Chronic perfluorooctane sulfonate (PFOS) exposure induces hepatic steatosis in zebrafish

International Nuclear Information System (INIS)

Cheng, Jiangfei; Lv, Suping; Nie, Shangfei; Liu, Jing; Tong, Shoufang; Kang, Ning; Xiao, Yanyan; Dong, Qiaoxiang; Huang, Changjiang; Yang, Dongren

2016-01-01

Highlights: • PFOS chronic exposure induces sex-dependent hepatic steotosis in zebrafish. • PFOS interferes with β-oxidation, lipid synthesis, and lipid hepatic export process. • Zebrafish could be used as an alternative model for PFOS chronic toxicity screening. - Abstract: Perfluorooctane sulfonate (PFOS), one persistent organic pollutant, has been widely detected in the environment, wildlife and human. Currently few studies have documented the effects of chronic PFOS exposure on lipid metabolism, especially in aquatic organisms. The underlying mechanisms of hepatotoxicity induced by chronic PFOS exposure are still largely unknown. The present study defined the effects of chronic exposure to low level of PFOS on lipid metabolism using zebrafish as a model system. Our findings revealed a severe hepatic steatosis in the liver of males treated with 0.5 μM PFOS as evidenced by hepatosomatic index, histological assessment and liver lipid profiles. Quantitative PCR assay further indicated that PFOS significantly increase the transcriptional expression of nuclear receptors (nr1h3, rara, rxrgb, nr1l2) and the genes associated with fatty acid oxidation (acox1, acadm, cpt1a). In addition, chronic PFOS exposure significantly decreased liver ATP content and serum level of VLDL/LDL lipoprotein in males. Taken together, these findings suggest that chronic PFOS exposure induces hepatic steatosis in zebrafish via disturbing lipid biosynthesis, fatty acid β-oxidation and excretion of VLDL/LDL lipoprotein, and also demonstrate the validity of using zebrafish as an alternative model for PFOS chronic toxicity screening.

Chronic perfluorooctane sulfonate (PFOS) exposure induces hepatic steatosis in zebrafish

Energy Technology Data Exchange (ETDEWEB)

Cheng, Jiangfei; Lv, Suping; Nie, Shangfei; Liu, Jing; Tong, Shoufang; Kang, Ning; Xiao, Yanyan; Dong, Qiaoxiang [Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms (China); Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou, 325035 (China); Huang, Changjiang, E-mail: cjhuang5711@163.com [Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms (China); Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou, 325035 (China); Yang, Dongren, E-mail: yangdongren@yahoo.com [Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms (China); Institute of Environmental Safety and Human Health, Wenzhou Medical University, Wenzhou, 325035 (China)

2016-07-15

Highlights: • PFOS chronic exposure induces sex-dependent hepatic steotosis in zebrafish. • PFOS interferes with β-oxidation, lipid synthesis, and lipid hepatic export process. • Zebrafish could be used as an alternative model for PFOS chronic toxicity screening. - Abstract: Perfluorooctane sulfonate (PFOS), one persistent organic pollutant, has been widely detected in the environment, wildlife and human. Currently few studies have documented the effects of chronic PFOS exposure on lipid metabolism, especially in aquatic organisms. The underlying mechanisms of hepatotoxicity induced by chronic PFOS exposure are still largely unknown. The present study defined the effects of chronic exposure to low level of PFOS on lipid metabolism using zebrafish as a model system. Our findings revealed a severe hepatic steatosis in the liver of males treated with 0.5 μM PFOS as evidenced by hepatosomatic index, histological assessment and liver lipid profiles. Quantitative PCR assay further indicated that PFOS significantly increase the transcriptional expression of nuclear receptors (nr1h3, rara, rxrgb, nr1l2) and the genes associated with fatty acid oxidation (acox1, acadm, cpt1a). In addition, chronic PFOS exposure significantly decreased liver ATP content and serum level of VLDL/LDL lipoprotein in males. Taken together, these findings suggest that chronic PFOS exposure induces hepatic steatosis in zebrafish via disturbing lipid biosynthesis, fatty acid β-oxidation and excretion of VLDL/LDL lipoprotein, and also demonstrate the validity of using zebrafish as an alternative model for PFOS chronic toxicity screening.

Exposure to persistent organic pollutants and risk of hypertension among Inuit from Greenland

DEFF Research Database (Denmark)

Valera, Beatriz; Jørgensen, Marit Eika; Jeppesen, Charlotte

2013-01-01

Exposure to persistent organic pollutants (POPs) is of concern in Arctic populations since these contaminants accumulate in fish and marine mammals, which is an important part of the traditional diet of these populations. Epidemiological and experimental studies have reported significant associat......Exposure to persistent organic pollutants (POPs) is of concern in Arctic populations since these contaminants accumulate in fish and marine mammals, which is an important part of the traditional diet of these populations. Epidemiological and experimental studies have reported significant...

Propofol Exposure in Pregnant Rats Induces Neurotoxicity and Persistent Learning Deficit in the Offspring

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Ming Xiong

2014-05-01

Full Text Available Propofol is a general anesthetic widely used in surgical procedures, including those in pregnant women. Preclinical studies suggest that propofol may cause neuronal injury to the offspring of primates if it is administered during pregnancy. However, it is unknown whether those neuronal changes would lead to long-term behavioral deficits in the offspring. In this study, propofol (0.4 mg/kg/min, IV, 2 h, saline, or intralipid solution was administered to pregnant rats on gestational day 18. We detected increased levels of cleaved caspase-3 in fetal brain at 6 h after propofol exposure. The neuronal density of the hippocampus of offspring was reduced significantly on postnatal day 10 (P10 and P28. Synaptophysin levels were also significantly reduced on P28. Furthermore, exploratory and learning behaviors of offspring rats (started at P28 were assessed in open-field trial and eight-arm radial maze. The offspring from propofol-treated dams showed significantly less exploratory activity in the open-field test and less spatial learning in the eight-arm radial maze. Thus, this study suggested that propofol exposure during pregnancy in rat increased cleaved caspsase-3 levels in fetal brain, deletion of neurons, reduced synaptophysin levels in the hippocampal region, and persistent learning deficits in the offspring.

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library.

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Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

2016-01-01

Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

Long-term exposure to political violence: The particular injury of persistent humiliation.

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Barber, Brian K; McNeely, Clea; Olsen, Joseph A; Belli, Robert F; Doty, Samuel Benjamin

2016-05-01

This study assessed the association between exposure to political violence over a 25-year period and adult functioning among a population that has experienced protracted and severe political conflict. Instead of aggregating exposure to political violence across time and type of exposure, as is commonly done, the event history calendar pioneered in this study assessed exposure to five forms of political violence annually from 1987 to 2011 in a representative sample of 1788 adults, aged 37 on average, in the occupied Palestinian territories (West Bank, East Jerusalem, and the Gaza Strip). This method allowed for the identification of trajectories of exposure to political violence from childhood to adulthood using latent profile analysis. We then correlated the trajectories of exposure to measures of economic, political, community, family, psychological, and health functioning. As expected, being shot at, having one's home raided, being hit or kicked, being verbally abused, and witnessing someone close being humiliated were all elevated during periods of heightened political conflict (the first intifada (1987-1993) and, less so, the second intifada (2000-2005)). In addition, 12% of women and men reported high and persistent levels of exposure to humiliation (being verbally abused and/or witnessing someone close being humiliated) across the entire 25-year period. These individuals lived predominantly in neighborhoods with a high Israeli military presence. Compared to those who experienced periodic exposure to political violence, persistently humiliated men and women reported significantly lower health, economic, political, and psychological functioning, as well as higher social cohesion and political expression. Relevant literatures are reviewed when concluding that persistent humiliation is a neglected form of political violence that is best represented as a direct (versus structural), acute (versus chronic), macro (versus micro), and high-grade (versus low

Persistent genetic instability induced by synergistic interaction between x-irradiation and 6-thioguanine

International Nuclear Information System (INIS)

Grosovsky, A.J.; Nelson, S.L.; Smith, L.E.

1995-01-01

Clonal karyotypic analysis was performed using G-banding on four groups of clones derived from TK6 human lymphoblasts: 25 HPRT - total gene deletion mutants induced by exposure to 2 Gy of x-rays; 8 spontaneous HPRT - total gene deletion mutants; 25 clones irradiated with 2 Gy, not selected with 6-thioguanine. Ten to twenty metaphases were examined for each clone. Extensive karyotypic heterogeneity was observed among x-ray induced HPRT - mutants involving translocations, deletions, duplications and aneuploidy; recovery of chromosomal aberrations and karyotypic heterogeneity was greater than the additive effects of clones treated with x-irradiation or 6-thioguanine alone. This synergistic interaction between x-irradiation and 6-thioguanine was observed despite a 7 day phenotypic expression interval between exposure to the two agents. Thus, x-irradiated TK6 cells appear to be persistently hypersensitive to the induction of genetic instability. Several mutants appeared to exhibit evidence of clonal evolution since aberrant chromosomes observed in one metaphase, were found to be further modified in other metaphases. In order to determine if genetic instability, identified by clonal karyotypic heterogeneity, affected specific locus mutation rates, we utilized the heterozygous thymidine kinase (tk) locus as a genetic marker. Four x-ray induced HPRT - mutants with extensive karyotypic heterogeneity, exhibited mutation rates at tk ranging from 5 to 8 fold higher than the parental TK6 cells. Further analysis, using fractionated low dose radiation exposure, is currently in progress

Persistent sexual dysfunction after early exposure to SSRIs

DEFF Research Database (Denmark)

Simonsen, Anders Lykkemark; Danborg, Pia Brandt; Gøtzsche, Peter Christian

2016-01-01

BACKGROUND: Sexual dysfunction is a common adverse effect of selective serotonin reuptake inhibitors (SSRIs) and there is a concern that the sexual harms might persist after discontinuation of therapy. OBJECTIVE: To assess whether the use of SSRIs in animals can lead to persistent sexual...... dysfunction. METHODS: Systematic review of animal studies measuring sexual behaviour after end of treatment with SSRIs or serotonin norepinephrine reuptake inhibitors. DATA SOURCES: We searched PubMed and EMBASE. RESULTS: We included 14 studies. The general quality of the studies was poor. Only four studies.......74; 95% CI = 0.60-0.92) and no ejaculation behaviour (RR = 0.49, 95% CI = 0.24-1.00). CONCLUSION: Our results showed substantial and lasting effects on sexual behaviour in rats after exposure to an SSRI early in life on important sexual outcomes....

Amnestically Induced Persistence in Random Walks

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Cressoni, J. C.; da Silva, Marco Antonio Alves; Viswanathan, G. M.

2007-02-01

We study how the Hurst exponent α depends on the fraction f of the total time t remembered by non-Markovian random walkers that recall only the distant past. We find that otherwise nonpersistent random walkers switch to persistent behavior when inflicted with significant memory loss. Such memory losses induce the probability density function of the walker’s position to undergo a transition from Gaussian to non-Gaussian. We interpret these findings of persistence in terms of a breakdown of self-regulation mechanisms and discuss their possible relevance to some of the burdensome behavioral and psychological symptoms of Alzheimer’s disease and other dementias.

Photocarcinogenesis and persistent hyperplasia in UV-irradiated SENCAR mouse skin

International Nuclear Information System (INIS)

Strickland, P.T.

