in the paddy field. After 96 h exposure to 1 mmol L{sup -1} NH{sub 4}Cl, the photosynthetic rate, F{sub v}/F{sub m} value, saturating irradiance for photosynthesis and PSII activity of Ge-Xian-Mi colonies were remarkably decreased. The chlorophyll synthesis of Ge-Xian-Mi was more sensitive to NH{sub 4}{sup +} toxicity than phycobiliproteins. Thus, the functional absorption cross section of Ge-Xian-Mi PSII was increased markedly at NH{sub 4}Cl levels {>=}1 mmol L{sup -1} and the electron transport on the acceptor side of PSII was significantly accelerated by NH{sub 4}Cl addition {>=}3 mmol L{sup -1}. Dark respiration of Ge-Xian-Mi was significantly increased by 246% and 384% at 5 and 10 mmol L{sup -1} NH{sub 4}Cl, respectively. The rapid fluorescence rise kinetics indicated that the oxygen-evolving complex of PSII was the inhibitory site of NH{sub 4}{sup +}.