1986-01-01

Susceptibility to photocarcinogenesis has been examined in several mouse strains and stocks including SENCAR, CD-1, BALB/c, C3H, C57Bl, and NZB. SENCAR mice are hypersusceptible to tumorigenesis caused by single high dose exposures to ultraviolet (UV) radiation but not by chronic low-dose exposures. SENCAR mice also exhibit an exaggerated and persistent epidermal hyperplasia in response to UV-induced tissue damage. The persistent hyperplasia is apparently due to a sustained proliferation of the epithelial basal cells, rather than to delayed cell differentiation. SENCAR mice did not exhibit persistent hyperplasia following other forms of tissue damage (surgical or thermal). In related studies, the levels of thymine dimers induced in SENCAR epidermis by UV radiation were comparable to those observed in BALB/c epidermis. In addition, no differences were found in the tissue distribution or persistence of thymine dimers in SENCAR and BALB/c skin

Cigarette Smoke-Induced Cell Death Causes Persistent Olfactory Dysfunction in Aged Mice

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Rumi Ueha

2018-06-01

Full Text Available Introduction: Exposure to cigarette smoke is a cause of olfactory dysfunction. We previously reported that in young mice, cigarette smoke damaged olfactory progenitors and decreased mature olfactory receptor neurons (ORNs, then, mature ORNs gradually recovered after smoking cessation. However, in aged populations, the target cells in ORNs by cigarette smoke, the underlying molecular mechanisms by which cigarette smoke impairs the regenerative ORNs, and the degree of ORN regeneration after smoking cessation remain unclear.Objectives: To explore the effects of cigarette smoke on the ORN cell system using an aged mouse model of smoking, and to investigate the extent to which smoke-induced damage to ORNs recovers following cessation of exposure to cigarette smoke in aged mice.Methods: We intranasally administered a cigarette smoke solution (CSS to 16-month-old male mice over 24 days, then examined ORN existence, cell survival, changes of inflammatory cytokines in the olfactory epithelium (OE, and olfaction using histological analyses, gene analyses and olfactory habituation/dishabituation tests.Results: CSS administration reduced the number of mature ORNs in the OE and induced olfactory dysfunction. These changes coincided with an increase in the number of apoptotic cells and Tumor necrosis factor (TNF expression and a decrease in Il6 expression. Notably, the reduction in mature ORNs did not recover even on day 28 after cessation of treatment with CSS, resulting in persistent olfactory dysfunction.Conclusion: In aged mice, by increasing ORN death, CSS exposure could eventually overwhelm the regenerative capacity of the OE, resulting in continued reduction in the number of mature ORNs and olfactory dysfunction.

Neuropsychological alterations in mercury intoxication persist several years after exposure.

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Zachi, Elaine Cristina; Taub, Anita; Faria, Marcília de Araújo Medrado; Ventura, Dora Fix

2008-01-01

Elemental mercury is a liquid toxic metal widely used in industry. Occupational exposure occurs mainly via inhalation. Previously, neuropsychological assessment detected deficits in former workers of a fluorescent lamp plant who had been exposed to elemental mercury vapor and were away from exposure for several years at the time of examination. The purpose of this work was to reexamine these functions after 18 months in order to evaluate their progression. Thirteen participants completed tests of attention, inhibitory control, verbal/visual memory, psychomotor speed, verbal fluency, visuomotor ability, executive function, semantic knowledge, and depression and anxiety inventories on 2 separate occasions. At baseline, the former workers indicated slower psychomotor and information processing speed, verbal spontaneous recall memory impairment, and increased depression and anxiety symptoms compared to controls (Precovery of functions, the neuropsychological effects related to mercury exposure are found to persist for many years.

Reversible antibiotic tolerance induced in Staphylococcus aureus by concurrent drug exposure

DEFF Research Database (Denmark)

Haaber, Jakob Krause; Friberg, Cathrine; McCreary, Mark

2015-01-01

UNLABELLED: Resistance of Staphylococcus aureus to beta-lactam antibiotics has led to increasing use of the glycopeptide antibiotic vancomycin as a life-saving treatment for major S. aureus infections. Coinfection by an unrelated bacterial species may necessitate concurrent treatment with a second...... antibiotic that targets the coinfecting pathogen. While investigating factors that affect bacterial antibiotic sensitivity, we discovered that susceptibility of S. aureus to vancomycin is reduced by concurrent exposure to colistin, a cationic peptide antimicrobial employed to treat infections by Gram......-negative pathogens. We show that colistin-induced vancomycin tolerance persists only as long as the inducer is present and is accompanied by gene expression changes similar to those resulting from mutations that produce stably inherited reduction of vancomycin sensitivity (vancomycin-intermediate S. aureus [VISA...

Modeling exposure to persistent chemicals in hazard and risk assessment.

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Cowan-Ellsberry, Christina E; McLachlan, Michael S; Arnot, Jon A; Macleod, Matthew; McKone, Thomas E; Wania, Frank

2009-10-01

Fate and exposure modeling has not, thus far, been explicitly used in the risk profile documents prepared for evaluating the significant adverse effect of candidate chemicals for either the Stockholm Convention or the Convention on Long-Range Transboundary Air Pollution. However, we believe models have considerable potential to improve the risk profiles. Fate and exposure models are already used routinely in other similar regulatory applications to inform decisions, and they have been instrumental in building our current understanding of the fate of persistent organic pollutants (POP) and persistent, bioaccumulative, and toxic (PBT) chemicals in the environment. The goal of this publication is to motivate the use of fate and exposure models in preparing risk profiles in the POP assessment procedure by providing strategies for incorporating and using models. The ways that fate and exposure models can be used to improve and inform the development of risk profiles include 1) benchmarking the ratio of exposure and emissions of candidate chemicals to the same ratio for known POPs, thereby opening the possibility of combining this ratio with the relative emissions and relative toxicity to arrive at a measure of relative risk; 2) directly estimating the exposure of the environment, biota, and humans to provide information to complement measurements or where measurements are not available or are limited; 3) to identify the key processes and chemical or environmental parameters that determine the exposure, thereby allowing the effective prioritization of research or measurements to improve the risk profile; and 4) forecasting future time trends, including how quickly exposure levels in remote areas would respond to reductions in emissions. Currently there is no standardized consensus model for use in the risk profile context. Therefore, to choose the appropriate model the risk profile developer must evaluate how appropriate an existing model is for a specific setting and

Persistence of Space Radiation Induced Cytogenetic Damage in the Blood Lymphocytes of Astronauts

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George, Kerry

Cytogenetic damage in astronaut's peripheral blood lymphocytes is a useful in vivo marker of space radiation induced damage. Moreover, if radiation induced chromosome translocations persist in peripheral blood lymphocytes for many years, as has been assumed, they could potentially be used to measure retrospective doses or prolonged low dose rate exposures. However, as more data becomes available, evidence suggests that the yield of translocations may decline with time after irradiation, at least for space radiation exposures. We present our latest follow-up measurements of chromosome aberrations in astronauts' blood lymphocytes assessed by FISH painting and collected at various times beginning directly after return from space to several years after flight. For most individuals the analysis of individual time-courses for translocations revealed a temporal decline of yields with different half-lives. Since the level of stable aberrations depends on the interplay between natural loss of circulating T-lymphocytes and replenishment from the stem or progenitor cells, the differences in the rates of decay could be explained by inter-individual variation in lymphocyte turn over. Biodosimetry estimates derived from cytogenetic analysis of samples collected a few days after return to earth lie within the range expected from physical dosimetry. However, a temporal decline in yields may indicate complications with the use of stable aberrations for retrospective dose reconstruction, and the differences in the decay time may reflect individual variability in risk from space radiation exposure. In addition, limited data on multiple flights show a lack of correlation between time in space and translocation yields. Data from one crewmember who has participated in two separate long-duration space missions and has been followed up for over 10 years provide limited information on the effect of repeat flights and show a possible adaptive response to space radiation exposure.

Disconnect between alcohol-induced alterations in chromatin structure and gene transcription in a mouse embryonic stem cell model of exposure.

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Veazey, Kylee J; Wang, Haiqing; Bedi, Yudhishtar S; Skiles, William M; Chang, Richard Cheng-An; Golding, Michael C

2017-05-01

Alterations to chromatin structure induced by environmental insults have become an attractive explanation for the persistence of exposure effects into subsequent life stages. However, a growing body of work examining the epigenetic impact that alcohol and other drugs of abuse exert consistently notes a disconnection between induced changes in chromatin structure and patterns of gene transcription. Thus, an important question is whether perturbations in the 'histone code' induced by prenatal exposures to alcohol implicitly subvert gene expression, or whether the hierarchy of cellular signaling networks driving development is such that they retain control over the transcriptional program. To address this question, we examined the impact of ethanol exposure in mouse embryonic stem cells cultured under 2i conditions, where the transcriptional program is rigidly enforced through the use of small molecule inhibitors. We find that ethanol-induced changes in post-translational histone modifications are dose-dependent, unique to the chromatin modification under investigation, and that the extent and direction of the change differ between the period of exposure and the recovery phase. Similar to in vivo models, we find post-translational modifications affecting histone 3 lysine 9 are the most profoundly impacted, with the signature of exposure persisting long after alcohol has been removed. These changes in chromatin structure associate with dose-dependent alterations in the levels of transcripts encoding Dnmt1, Uhrf1, Tet1, Tet2, Tet3, and Polycomb complex members Eed and Ezh2. However, in this model, ethanol-induced changes to the chromatin template do not consistently associate with changes in gene transcription, impede the process of differentiation, or affect the acquisition of monoallelic patterns of expression for the imprinted gene Igf2R. These findings question the inferred universal relevance of epigenetic changes induced by drugs of abuse and suggest that changes

Persistence of asthmatic response after ammonium persulfate-induced occupational asthma in mice.

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Marta Ollé-Monge

Full Text Available INTRODUCTION: Since persulfate salts are an important cause of occupational asthma (OA, we aimed to study the persistence of respiratory symptoms after a single exposure to ammonium persulfate (AP in AP-sensitized mice. MATERIAL AND METHODS: BALB/c mice received dermal applications of AP or dimethylsulfoxide (DMSO on days 1 and 8. On day 15, they received a single nasal instillation of AP or saline. Airway hyperresponsiveness (AHR was assessed using methacholine provocation, while pulmonary inflammation was evaluated in bronchoalveolar lavage (BAL, and total serum immunoglobulin E (IgE, IgG1 and IgG2a were measured in blood at 1, 4, 8, 24 hours and 4, 8, 15 days after the single exposure to the causal agent. Histological studies of lungs were assessed. RESULTS: AP-treated mice showed a sustained increase in AHR, lasting up to 4 days after the challenge. There was a significant increase in the percentage of neutrophils 8 hours after the challenge, which persisted for 24 hours in AP-treated mice. The extent of airway inflammation was also seen in the histological analysis of the lungs from challenged mice. Slight increases in total serum IgE 4 days after the challenge were found, while IgG gradually increased further 4 to 15 days after the AP challenge in AP-sensitized mice. CONCLUSIONS: In AP-sensitized mice, an Ig-independent response is induced after AP challenge. AHR appears immediately, but airway neutrophil inflammation appears later. This response decreases in time; at early stages only respiratory and inflammatory responses decrease, but later on immunological response decreases as well.

Titanium Dioxide Exposure Induces Acute Eosinophilic Lung Inflammation in Rabbits

Science.gov (United States)

CHOI, Gil Soon; OAK, Chulho; CHUN, Bong-Kwon; WILSON, Donald; JANG, Tae Won; KIM, Hee-Kyoo; JUNG, Mannhong; TUTKUN, Engin; PARK, Eun-Kee

2014-01-01

Titanium dioxide (TiO2) is increasingly widely used in industrial, commercial and home products. TiO2 aggravates respiratory symptoms by induction of pulmonary inflammation although the mechanisms have not been well investigated. We aimed to investigate lung inflammation in rabbits after intratracheal instillation of P25 TiO2. One ml of 10, 50 and 250 µg of P25 TiO2 was instilled into one of the lungs of rabbits, chest computed-tomography was performed, and bronchoalveolar lavage (BAL) fluid was collected before, at 1 and 24 h after P25 TiO2 exposure. Changes in inflammatory cells in the BAL fluids were measured. Lung pathological assay was also carried out at 24 h after P25 TiO2 exposure. Ground glass opacities were noted in both lungs 1 h after P25 TiO2 and saline (control) instillation. Although the control lung showed complete resolution at 24 h, the lung exposed to P25 TiO2 showed persistent ground glass opacities at 24 h. The eosinophil counts in BAL fluid were significantly increased after P25 TiO2 exposure. P25 TiO2 induced a dose dependent increase of eosinophils in BAL fluid but no significant differences in neutrophil and lymphocyte cell counts were detected. The present findings suggest that P25 TiO2 induces lung inflammation in rabbits which is associated with eosinophilic inflammation. PMID:24705802

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse.

Science.gov (United States)

Korpi, Esa R; den Hollander, Bjørnar; Farooq, Usman; Vashchinkina, Elena; Rajkumar, Ramamoorthy; Nutt, David J; Hyytiä, Petri; Dawe, Gavin S

2015-10-01

Adaptation of the nervous system to different chemical and physiologic conditions is important for the homeostasis of brain processes and for learning and remembering appropriate responses to challenges. Although processes such as tolerance and dependence to various drugs of abuse have been known for a long time, it was recently discovered that even a single pharmacologically relevant dose of various drugs of abuse induces neuroplasticity in selected neuronal populations, such as the dopamine neurons of the ventral tegmental area, which persist long after the drug has been excreted. Prolonged (self-) administration of drugs induces gene expression, neurochemical, neurophysiological, and structural changes in many brain cell populations. These region-specific changes correlate with addiction, drug intake, and conditioned drugs effects, such as cue- or stress-induced reinstatement of drug seeking. In rodents, adolescent drug exposure often causes significantly more behavioral changes later in adulthood than a corresponding exposure in adults. Clinically the most impairing and devastating effects on the brain are produced by alcohol during fetal development. In adult recreational drug users or in medicated patients, it has been difficult to find persistent functional or behavioral changes, suggesting that heavy exposure to drugs of abuse is needed for neurotoxicity and for persistent emotional and cognitive alterations. This review describes recent advances in this important area of research, which harbors the aim of translating this knowledge to better treatments for addictions and related neuropsychiatric illnesses. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Prenatal and postnatal exposure to persistent organic pollutants and infant growth: A pooled analysis of seven European birth cohorts

NARCIS (Netherlands)

N. Iszatt (Nina); H. Stigum (Hein); M.-A. Verner (Marc-André); R.G. White (Richard); E. Govarts (Eva); L.P. Murinova (Lubica Palkovicova); G. Schoeters (Greet); T. Trnovec (Tomáš); J. Legler (Juliette); F. Pele (Fabienne); J. Botton (Jérémie); C. Chevrier (Cécile); J. Wittsiepe (Jürgen); U. Ranft (Ulrich); S. Vandentorren (Stéphanie); M. Kasper-Sonnenberg (Monika); C. Klümper (Claudia); N. Weisglas-Kuperus (Nynke); A. Polder (Anuschka); M. Eggesbø (Merete)

2015-01-01

textabstractBackground: Infant exposure to persistent organic pollutants (POPs) may contribute to obesity. However, many studies so far have been small, focused on transplacental exposure, used an inappropriate measure to assess postnatal exposure through breastfeeding if any, or did not discern

Developmental Deltamethrin Exposure Causes Persistent Changes in Dopaminergic Gene Expression, Neurochemistry, and Locomotor Activity in Zebrafish.

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Kung, Tiffany S; Richardson, Jason R; Cooper, Keith R; White, Lori A

2015-08-01

Pyrethroids are commonly used insecticides that are considered to pose little risk to human health. However, there is an increasing concern that children are more susceptible to the adverse effects of pesticides. We used the zebrafish model to test the hypothesis that developmental exposure to low doses of the pyrethroid deltamethrin results in persistent alterations in dopaminergic gene expression, neurochemistry, and locomotor activity. Zebrafish embryos were treated with deltamethrin (0.25-0.50 μg/l), at concentrations below the LOAEL, during the embryonic period [3-72 h postfertilization (hpf)], after which transferred to fresh water until the larval stage (2-weeks postfertilization). Deltamethrin exposure resulted in decreased transcript levels of the D1 dopamine (DA) receptor (drd1) and increased levels of tyrosine hydroxylase at 72 hpf. The reduction in drd1 transcripts persisted to the larval stage and was associated with decreased D2 dopamine receptor transcripts. Larval fish, exposed developmentally to deltamethrin, had increased levels of homovanillic acid, a DA metabolite. Since the DA system is involved in locomotor activity, we measured the swim activity of larval fish following a transition to darkness. Developmental exposure to deltamethrin significantly increased larval swim activity which was attenuated by concomitant knockdown of the DA transporter. Acute exposure to methylphenidate, a DA transporter inhibitor, increased swim activity in control larva, while reducing swim activity in larva developmentally exposed to deltamethrin. Developmental exposure to deltamethrin causes locomotor deficits in larval zebrafish, which is likely mediated by dopaminergic dysfunction. This highlights the need to understand the persistent effects of low-dose neurotoxicant exposure during development. © 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.

Persistence of endocrine disruption in zebrafish (Danio rerio) after discontinued exposure to the androgen 17β-trenbolone

DEFF Research Database (Denmark)

Baumann, Lisa; Knörr, Susanne; Keiter, Susanne

2014-01-01

The aim of the present study was to investigate the effects of the androgenic endocrine disruptor 17β-trenbolone on the sexual development of zebrafish (Danio rerio) with special emphasis on the question whether adverse outcomes of developmental exposure are reversible or persistent. An exposure...... scenario including a recovery phase was chosen to assess the potential reversibility of androgenic effects. Zebrafish were exposed to environmentally relevant concentrations of 17β-trenbolone (1 - 30 ng/L) from fertilization until completion of gonad sexual differentiation (60 days post-hatch, dph...... with respect to exposure duration nor to concentration. Gonad morphological masculinization as well as the decrease of vitellogenin persisted after depuration over 40 d in clean water. This lack of recovery suggests that androgenic effects on sexual development of zebrafish are irreversible....

Persistence of DNA damage following exposure of human bladder cells to chronic monomethylarsonous acid

International Nuclear Information System (INIS)

Wnek, S.M.; Medeiros, M.K.; Eblin, K.E.; Gandolfi, A.J.

2009-01-01

Malignant transformation was demonstrated in UROtsa cells following 52-weeks of exposure to 50 nM monomethylarsonous acid (MMA III ); the result was the malignantly transformed cell line, URO-MSC. URO-MSC cells were used to study the induction of DNA damage and the alteration of DNA repair enzymes in both the presence of MMA III [URO-MSC(+)] and after subsequent removal of MMA III [URO-MSC(-)] following chronic, low-level exposure. In the presence of MMA III , URO-MSC(+) cells demonstrated a sustained increase in DNA damage following 12-weeks of exposure; in particular, a significant increase in DNA single-strand breaks at 12-weeks of exposure consistently elevated through 52 weeks. The persistence of DNA damage in URO-MSC cells was assessed after a 2-week removal of MMA III . URO-MSC(-) cells demonstrated a decrease in DNA damage compared to URO-MSC(+); however, DNA damage in URO-MSC(-) remained significantly elevated when compared to untreated UROtsa and increased in a time-dependent manner. Reactive oxygen species (ROS) were demonstrated to be a critical component in the generation of DNA damage determined through the incubation of ROS scavengers with URO-MSC cells. Poly (ADP-ribose) polymerase (PARP) is a key repair enzyme in DNA single-strand break repair. URO-MSC(+) resulted in a slight increase in PARP activity after 36-weeks of MMA III exposure, suggesting the presence of MMA III is inhibiting the increase in PARP activity. In support, PARP activity in URO-MSC(-) increased significantly, coinciding with a subsequent decrease in DNA damage demonstrated in URO-MSC(-) compared to URO-MSC(+). These data demonstrate that chronic, low-level exposure of UROtsa cells to 50 nM MMA III results in: the induction of DNA damage that remains elevated upon removal of MMA III ; increased levels of ROS that play a role in MMA III induced-DNA damage; and decreased PARP activity in the presence of MMA III .

Electrostatic stiffening and induced persistence length for coassembled molecular bottlebrushes

Science.gov (United States)

Storm, Ingeborg M.; Stuart, Martien A. Cohen; de Vries, Renko; Leermakers, Frans A. M.

2018-03-01

A self-consistent field analysis for tunable contributions to the persistence length of isolated semiflexible polymer chains including electrostatically driven coassembled deoxyribonucleic acid (DNA) bottlebrushes is presented. When a chain is charged, i.e., for polyelectrolytes, there is, in addition to an intrinsic rigidity, an electrostatic stiffening effect, because the electric double layer resists bending. For molecular bottlebrushes, there is an induced contribution due to the grafts. We explore cases beyond the classical phantom main-chain approximation and elaborate molecularly more realistic models where the backbone has a finite volume, which is necessary for treating coassembled bottlebrushes. We find that the way in which the linear charge density or the grafting density is regulated is important. Typically, the stiffening effect is reduced when there is freedom for these quantities to adapt to the curvature stresses. Electrostatically driven coassembled bottlebrushes, however, are relatively stiff because the chains have a low tendency to escape from the compressed regions and the electrostatic binding force is largest in the convex part. For coassembled bottlebrushes, the induced persistence length is a nonmonotonic function of the polymer concentration: For low polymer concentrations, the stiffening grows quadratically with coverage; for semidilute polymer concentrations, the brush chains retract and regain their Gaussian size. When doing so, they lose their induced persistence length contribution. Our results correlate well with observed physical characteristics of electrostatically driven coassembled DNA-bioengineered protein-polymer bottlebrushes.

Induction and persistence of abnormal testicular germ cells following gestational exposure to di-(n-butyl) phthalate in p53-null mice.

Science.gov (United States)

Saffarini, Camelia M; Heger, Nicholas E; Yamasaki, Hideki; Liu, Tao; Hall, Susan J; Boekelheide, Kim

2012-01-01

Phthalate esters are commonly used plasticizers found in many household items, personal care products, and medical devices. Animal studies have shown that in utero exposure to di-(n-butyl) phthalate (DBP) within a critical window during gestation causes male reproductive tract abnormalities resembling testicular dysgenesis syndrome. Our studies utilized p53-deficient mice for their ability to display greater resistance to apoptosis during development. This model was chosen to determine whether multinucleated germ cells (MNG) induced by gestational DBP exposure could survive postnatally and evolve into testicular germ cell cancer. Pregnant dams were exposed to DBP (500 mg/kg/day) by oral gavage from gestational day 12 until birth. Perinatal effects were assessed on gestational day 19 and postnatal days 1, 4, 7, and 10 for the number of MNGs present in control and DBP-treated p53-heterozygous and null animals. As expected, DBP exposure induced MNGs, with greater numbers found in p53-null mice. Additionally, there was a time-dependent decrease in the incidence of MNGs during the early postnatal period. Histologic examination of adult mice exposed in utero to DBP revealed persistence of abnormal germ cells only in DBP-treated p53-null mice, not in p53-heterozygous or wild-type mice. Immunohistochemical staining of perinatal MNGs and adult abnormal germ cells was negative for both octamer-binding protein 3/4 and placental alkaline phosphatase. This unique model identified a role for p53 in the perinatal apoptosis of DBP-induced MNGs and provided insight into the long-term effects of gestational DBP exposure within a p53-null environment.

Neuropsychological alterations in mercury intoxication persist several years after exposure

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Elaine Cristina Zachi

Full Text Available Abstract Elemental mercury is a liquid toxic metal widely used in industry. Occupational exposure occurs mainly via inhalation. Previously, neuropsychological assessment detected deficits in former workers of a fluorescent lamp plant who had been exposed to elemental mercury vapor and were away from exposure for several years at the time of examination. Objectives: The purpose of this work was to reexamine these functions after 18 months in order to evaluate their progression. Methods: Thirteen participants completed tests of attention, inhibitory control, verbal/visual memory, psychomotor speed, verbal fluency, visuomotor ability, executive function, semantic knowledge, and depression and anxiety inventories on 2 separate occasions. Results: At baseline, the former workers indicated slower psychomotor and information processing speed, verbal spontaneous recall memory impairment, and increased depression and anxiety symptoms compared to controls (P<0.05. Paired comparisons of neuropsychological functioning within the exposed group at baseline and 1.5 years later showed poorer immediate memory performance (P<0.05. There were no differences on other measures. Conclusions: Although the literature show signs of recovery of functions, the neuropsychological effects related to mercury exposure are found to persist for many years.

Academic achievement and college persistence of African American students with trauma exposure.

Science.gov (United States)

Boyraz, Güler; Horne, Sharon G; Owens, Archandria C; Armstrong, Aisha P

2013-10-01

This study examined the relationship between posttraumatic stress disorder (PTSD) symptomatology and college persistence in African American 1st-year students from 2 universities. Of the 569 participants, 423 (74%) reported lifetime exposure to traumatic events; 20.6% of these students met the criteria for PTSD. For trauma-exposed females, after controlling for academic and nonacademic factors, higher levels of PTSD symptomatology in the 1st semester of college were associated with increased likelihood of leaving college prior to the end of the 2nd year of college; the relationship between the 2 variables was partially mediated by 1st-year grade point average (GPA). PTSD symptomatology was not significantly associated with academic achievement or persistence for males. For trauma-exposed females, in addition to PTSD symptomatology, being a student at a predominantly White institution and entering college with low high school GPA were identified as risk factors for low academic achievement and college dropout; on the other hand, involvement in on-campus activities and higher levels of perceived academic integration in the 1st semester were associated with higher 1st-year GPA, which, in turn, was related to increased likelihood of remaining in college. Clinical implications and strategies to support students with trauma exposure and PTSD are discussed.

Preventive effect of curcumin and its highly bioavailable preparation on hearing loss induced by single or repeated exposure to noise: A comparative and mechanistic study

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Taro Yamaguchi

2017-08-01

Full Text Available We sought to determine the preventive effects of curcumin and its highly bioavailable preparation on noise-induced hearing loss in a novel murine model of permanent hearing loss developed by repeated exposure to noise. Upon exposure to noise (8-kHz octave band noise, 90 dB sound pressure level, 1 h, hearing ability was impaired in a temporary and reversible manner. During repeated noise exposure (1-h exposure per day, 5 days, there was a progressive increase in the auditory threshold shift at 12 and 20 kHz. The threshold shift persisted for at least 6 days after noise exposure. Oral administration of curcumin for 3 days before and each day during noise exposure significantly alleviated the hearing loss induced by repeated noise exposure. Curcumin abolished intranuclear translocation of nuclear factor-κB-p65 and generation of 4-hydroxynonenal-adducted proteins found in the cochlea after noise exposure. Theracurmin®, a highly absorbable and bioavailable preparation of curcumin, had strong preventive effects on hearing loss induced by repeated noise exposure. Together, these data suggest that curcumin exerts a preventive effect on noise-induced hearing loss and is therefore a good therapeutic candidate for preventing sensorineural hearing loss.

Inhalation exposure to ethylene induces eosinophilic rhinitis and nasal epithelial remodeling in Fischer 344 rats.

Science.gov (United States)

Brandenberger, Christina; Hotchkiss, Jon A; Krieger, Shannon M; Pottenger, Lynn H; Harkema, Jack R

2015-11-05

This study investigated the time- and concentration-dependent effects of inhaled ethylene on eosinophilic rhinitis and nasal epithelial remodeling in Fisher 344 rats exposed to 0, 10, 50, 300, or 10,000 ppm ethylene, 6 h/day, 5 days/week for up to 4 weeks. Morphometric quantitation of eosinophilic inflammation and mucous cell metaplasia/hyperplasia (MCM) and nasal mucosal gene expression were evaluated at anatomic sites previously shown to undergo ethylene-induced epithelial remodeling. Serum levels of total IgE, IgG1 and IgG2a were measured to determine if ethylene exposure increased the expression of Th2-associated (IgE and IgG1) relative to Th1-associated (IgG2a) antibody isotypes. Rats exposed to 0 or 10,000 ppm for 1, 3, 5, 10, or 20 days were analyzed to assess the temporal pattern of ethylene-induced alterations in nasal epithelial cell proliferation, morphology and gene expression. Rats exposed to 0, 10, 50, 300, and 10,000 ppm ethylene for 20 days were analyzed to assess concentration-dependent effects on lesion development. Additional rats exposed 4 weeks to 0, 300, or 10,000 ppm ethylene were held for 13 weeks post-exposure to examine the persistence of ethylene-induced mucosal alterations. The data indicate that cell death and reparative cell proliferation were not a part of the pathogenesis of ethylene-induced nasal lesions. Enhanced gene expression of Th2 cytokines (e.g., IL-5, IL-13) and chitinase (YM1/2) in the nasal mucosa was much greater than that of Th1 cytokines (e.g., IFNγ) after ethylene exposure. A significant increase in MCM was measured after 5 days of exposure to 10,000 ppm ethylene and after 20 days of exposure 10 ppm ethylene. Ethylene-induced MCM was reversible after cessation of exposure. No increase in total serum IgE, IgG1 or IgG2a was measured in any ethylene-exposed group. These data do not support involvement of an immune-mediated allergic mechanism in the pathogenesis of ethylene-induced nasal lesions in rats. Repeated

Androgen receptor gene CAG repeat length as modifier of the association between Persistent Organohalogen Pollutant exposure markers and semen characteristics

DEFF Research Database (Denmark)

Giwercman, Aleksander; Rylander, Lars; Rignell-Hydbom, Anna

2007-01-01

OBJECTIVES: Exposure to persistent organohalogen pollutants was suggested to impair male reproductive function. A gene-environment interaction has been proposed. No genes modifying the effect of persistent organohalogen pollutants on reproductive organs have yet been identified. We aimed to inves...

Environmentally persistent free radicals induce airway hyperresponsiveness in neonatal rat lungs

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Lominiki Slawo

2011-03-01

Full Text Available Abstract Background Increased asthma risk/exacerbation in children and infants is associated with exposure to elevated levels of ultrafine particulate matter (PM. The presence of a newly realized class of pollutants, environmentally persistent free radicals (EPFRs, in PM from combustion sources suggests a potentially unrecognized risk factor for the development and/or exacerbation of asthma. Methods Neonatal rats (7-days of age were exposed to EPFR-containing combustion generated ultrafine particles (CGUFP, non-EPFR containing CGUFP, or air for 20 minutes per day for one week. Pulmonary function was assessed in exposed rats and age matched controls. Lavage fluid was isolated and assayed for cellularity and cytokines and in vivo indicators of oxidative stress. Pulmonary histopathology and characterization of differential protein expression in lung homogenates was also performed. Results Neonates exposed to EPFR-containing CGUFP developed significant pulmonary inflammation, and airway hyperreactivity. This correlated with increased levels of oxidative stress in the lungs. Using differential two-dimensional electrophoresis, we identified 16 differentially expressed proteins between control and CGUFP exposed groups. In the rats exposed to EPFR-containing CGUFP; peroxiredoxin-6, cofilin1, and annexin A8 were upregulated. Conclusions Exposure of neonates to EPFR-containing CGUFP induced pulmonary oxidative stress and lung dysfunction. This correlated with alterations in the expression of various proteins associated with the response to oxidative stress and the regulation of glucocorticoid receptor translocation in T lymphocytes.

The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice.

Science.gov (United States)

Zhu, Lin; Xue, Junyi; Xia, Qingsu; Fu, Peter P; Lin, Ge

2017-02-01

Pyrrolizidine alkaloid (PA)-containing plants are widespread in the world and the most common poisonous plants affecting livestock, wildlife, and humans. Our previous studies demonstrated that PA-derived DNA adducts can potentially be a common biological biomarker of PA-induced liver tumor formation. In order to validate the use of these PA-derived DNA adducts as a biomarker, it is necessary to understand the basic kinetics of the PA-derived DNA adducts formed in vivo. In this study, we studied the dose-dependent response and kinetics of PA-derived DNA adduct formation and removal in male ICR mice orally administered with a single dose (40 mg/kg) or multiple doses (10 mg/kg/day) of retrorsine, a representative carcinogenic PA. In the single-dose exposure, the PA-derived DNA adducts exhibited dose-dependent linearity and persisted for up to 4 weeks. The removal of the adducts following a single-dose exposure to retrorsine was biphasic with half-lives of 9 h (t 1/2α ) and 301 h (~12.5 days, t 1/2β ). In the 8-week multiple exposure study, a marked accumulation of PA-derived DNA adducts without attaining a steady state was observed. The removal of adducts after the multiple exposure also demonstrated a biphasic pattern but with much extended half-lives of 176 h (~7.33 days, t 1/2α ) and 1736 h (~72.3 days, t 1/2β ). The lifetime of PA-derived DNA adducts was more than 8 weeks following the multiple-dose treatment. The significant persistence of PA-derived DNA adducts in vivo supports their role in serving as a biomarker of PA exposure.

Tetracapsuloides bryosalmonae persists in brown trout Salmo trutta for five years post exposure.

Science.gov (United States)

Soliman, Hatem; Kumar, Gokhlesh; El-Matbouli, Mansour

2018-01-31

Tetracapsuloides bryosalmonae is a malacosporean parasite and the causative agent of proliferative kidney disease (PKD) that seriously impacts farmed and wild salmonids. The parasite's life cycle includes an invertebrate host, the bryozoan Fredericella sultana, and a vertebrate host, salmonid fish. The persistence of T. bryosalmonae in brown trout Salmo trutta for up to 2 yr following exposure is well documented. Results from the present study confirmed that one brown trout that had recovered from PKD did not completely clear the parasite from its tissues and that T. bryosalmonae could persist in brown trout for up to 5 yr post exposure. Furthermore, recovered infected brown trout can release viable T. bryosalmonae spores that are able to infect specific pathogen-free F. sultana colonies. T. bryosalmonae DNA was detected by PCR in every organ, and parasite stages were observed in the kidney, spleen and liver following immunohistochemistry. This finding indicates that T. bryosalmonae-infected brown trout can act as asymptomatic carriers and release the parasite for several years after the initial infection, acting as a reservoir of infection, and contributing to the dissemination of the parasite to new areas.

Persistent Organic Pollutant Exposure Leads to Insulin Resistance Syndrome

DEFF Research Database (Denmark)

Ruzzin, Jérôme; Petersen, Rasmus; Meugnier, Emmanuelle

2010-01-01

BACKGROUND: The incidence of the insulin resistance syndrome has increased at an alarming rate worldwide creating a serious challenge to public health care in the 21st century. Recently, epidemiological studies have associated the prevalence of type 2 diabetes with elevated body burdens...... of persistent organic pollutants (POPs). However, experimental evidence demonstrating a causal link between POPs and the development of insulin resistance is lacking. OBJECTIVE: We investigated whether exposure to POPs contributes to insulin resistance and metabolic disorders. METHODS: Wistar rats were exposed...... salmon oil. We measured body weight, whole-body insulin sensitivity, POP accumulation, lipid and glucose homeostasis, gene expression and performed microarray analysis. RESULTS: Adult male rats exposed to crude, but not refined, salmon oil developed insulin resistance, abdominal obesity...

Exposure to Atrazine and Selected Non-Persistent Pesticides among Corn Farmers during a Growing Season

Science.gov (United States)

Bakke, Berit; De Roos, Anneclaire J.; Barr, Dana B.; Stewart, Patricia A.; Blair, Aaron; Freeman, Laura Beane; Lynch, Charles F.; Allen, Ruth H.; Alavanja, Michael C.R.; Vermeulen, Roel

2011-01-01

Objectives The aim was to develop quantitative estimates of farmers’ pesticide exposure to atrazine and to provide an overview of background levels of selected non-persistent pesticides among corn farmers in a longitudinal molecular epidemiologic study. Methods The study population consisted of 30 Agricultural Health Study farmers from Iowa and 10 nonfarming controls. Farmers completed daily and weekly diaries from March to November in 2002 and 2003 on pesticide use and other exposure determinants. Urine samples were collected at 10 timepoints relative to atrazine application and other farming activities. Pesticide exposure was assessed using urinary metabolites and diaries. Results The analytical limit of detection (LOD) ranged between 0.1–0.2 μg/l for all pesticide analytes except for isazaphos (1.5 μg/l) and diazinon (0.7 μg/l). Farmers had higher geometric mean urinary atrazine mercapturate (AZM) values than controls during planting (1.1 vs. urine collection (38% vs. 6%, p<0.0001). A similar pattern was observed for 2,4-D and acetochlor (92% vs. 47%, p<0.0001 and 45% vs. 4%, p<0.0001, respectively). Conclusion Urinary AZM levels in farmers were largely driven by recent application of atrazine. Therefore, the amount of atrazine applied is likely to provide valid surrogates of atrazine exposure in epidemiologic studies. Elevated background levels of non-persistent pesticides, especially 2,4-D, indicate importance in epidemiologic studies of capturing pesticide exposures that might not be directly related to the actual application. PMID:19052531

Chronic lead exposure induces cochlear oxidative stress and potentiates noise-induced hearing loss.

Science.gov (United States)

Jamesdaniel, Samson; Rosati, Rita; Westrick, Judy; Ruden, Douglas M

2018-08-01

Acquired hearing loss is caused by complex interactions of multiple environmental risk factors, such as elevated levels of lead and noise, which are prevalent in urban communities. This study delineates the mechanism underlying lead-induced auditory dysfunction and its potential interaction with noise exposure. Young-adult C57BL/6 mice were exposed to: 1) control conditions; 2) 2 mM lead acetate in drinking water for 28 days; 3) 90 dB broadband noise 2 h/day for two weeks; and 4) both lead and noise. Blood lead levels were measured by inductively coupled plasma mass spectrometry analysis (ICP-MS) lead-induced cochlear oxidative stress signaling was assessed using targeted gene arrays, and the hearing thresholds were assessed by recording auditory brainstem responses. Chronic lead exposure downregulated cochlear Sod1, Gpx1, and Gstk1, which encode critical antioxidant enzymes, and upregulated ApoE, Hspa1a, Ercc2, Prnp, Ccl5, and Sqstm1, which are indicative of cellular apoptosis. Isolated exposure to lead or noise induced 8-12 dB and 11-25 dB shifts in hearing thresholds, respectively. Combined exposure induced 18-30 dB shifts, which was significantly higher than that observed with isolated exposures. This study suggests that chronic exposure to lead induces cochlear oxidative stress and potentiates noise-induced hearing impairment, possibly through parallel pathways. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Preventive effect of curcumin and its highly bioavailable preparation on hearing loss induced by single or repeated exposure to noise: A comparative and mechanistic study.

Science.gov (United States)

Yamaguchi, Taro; Yoneyama, Masanori; Onaka, Yusuke; Imaizumi, Atsushi; Ogita, Kiyokazu

2017-08-01

We sought to determine the preventive effects of curcumin and its highly bioavailable preparation on noise-induced hearing loss in a novel murine model of permanent hearing loss developed by repeated exposure to noise. Upon exposure to noise (8-kHz octave band noise, 90 dB sound pressure level, 1 h), hearing ability was impaired in a temporary and reversible manner. During repeated noise exposure (1-h exposure per day, 5 days), there was a progressive increase in the auditory threshold shift at 12 and 20 kHz. The threshold shift persisted for at least 6 days after noise exposure. Oral administration of curcumin for 3 days before and each day during noise exposure significantly alleviated the hearing loss induced by repeated noise exposure. Curcumin abolished intranuclear translocation of nuclear factor-κB-p65 and generation of 4-hydroxynonenal-adducted proteins found in the cochlea after noise exposure. Theracurmin ® , a highly absorbable and bioavailable preparation of curcumin, had strong preventive effects on hearing loss induced by repeated noise exposure. Together, these data suggest that curcumin exerts a preventive effect on noise-induced hearing loss and is therefore a good therapeutic candidate for preventing sensorineural hearing loss. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Cumulative Antiretroviral Exposure Measured in Hair Is Not Associated With Measures of HIV Persistence or Inflammation Among Individuals on Suppressive ART.

Science.gov (United States)

Gandhi, Monica; Gandhi, Rajesh T; Stefanescu, Andrei; Bosch, Ronald J; Cyktor, Joshua C; Horng, Howard; Louie, Alexander; Phung, Nhi; Eron, Joseph J; Hogg, Evelyn; Macatangay, Bernard J C; Hensel, Christopher; Fletcher, Courtney V; Mellors, John W; McMahon, Deborah K

2018-06-20

Data on the relationship of antiretroviral exposure to measures of human immunodeficiency virus (HIV) persistence are limited. To address this gap, multiple viral, immunologic, and pharmacologic measures were analyzed from individuals with sustained virologic suppression on therapy (median 7 years) in the AIDS Clinical Trials Group A5321 cohort. Among 110 participants on tenofovir-(TFV)-disoproxil-fumarate (TDF)/emtricitabine (FTC)-containing regimens, we found no significant correlation between hair concentrations of individual antiretrovirals (ARVs) in the regimen and measures of HIV persistence (plasma HIV-1 RNA by single copy assay, cell-associated-DNA, cell-associated RNA) or soluble markers of inflammation. These findings suggest that higher systemic ARV exposure may not impact HIV persistence or inflammation.

Acute lung injury and persistent small airway disease in a rabbit model of chlorine inhalation

Energy Technology Data Exchange (ETDEWEB)

Musah, Sadiatu; Schlueter, Connie F.; Humphrey, David M. [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States); Powell, Karen S. [Research Resource Facilities, University of Louisville, Louisville, KY (United States); Roberts, Andrew M. [Department of Physiology, University of Louisville, Louisville, KY (United States); Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu [Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, KY (United States)

2017-01-15

Chlorine is a pulmonary toxicant to which humans can be exposed through accidents or intentional releases. Acute effects of chlorine inhalation in humans and animal models have been well characterized, but less is known about persistent effects of acute, high-level chlorine exposures. In particular, animal models that reproduce the long-term effects suggested to occur in humans are lacking. Here, we report the development of a rabbit model in which both acute and persistent effects of chlorine inhalation can be assessed. Male New Zealand White rabbits were exposed to chlorine while the lungs were mechanically ventilated. After chlorine exposure, the rabbits were extubated and were allowed to survive for up to 24 h after exposure to 800 ppm chlorine for 4 min to study acute effects or up to 7 days after exposure to 400 ppm for 8 min to study longer term effects. Acute effects observed 6 or 24 h after inhalation of 800 ppm chlorine for 4 min included hypoxemia, pulmonary edema, airway epithelial injury, inflammation, altered baseline lung mechanics, and airway hyperreactivity to inhaled methacholine. Seven days after recovery from inhalation of 400 ppm chlorine for 8 min, rabbits exhibited mild hypoxemia, increased area of pressure–volume loops, and airway hyperreactivity. Lung histology 7 days after chlorine exposure revealed abnormalities in the small airways, including inflammation and sporadic bronchiolitis obliterans lesions. Immunostaining showed a paucity of club and ciliated cells in the epithelium at these sites. These results suggest that small airway disease may be an important component of persistent respiratory abnormalities that occur following acute chlorine exposure. This non-rodent chlorine exposure model should prove useful for studying persistent effects of acute chlorine exposure and for assessing efficacy of countermeasures for chlorine-induced lung injury. - Highlights: • A novel rabbit model of chlorine-induced lung disease was developed. �

Persistence of Positive Carryover Effects in the Oyster, Saccostrea glomerata, following Transgenerational Exposure to Ocean Acidification.

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Laura M Parker

Full Text Available Ocean acidification (OA is predicted to have widespread implications for marine organisms, yet the capacity for species to acclimate or adapt over this century remains unknown. Recent transgenerational studies have shown that for some marine species, exposure of adults to OA can facilitate positive carryover effects to their larval and juvenile offspring that help them to survive in acidifying oceanic conditions. But whether these positive carryover effects can persist into adulthood or the next generation is unknown. Here we tested whether positive carryover effects found in larvae of the oyster, Saccostrea glomerata following transgenerational exposure to elevated CO2, could persist into adulthood and whether subsequent transgenerational exposure of adults to elevated CO2 would facilitate similar adaptive responses in the next generation of larvae and juveniles. Following our previous transgenerational exposure of parental adults and first generation (F1 larvae to ambient (385 μatm and elevated (856 μatm CO2, newly settled F1 juveniles were transferred to the field at ambient CO2 for 14 months, until they reached reproductive maturity. At this time, the F1 adults were returned to the laboratory and the previous transgenerational CO2 exposure was repeated to produce F2 offspring. We found that the capacity of adults to regulate extracellular pH at elevated CO2 was improved if they had a prior history of transgenerational exposure to elevated CO2. In addition, subsequent transgenerational exposure of these adults led to an increase in the resilience of their larval and juvenile offspring. Offspring with a history of transgenerational exposure to elevated CO2 had a lower percentage abnormality, faster development rate, faster shell growth and increased heart rate at elevated CO2 compared with F2 offspring with no prior history of exposure to elevated CO2. Our results suggest that positive carryover effects originating during parental and larval

The Drinking Water Disparities Framework: On the Origins and Persistence of Inequities in Exposure

Science.gov (United States)

Balazs, Carolina L.; Ray, Isha

2014-01-01

With this article, we develop the Drinking Water Disparities Framework to explain environmental injustice in the context of drinking water in the United States. The framework builds on the social epidemiology and environmental justice literatures, and is populated with 5 years of field data (2005–2010) from California’s San Joaquin Valley. We trace the mechanisms through which natural, built, and sociopolitical factors work through state, county, community, and household actors to constrain access to safe water and to financial resources for communities. These constraints and regulatory failures produce social disparities in exposure to drinking water contaminants. Water system and household coping capacities lead, at best, to partial protection against exposure. This composite burden explains the origins and persistence of social disparities in exposure to drinking water contaminants. PMID:24524500

Considerations on the medico-legal compensation for stochastic effects induced by the exposure to ionizing radiations in working environment

International Nuclear Information System (INIS)

Lafontaine, M.

1988-01-01

A better detection of stochastic diseases induced by the exposure to ionizing radiations and the establishment of causative correlation are presently reasons to justify new medico-legal approaches. The right to reparation for workers suffering from diseases which may have been caused by occupational exposure to ionizing radiations in Belgium, is covered by the law on occupational diseases and by the legislation on industrial accidents. However, some difficulties persist, concerning the right for compensation, consisting in the very short delay for prescription, the existence of an administrative list of diseases eligible for compensation and in the burden of proof to establish an obvious etiological relation. (Author)

Drosophila Insulin receptor regulates the persistence of injury-induced nociceptive sensitization

Science.gov (United States)

Patel, Atit A.

2018-01-01

ABSTRACT Diabetes-associated nociceptive hypersensitivity affects diabetic patients with hard-to-treat chronic pain. Because multiple tissues are affected by systemic alterations in insulin signaling, the functional locus of insulin signaling in diabetes-associated hypersensitivity remains obscure. Here, we used Drosophila nociception/nociceptive sensitization assays to investigate the role of Insulin receptor (Insulin-like receptor, InR) in nociceptive hypersensitivity. InR mutant larvae exhibited mostly normal baseline thermal nociception (absence of injury) and normal acute thermal hypersensitivity following UV-induced injury. However, their acute thermal hypersensitivity persists and fails to return to baseline, unlike in controls. Remarkably, injury-induced persistent hypersensitivity is also observed in larvae that exhibit either type 1 or type 2 diabetes. Cell type-specific genetic analysis indicates that InR function is required in multidendritic sensory neurons including nociceptive class IV neurons. In these same nociceptive sensory neurons, only modest changes in dendritic morphology were observed in the InRRNAi-expressing and diabetic larvae. At the cellular level, InR-deficient nociceptive sensory neurons show elevated calcium responses after injury. Sensory neuron-specific expression of InR rescues the persistent thermal hypersensitivity of InR mutants and constitutive activation of InR in sensory neurons ameliorates the hypersensitivity observed with a type 2-like diabetic state. Our results suggest that a sensory neuron-specific function of InR regulates the persistence of injury-associated hypersensitivity. It is likely that this new system will be an informative genetically tractable model of diabetes-associated hypersensitivity. PMID:29752280

Inducing Sadness and Anxiousness through Visual Media: Measurement Techniques and Persistence

OpenAIRE

Kuijsters, Andre; Redi, Judith; de Ruyter, Boris; Heynderickx, Ingrid

2016-01-01

textabstractThe persistence of negative moods (sadness and anxiousness) induced by three visual Mood Induction Procedures (MIP) was investigated. The evolution of the mood after the MIP was monitored for a period of 8 min with the Self-Assessment Manikin (SAM; every 2 min) and with recordings of skin conductance level (SCL) and electrocardiography (ECG). The SAM pleasure ratings showed that short and longer film fragments were effective in inducing a longer lasting negative mood, whereas the ...

Persistence of the immune response induced by BCG vaccination

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Blitz Rose

2008-01-01

Full Text Available Abstract Background Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. Methods A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-γ response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD in a whole blood assay before, 3 months, 12 months (n = 148 and 3 years (n = 19 after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16. Results A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13% failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13% or 3 (3/19; 16% years. IFN-γ response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81% made a detectable IFN-γ response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38% matched unvaccinated controls (p = 0.012; teenagers vaccinated in infancy were 19 times more likely to make an IFN-γ response of > 500 pg/ml than unvaccinated teenagers. Conclusion BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the

Inducing sadness and anxiousness through visual media: Measurement techniques and persistence

NARCIS (Netherlands)

Kuijsters, A.; Redi, J.; Ruyter, B.E.R. de; Heynderickx, I.

2016-01-01

The persistence of negative moods (sadness and anxiousness) induced by three visual Mood Induction Procedures (MIP) was investigated. The evolution of the mood after the MIP was monitored for a period of 8 minutes with the Self-Assessment Manikin (every 2 minutes) and with recordings of skin

Paternal preconception ethanol exposure blunts hypothalamic-pituitary-adrenal axis responsivity and stress-induced excessive fluid intake in male mice.

Science.gov (United States)

Rompala, Gregory R; Finegersh, Andrey; Homanics, Gregg E

2016-06-01

A growing number of environmental insults have been shown to induce epigenetic effects that persist across generations. For instance, paternal preconception exposures to ethanol or stress have independently been shown to exert such intergenerational effects. Since ethanol exposure is a physiological stressor that activates the hypothalamic-pituitary-adrenal (HPA) axis, we hypothesized that paternal ethanol exposure would impact stress responsivity of offspring. Adult male mice were exposed to chronic intermittent vapor ethanol or control conditions for 5 weeks before being mated with ethanol-naïve females to produce ethanol (E)- and control (C)-sired offspring. Adult male and female offspring were tested for plasma corticosterone (CORT) levels following acute restraint stress and the male offspring were further examined for stress-evoked 2-bottle choice ethanol-drinking. Paternal ethanol exposure blunted plasma CORT levels following acute restraint stress selectively in male offspring; females were unaffected. In a stress-evoked ethanol-drinking assay, there was no effect of stress on ethanol consumption. However, C-sired males exhibited increased total fluid intake (polydipsia) in response to stress while E-sired males were resistant to this stress-induced phenotype. Taken together, these data suggest that paternal ethanol exposure imparts stress hyporesponsivity to male offspring. Copyright © 2016 Elsevier Inc. All rights reserved.

Inducing sadness and anxiousness through visual media: measurement techniques and persistence

NARCIS (Netherlands)

A. Kuijsters (Andre); J.A. Redi (Judith); B. de Ruyter (Boris); I. Heynderickx (Ingrid)

2016-01-01

textabstractThe persistence of negative moods (sadness and anxiousness) induced by three visual Mood Induction Procedures (MIP) was investigated. The evolution of the mood after the MIP was monitored for a period of 8 min with the Self-Assessment Manikin (SAM; every 2 min) and with recordings of

EPR persistence measurements of UV-induced melanin free radicals in whole skin

International Nuclear Information System (INIS)

Collins, B.; Poehler, T.O.; Bryden, W.A.

1995-01-01

Electron paramagnetic resonance is used to detect the formation of free radicals caused by exposure to ultraviolet radiation in chemically untreated rabbit skin. A fast jump in EPR signal level, occurring over a few seconds, is observed immediately after a skin sample is exposed to UV. This is followed by a slower increase toward an elevated steady-state signal over a period of hours as the skin is continuously exposed to a UV light source. Upon cessation of UV light exposure, EPR signal levels undergo an abrupt drop followed by a slower decay toward natural levels. Elevated free radical concentrations following UV exposure are found to persist for several hours in whole skin. These results are consistent with time resolved EPR measurements of photoinduced radicals in various natural melanins. (Author)

Infection of the malaria mosquito, Anopheles gambiae, with two species of entomopathogenic fungi: effects of concentration, co-formulation, exposure time and persistence

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Lwetoijera Dickson W

2009-12-01

Full Text Available Abstract Background Entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana isolates have been shown to infect and reduce the survival of mosquito vectors. Methods Here four different bioassays were conducted to study the effect of conidia concentration, co-formulation, exposure time and persistence of the isolates M. anisopliae ICIPE-30 and B. bassiana I93-925 on infection and survival rates of female Anopheles gambiae sensu stricto. Test concentrations and exposure times ranged between 1 × 107 - 4 × 1010 conidia m-2 and 15 min - 6 h. In co-formulations, 2 × 1010 conidia m-2 of both fungus isolates were mixed at ratios of 4:1, 2:1, 1:1,1:0, 0:1, 1:2 and 1:4. To determine persistence, mosquitoes were exposed to surfaces treated 1, 14 or 28 d previously, with conidia concentrations of 2 × 109, 2 × 1010 or 4 × 1010. Results Mosquito survival varied with conidia concentration; 2 × 1010 conidia m-2 was the concentration above which no further reductions in survival were detectable for both isolates of fungus. The survival of mosquitoes exposed to single and co-formulated treatments was similar and no synergistic or additive effects were observed. Mosquitoes were infected within 30 min and longer exposure times did not result in a more rapid killing effect. Fifteen min exposure still achieved considerable mortality rates (100% mortality by 14 d of mosquitoes, but at lower speed than with 30 min exposure (100% mortality by 9 d. Conidia remained infective up to 28 d post-application but higher concentrations did not increase persistence. Conclusion Both fungus isolates are effective and persistent at low concentrations and short exposure times.

Estimation of TiO₂ nanoparticle-induced genotoxicity persistence and possible chronic gastritis-induction in mice.

Science.gov (United States)

Mohamed, Hanan Ramadan Hamad

2015-09-01

Titanium dioxide (TiO2) nanoparticles are widely used as a food additive and coloring agent in many consumer products however limited data is available on the nano-TiO2 induced genotoxicity persistence. Thus, this study investigated the persistence of nano-TiO2 induced genotoxicity and possible induction of chronic gastritis in mice. The mice were orally administered 5, 50 or 500 mg/kg body weight nano-TiO2 for five consecutive days, and then mice from each dosage group were sacrificed 24 h or one or two weeks after the last treatment. The administration of nano-TiO2 resulted in persistent apoptotic DNA fragmentation and mutations in p53 exons (5-8) as well as significant persistent elevations in malondialdehyde and nitric oxide levels and decreases in the reduced glutathione level and catalase activity compared with the control mice in a dose- and time-dependent manner. Necrosis and inflammation were evident upon histological examination. These findings could be attributed to the persistent accumulation of nano-TiO2 at the tested doses at all three time points. Based on these findings, we conclude that the administration of nano-TiO2, even at low doses, leads to persistent accumulation of nano-TiO2 in mice, resulting in persistent inflammation, apoptosis and oxidative stress, ultimately leading to the induction of chronic gastritis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Exposure to Mozart music reduces cognitive impairment in pilocarpine-induced status epilepticus rats.

Science.gov (United States)

Xing, Yingshou; Qin, Yi; Jing, Wei; Zhang, Yunxiang; Wang, Yanran; Guo, Daqing; Xia, Yang; Yao, Dezhong

2016-02-01

Patients with temporal lobe epilepsy (TLE) often display cognitive deficits. However, current epilepsy therapeutic interventions mainly aim at how to reduce the frequency and degree of epileptic seizures. Recovery of cognitive impairment is not attended enough, resulting in the lack of effective approaches in this respect. In the pilocarpine-induced temporal lobe epilepsy rat model, memory impairment has been classically reported. Here we evaluated spatial cognition changes at different epileptogenesis stages in rats of this model and explored the effects of long-term Mozart music exposure on the recovery of cognitive ability. Our results showed that pilocarpine rats suffered persisting cognitive impairment during epileptogenesis. Interestingly, we found that Mozart music exposure can significantly enhance cognitive ability in epileptic rats, and music intervention may be more effective for improving cognitive function during the early stages after Status epilepticus. These findings strongly suggest that Mozart music may help to promote the recovery of cognitive damage due to seizure activities, which provides a novel intervention strategy to diminish cognitive deficits in TLE patients.

Persistence in the WFC3 IR Detector: Intrinsic Variability

Science.gov (United States)

Long, Knox S.; Baggett, Sylvia M.

2018-03-01

When the WFC3 IR detector is exposed to a bright source or sources, the sources can appear as afterimages in subsequent exposures, a phenomenon known as persistence. This can affect the science obtained with the IR channel. We have been involved in an effort to predict the brightness of the afterimages so that users can (at a minimum) flag the affected pixels and remove them from their analysis or (even better) subtract the afterimages from their science images to salvage the data. The ability of any model to remove afterimages depends on the degree to which persistence is the same for identical sets of exposures. We investigate possible time variability of persistence in the WFC3 detector using sets of (almost) identical visits comprised of single exposures of Omega Cen followed by a series of darks in which persistence is measured. We analyze 8 data sets, each consisting of two or three identical visits, with stimulus exposures between 49 and 1199 s, and find clear evidence of variability in several of the datasets in darks taken within 1000 s of the stimulus exposure. In most of the datasets, the difference in persistence for saturated pixels in the stimulus exposure is a power law decay; the visit with higher persistence has a higher power law amplitude. There was nothing unusual about the observing conditions preceding and during each of these visits that can explain the discrepancy in persistence levels. Variation in persistence implies that: (1) Unless and until the source of the variability is understood, any persistence model for the WFC3 array will be limited in its ability to predict persistence in a single observation, and, (2) as a consequence, users should always carefully inspect the results of any attempt to subtract persistence from WFC3 IR data based on a model prediction.

Inducing sadness and anxiousness through visual media: measurement techniques and persistence

Directory of Open Access Journals (Sweden)

Andre Kuijsters

2016-08-01

Full Text Available The persistence of negative moods (sadness and anxiousness induced by three visual Mood Induction Procedures (MIP was investigated. The evolution of the mood after the MIP was monitored for a period of 8 minutes with the Self-Assessment Manikin (every 2 minutes and with recordings of skin conductance level (SCL and electrocardiography (ECG. The SAM pleasure ratings showed that short and longer film fragments were effective in inducing a longer lasting negative mood, whereas the negative mood induced by the IAPS slideshow was short lived. The induced arousal during the anxious MIPs diminished quickly after the mood induction; nevertheless, the SCL data suggest longer lasting arousal effects for both movies. The decay of the induced mood follows a logarithmic function; diminishing quickly in the first minutes, thereafter returning slowly back to baseline. These results reveal that caution is needed when investigating the effects of the induced mood on a task or the effect of interventions on induced moods, because the induced mood diminishes quickly after the mood induction.

Inducing Sadness and Anxiousness through Visual Media: Measurement Techniques and Persistence.

Science.gov (United States)

Kuijsters, Andre; Redi, Judith; de Ruyter, Boris; Heynderickx, Ingrid

2016-01-01

The persistence of negative moods (sadness and anxiousness) induced by three visual Mood Induction Procedures (MIP) was investigated. The evolution of the mood after the MIP was monitored for a period of 8 min with the Self-Assessment Manikin (SAM; every 2 min) and with recordings of skin conductance level (SCL) and electrocardiography (ECG). The SAM pleasure ratings showed that short and longer film fragments were effective in inducing a longer lasting negative mood, whereas the negative mood induced by the IAPS slideshow was short lived. The induced arousal during the anxious MIPs diminished quickly after the mood induction; nevertheless, the SCL data suggest longer lasting arousal effects for both movies. The decay of the induced mood follows a logarithmic function; diminishing quickly in the first minutes, thereafter returning slowly back to baseline. These results reveal that caution is needed when investigating the effects of the induced mood on a task or the effect of interventions on induced moods, because the induced mood diminishes quickly after the mood induction.

Irregular persistent activity induced by synaptic excitatory feedback

Directory of Open Access Journals (Sweden)

Francesca Barbieri

2007-11-01

Full Text Available Neurophysiological experiments on monkeys have reported highly irregular persistent activity during the performance of an oculomotor delayed-response task. These experiments show that during the delay period the coefficient of variation (CV of interspike intervals (ISI of prefrontal neurons is above 1, on average, and larger than during the fixation period. In the present paper, we show that this feature can be reproduced in a network in which persistent activity is induced by excitatory feedback, provided that (i the post-spike reset is close enough to threshold , (ii synaptic efficacies are a non-linear function of the pre-synaptic firing rate. Non-linearity between presynaptic rate and effective synaptic strength is implemented by a standard short-term depression mechanism (STD. First, we consider the simplest possible network with excitatory feedback: a fully connected homogeneous network of excitatory leaky integrate-and-fire neurons, using both numerical simulations and analytical techniques. The results are then confirmed in a network with selective excitatory neurons and inhibition. In both the cases there is a large range of values of the synaptic efficacies for which the statistics of firing of single cells is similar to experimental data.

Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease

International Nuclear Information System (INIS)

Wahlang, Banrida; Song, Ming; Beier, Juliane I.; Cameron Falkner, K.; Al-Eryani, Laila; Clair, Heather B.; Prough, Russell A.; Osborne, Tanasa S.; Malarkey, David E.; Christopher States, J.; Cave, Matthew C.

2014-01-01

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20 mg/kg or 200 mg/kg in corn oil) for 12 weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260 + HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNFα were increased only at 20 mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200 mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200 mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant “second hit” in the transformation of steatosis to steatohepatitis. - Highlights: • Aroclor 1260 exposure decreased adiposity in mice fed with high fat diet • Aroclor 1260 exposure induced steatohepatitis in diet-induced obese mice • Aroclor 1260 (20 and 200 mg/kg) induced

Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease

Energy Technology Data Exchange (ETDEWEB)

Wahlang, Banrida [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Song, Ming [Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Beier, Juliane I. [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Cameron Falkner, K. [Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Al-Eryani, Laila [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Clair, Heather B.; Prough, Russell A. [Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Osborne, Tanasa S.; Malarkey, David E. [Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Christopher States, J. [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Cave, Matthew C., E-mail: matt.cave@louisville.edu [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202 (United States); The Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206 (United States)

2014-09-15

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20 mg/kg or 200 mg/kg in corn oil) for 12 weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260 + HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNFα were increased only at 20 mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200 mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200 mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant “second hit” in the transformation of steatosis to steatohepatitis. - Highlights: • Aroclor 1260 exposure decreased adiposity in mice fed with high fat diet • Aroclor 1260 exposure induced steatohepatitis in diet-induced obese mice • Aroclor 1260 (20 and 200 mg/kg) induced

Familial factors responsible for persistent crying-induced asthma: a case report.

Science.gov (United States)

Weinstein, A G

1987-10-01

Crying behavior of the asthmatic child may induce wheezing symptoms. This may be a clinical problem for families with asthmatic children who exhibit frequent and persistent crying behavior. This case report identifies behaviors by the child and parents that may be responsible for continual crying. Child factors include (1) "spoiled" personality, (2) poor self-image, (3) biologic sensitivity to foods, medication, and environmental allergens producing irritability. Parental factors include poor disciplinary practices secondary to (1) disrupted home life, (2) guilt, and (3) overprotective behavior. Identification of these factors may be helpful in establishing clinical management strategies to reduce crying-induced asthma.

Long-stay psychiatric patients: a prospective study revealing persistent antipsychotic-induced movement disorder.

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P Roberto Bakker

Full Text Available OBJECTIVE: The purpose of this study was to assess the frequency of persistent drug-induced movement disorders namely, tardive dyskinesia (TD, parkinsonism, akathisia and tardive dystonia in a representative sample of long-stay patients with chronic severe mental illness. METHOD: Naturalistic study of 209, mainly white, antipsychotic-treated patients, mostly diagnosed with psychotic disorder. Of this group, the same rater examined 194 patients at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia. RESULTS: The frequencies of persistent movement disorders in the sample were 28.4% for TD, 56.2% for parkinsonism, 4.6% for akathisia and 5.7% for tardive dystonia. Two-thirds of the participants displayed at least one type of persistent movement disorder. CONCLUSIONS: Persistent movement disorder continues to be the norm for long-stay patients with chronic mental illness and long-term antipsychotic treatment. Measures are required to remedy this situation.

Single Silver Nanoparticle Instillation Induced Early and Persisting Moderate Cortical Damage in Rat Kidneys

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Elisa Roda

2017-10-01

Full Text Available The potential toxic effects of silver nanoparticles (AgNPs, administered by a single intratracheal instillation (i.t, was assessed in a rat model using commercial physico-chemical characterized nanosilver. Histopathological changes, overall toxic response and oxidative stress (kidney and plasma protein carbonylation, paralleled by ultrastructural observations (TEM, were evaluated to examine renal responses 7 and 28 days after i.t. application of a low AgNP dose (50 µg/rat, compared to an equivalent dose of ionic silver (7 µg AgNO3/rat. The AgNPs caused moderate renal histopathological and ultrastructural alteration, in a region-specific manner, being the cortex the most affected area. Notably, the bulk AgNO3, caused similar adverse effects with a slightly more marked extent, also triggering apoptotic phenomena. Specifically, 7 days after exposure to both AgNPs and AgNO3, dilatation of the intercapillary and peripheral Bowman’s space was observed, together with glomerular shrinkage. At day 28, these effects still persisted after both treatments, accompanied by an additional injury involving the vascular component of the mesangium, with interstitial micro-hemorrhages. Neither AgNPs nor AgNO3 induced oxidative stress effects in kidneys and plasma, at either time point. The AgNP-induced moderate renal effects indicate that, despite their benefits, novel AgNPs employed in consumer products need exhaustive investigation to ensure public health safety.

Persistent optically induced magnetism in oxygen-deficient strontium titanate.

Science.gov (United States)

Rice, W D; Ambwani, P; Bombeck, M; Thompson, J D; Haugstad, G; Leighton, C; Crooker, S A

2014-05-01

Strontium titanate (SrTiO3) is a foundational material in the emerging field of complex oxide electronics. Although its bulk electronic and optical properties are rich and have been studied for decades, SrTiO3 has recently become a renewed focus of materials research catalysed in part by the discovery of superconductivity and magnetism at interfaces between SrTiO3 and other non-magnetic oxides. Here we illustrate a new aspect to the phenomenology of magnetism in SrTiO3 by reporting the observation of an optically induced and persistent magnetization in slightly oxygen-deficient bulk SrTiO3-δ crystals using magnetic circular dichroism (MCD) spectroscopy and SQUID magnetometry. This zero-field magnetization appears below ~18 K, persists for hours below 10 K, and is tunable by means of the polarization and wavelength of sub-bandgap (400-500 nm) light. These effects occur only in crystals containing oxygen vacancies, revealing a detailed interplay between magnetism, lattice defects, and light in an archetypal complex oxide material.

Mixed chemical-induced oxidative stress in occupational exposure ...

African Journals Online (AJOL)

Mixed chemical-induced oxidative stress in occupational exposure in Nigerians. JI Anetor, SA Yaqub, GO Anetor, AC Nsonwu, FAA Adeniyi, S Fukushima. Abstract. Exposure to single chemicals and associated disorders in occupational environments has received significant attention. Understanding these events holds ...

[Morphological recovery in the polycystic ovaries of persistent-estrus rats induced by continuous illumination (author's transl)].

Science.gov (United States)

Sawada, T; Kosaka, T

1981-10-01

When mature female rats having been showing at least 2 consecutive 4-day estrous cycles were raised in a room with continuous lighting (LL), their vaginal smear pattern became irregular by 7 to 9 days. and a persistent-estrus (P-E) appeared around 25 to 75 days of exposure. Ovaries from LL-exposed rats showing irregular cycles or P-E had signs of cystic follicles and anovulatory polycystic follicles, respectively. When P-E rats were placed again under the light-dark cycling condition (14L: 10D; Lights on 05: 00 h), the regular 4-day cycles were recovered soon and ovarian structures became normal after about 5 cycles. In P-E rats injected i.v. with 10 microgram LH/day at 4-day intervals under the LL condition, the regular estrous cycle reappeared and ovarian structures became normal after 5 administrations. These results suggest that the polycystic ovary of P-E rat induced by LL is reversible with cyclic stimulation by LH.

Prenatal exposure to persistent organic pollutants and offspring allergic sensitization and lung function at 20 years of age

DEFF Research Database (Denmark)

Hansen, Susanne; Strøm, Marin; Olsen, Sjurdur F

2016-01-01

BACKGROUND: Prenatal exposures to persistent organic pollutants (POPs) have been associated with asthma medication use and self-reported symptoms, but associations with lung function and allergic sensitization have been minimally explored. The aim of the study was to examine associations between...... with reduced lung function (FEV1 %predicted valuediseases may have...

Maternal L-glutamine supplementation prevents prenatal alcohol exposure-induced fetal growth restriction in an ovine model.

Science.gov (United States)

Sawant, Onkar B; Wu, Guoyao; Washburn, Shannon E

2015-06-01

Prenatal alcohol exposure is known to cause fetal growth restriction and disturbances in amino acid bioavailability. Alterations in these parameters can persist into adulthood and low birth weight can lead to altered fetal programming. Glutamine has been associated with the synthesis of other amino acids, an increase in protein synthesis and it is used clinically as a nutrient supplement for low birth weight infants. The aim of this study was to explore the effect of repeated maternal alcohol exposure and L-glutamine supplementation on fetal growth and amino acid bioavailability during the third trimester-equivalent period in an ovine model. Pregnant sheep were randomly assigned to four groups, saline control, alcohol (1.75-2.5 g/kg), glutamine (100 mg/kg, three times daily) or alcohol + glutamine. In this study, a weekend binge drinking model was followed where treatment was done 3 days per week in succession from gestational day (GD) 109-132 (normal term ~147). Maternal alcohol exposure significantly reduced fetal body weight, height, length, thoracic girth and brain weight, and resulted in decreased amino acid bioavailability in fetal plasma and placental fluids. Maternal glutamine supplementation successfully mitigated alcohol-induced fetal growth restriction and improved the bioavailability of glutamine and glutamine-related amino acids such as glycine, arginine, and asparagine in the fetal compartment. All together, these findings show that L-glutamine supplementation enhances amino acid availability in the fetus and prevents alcohol-induced fetal growth restriction.

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-induced Round Bodies of Borrelia burgdorferi Persisters from an FDA Drug Library

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Jie eFeng

2016-05-01

Full Text Available Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that are not killed by current Lyme antibiotics. To identify more effective drugs that are active against the round bodies of B. burgdorferi, we established a round body persister model induced by amoxicillin and screened the Food and Drug Administration (FDA drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide (PI viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven of these scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. While some drug candidates such as daptomycin and clofazimine overlapped with a previous screen against stationary phase B. burgdorferi persisters, additional drug candidates active against round bodies we identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even if pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.

Tick exposure and extreme climate events impact survival and threaten the persistence of a long-lived lizard.

Science.gov (United States)

Jones, Alice R; Bull, C Michael; Brook, Barry W; Wells, Konstans; Pollock, Kenneth H; Fordham, Damien A

2016-03-01

Assessing the impacts of multiple, often synergistic, stressors on the population dynamics of long-lived species is becoming increasingly important due to recent and future global change. Tiliqua rugosa (sleepy lizard) is a long-lived skink (>30 years) that is adapted to survive in semi-arid environments with varying levels of parasite exposure and highly seasonal food availability. We used an exhaustive database of 30 years of capture-mark-recapture records to quantify the impacts of both parasite exposure and environmental conditions on the lizard's survival rates and long-term population dynamics. Lizard abundance was relatively stable throughout the study period; however, there were changing patterns in adult and juvenile apparent survival rates, driven by spatial and temporal variation in levels of tick exposure and temporal variation in environmental conditions. Extreme weather events during the winter and spring seasons were identified as important environmental drivers of survival. Climate models predict a dramatic increase in the frequency of extreme hot and dry winter and spring seasons in our South Australian study region; from a contemporary probability of 0.17 up to 0.47-0.83 in 2080 depending on the emissions scenario. Our stochastic population model projections showed that these future climatic conditions will induce a decline in the abundance of this long-lived reptile of up to 67% within 30 years from 2080, under worst case scenario modelling. The results have broad implications for future work investigating the drivers of population dynamics and persistence. We highlight the importance of long-term data sets and accounting for synergistic impacts between multiple stressors. We show that predicted increases in the frequency of extreme climate events have the potential to considerably and negatively influence a long-lived species, which might previously have been assumed to be resilient to environmental perturbations. © 2015 The Authors. Journal of

Persistent Seroconversion after Accidental Eye Exposure to Calcifying Nanoparticles

Science.gov (United States)

Ciftcioglu, Neva; Aho, Katja M.; McKay, David S.; Kajander, E. Olavi

2007-01-01

Biosafety of nanomaterials has attracted much attention recently. We report here a case where accidental human eye exposure to biogenic nanosized calcium phosphate in the form of calcifying nanoparticles (CNP) raised a strong IgG immune response against proteins carried by CNP. The antibody titer has persisted over ten years at the high level. The IgG was detected by ELISA using CNPs propagated in media containing bovine and human serum as antigen. The exposure incident occurred to a woman scientist (WS) at a research laboratory in Finland at 1993. CNP, also termed "nanobacteria", is a unique self-replicating agent that has not been fully characterized and no data on biohazards were available at that time. Before the accident, her serum samples were negative for both CNP antigen and anti-CNP antibody using specific ELISA tests (Nanobac Oy, Kuopio, Finland). The accident occurred while WS was harvesting CNP cultures. Due to a high pressure in pipetting, CNP pellet splashed into her right eye. Both eyes were immediately washed with water and saline. The following days there was irritation and redness in the right eye. These symptoms disappeared within two weeks without any treatment. Three months after the accident, blood and urine samples of WS were tested for CNP cultures (2), CNP-specific ELISA tests, and blood cell counts. Blood cell counts were normal, CNP antigen and culture tests were negative. A high IgG anti-CNP antibody titer was detected (see Figure). The antibodies of this person have been used thereafter as positive control and standard in ELISA manufacturing (Nano-Sero IgG ELISA, Nanobac Oy, Kuopio, Finland).

Lead Exposure Induces Telomere Instability in Human Cells.

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Géraldine Pottier

Full Text Available Lead (Pb is an important environmental contaminant due to its widespread use over many centuries. While it affects primarily every organ system of the body, the most pernicious effects of Pb are on the central nervous system leading to cognitive and behavioral modification. Despite decades of research, the mechanisms responsible for Pb toxicity remain poorly understood. Recent work has suggested that Pb exposure may have consequences on chromosomal integrity as it was shown that Pb exposure leads to the generation of γH2Ax foci, a well-established biomarker for DNA double stranded break (DSB formation. As the chromosomal localization of γH2Ax foci plays an important role in determining the molecular mechanism responsible for their formation, we examined the localization of Pb-induced foci with respect to telomeres. Indeed, short or dysfunctional telomeres (uncapped or damaged telomeres may be recognized as DSB by the DNA repair machinery, leading to "telomere-Induced Foci" (TIFs. In the current study, we show that while Pb exposure did not increase intra-chromosomal foci, it significantly induced TIFs, leading in some cases, to chromosomal abnormalities including telomere loss. The evidence suggests that these chromosomal abnormalities are likely due to perturbation of telomere replication, in particular on the lagging DNA strand. We propose a mechanism by which Pb exposure leads to the loss of telomere maintenance. As numerous studies have demonstrated a role for telomere maintenance in brain development and tissue homeostasis, our results suggest a possible mechanism for lead-induced neurotoxicity.

Breast cancer induced by protracted radiation exposures

International Nuclear Information System (INIS)

Elkind, M.M.

1997-01-01

The experience at Hiroshima/Nagasaki demonstrated that breast cancer can be induced by single doses of ionizing radiation following latencies of 10-40 years. Several epidemiological studies, usually involving ancillary low-LET radiation to the breast, have demonstrated that breast cancer can be induced by protracted exposures, with similar latencies, and with similar dependencies on dose. Radiobiologically these results suggest that the target cells involved were deficient in repair of low-LET damage even when the protraction was over months to years. Since three-quarters of breast tumors originate in the ducts where their proliferation is controlled by menstrual-cycle timed estrogen/progesterone secretions, these cells periodically were in cycle. Thus, the two main elements of a conceptual model for radon-induced lung cancer -- kinetics and deficient repair -- are satisfied. The model indicates that breast cancer could be the cumulative effect of protracted small exposures, the risk from any one of which ordinarily would be quite small. (author)

Intestinal exposure to PCB 153 induces inflammation via the ATM/NEMO pathway.

Science.gov (United States)

Phillips, Matthew C; Dheer, Rishu; Santaolalla, Rebeca; Davies, Julie M; Burgueño, Juan; Lang, Jessica K; Toborek, Michal; Abreu, Maria T

2018-01-15

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that adversely affect human health. PCBs bio-accumulate in organisms important for human consumption. PCBs accumulation in the body leads to activation of the transcription factor NF-κB, a major driver of inflammation. Despite dietary exposure being one of the main routes of exposure to PCBs, the gut has been widely ignored when studying the effects of PCBs. We investigated the effects of PCB 153 on the intestine and addressed whether PCB 153 affected intestinal permeability or inflammation and the mechanism by which this occurred. Mice were orally exposed to PCB 153 and gut permeability was assessed. Intestinal epithelial cells (IECs) were collected and evaluated for evidence of genotoxicity and inflammation. A human IEC line (SW480) was used to examine the direct effects of PCB 153 on epithelial function. NF-кB activation was measured using a reporter assay, DNA damage was assessed, and cytokine expression was ascertained with real-time PCR. Mice orally exposed to PCB 153 had an increase in intestinal permeability and inflammatory cytokine expression in their IECs; inhibition of NF-кB ameliorated both these effects. This inflammation was associated with genotoxic damage and NF-кB activation. Exposure of SW480 cells to PCB 153 led to similar effects as seen in vivo. We found that activation of the ATM/NEMO pathway by genotoxic stress was upstream of NF-kB activation. These results demonstrate that oral exposure to PCB 153 is genotoxic to IECs and induces downstream inflammation and barrier dysfunction in the intestinal epithelium. Copyright © 2017 Elsevier Inc. All rights reserved.

Transgenerational effects of stress exposure on offspring phenotypes in apomictic dandelion

NARCIS (Netherlands)

Verhoeven, K.J.F.; Van Gurp, T.P.

2012-01-01

Heritable epigenetic modulation of gene expression is a candidate mechanism to explain parental environmental effects on offspring phenotypes, but current evidence for environment-induced epigenetic changes that persist in offspring generations is scarce. In apomictic dandelions, exposure to various

Transgenerational Effects of Stress Exposure on Offspring Phenotypes in Apomictic Dandelion

NARCIS (Netherlands)

Verhoeven, K.J.F.; Gurp, van T.P.

2012-01-01

Heritable epigenetic modulation of gene expression is a candidate mechanism to explain parental environmental effects on offspring phenotypes, but current evidence for environment-induced epigenetic changes that persist in offspring generations is scarce. In apomictic dandelions, exposure to various

One week's holiday sun exposure induces expression of photoaging biomarkers.

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Lesiak, Aleksandra; Rogowski-Tylman, Michal; Danilewicz, Marian; Wozniacka, Anna; Narbutt, Joanna

2016-01-01

Skin aging is accompanied by the upregulation of the expression of various matrix metalloproteinases (MMPs). It was shown that exposure to ultraviolet radiation (UVR) may induce skin expression of MMPs and dysregulation of the transforming growth factor beta (TGF-β)/Smad pathway. The aim of our study was to compare the effects of short holiday UVR exposure and lifetime UVR exposure, on the expression of MMP-8, TGF-β1, and Smad2 in human skin biopsies. Skin biopsies were taken from the outer upper arm of 15 elderly people with significant photoaging (mean age 64.1 years) (Group 1) and from 15 healthy young adult volunteers (mean age 24.1 y) who participated in a six-day sun holiday. Biopsies were taken twice: 24 hours before leaving for holiday (Group 2a) and 24 hours after returning (Group 2b). The expression of TGF-β1, Smad2, and MMP-8 was examined by immunochemistry and measured semiquantitatively by two independent pathologists. The mean expression of TGF-β1 in dermal fibroblasts and keratinocytes in Group 1 and Group 2b was significantly lower than in Group 2a (0.54% ± 0.44% and 0.48% ± 0.51% vs. 1.48% ± 0.72%, respectively). The percentage of Smad2 (+) cells in Group 1 and Group 2b was lower than in Group 2a (2.13% ± 1.39% and 1.81% ± 1.16% vs. 4.13% ± 1.58%, respectively). The MMP-8 expression in Group 2b was 1.36% ± 0.68% and was significantly higher than in Group 1 (0.34% ± 0.42%) and Group 2a in which the protein was not detected (p < 0.001). We conclude that the decrease in the expression of TGF-β1 and Smad2 is a persistent biomarker of skin photoaging, while the increased expression of MMP-8 in keratinocytes can be regarded as a marker of acute sun exposure.

Colossal X-Ray-Induced Persistent Photoconductivity in Current-Perpendicular-to-Plane Ferroelectric/Semiconductor Junctions

KAUST Repository

Hu, Weijin

2017-12-07

Persistent photoconductivity (PPC) is an intriguing physical phenomenon, where electric conduction is retained after the termination of electromagnetic radiation, which makes it appealing for applications in a wide range of optoelectronic devices. So far, PPC has been observed in bulk materials and thin-film structures, where the current flows in the plane, limiting the magnitude of the effect. Here using epitaxial Nb:SrTiO3/Sm0.1Bi0.9FeO3/Pt junctions with a current-perpendicular-to-plane geometry, a colossal X-ray-induced PPC (XPPC) is achieved with a magnitude of six orders. This PPC persists for days with negligible decay. Furthermore, the pristine insulating state could be fully recovered by thermal annealing for a few minutes. Based on the electric transport and microstructure analysis, this colossal XPPC effect is attributed to the X-ray-induced formation and ionization of oxygen vacancies, which drives nonvolatile modification of atomic configurations and results in the reduction of interfacial Schottky barriers. This mechanism differs from the conventional mechanism of photon-enhanced carrier density/mobility in the current-in-plane structures. With their persistent nature, such ferroelectric/semiconductor heterojunctions open a new route toward X-ray sensing and imaging applications.

Integrated toxic evaluation of sulfamethazine on zebrafish: Including two lifespan stages (embryo-larval and adult) and three exposure periods (exposure, post-exposure and re-exposure).

Science.gov (United States)

Yan, Zhengyu; Yang, Qiulian; Jiang, Weili; Lu, Jilai; Xiang, Zhongrun; Guo, Ruixin; Chen, Jianqiu

2018-03-01

Persistence of antibiotics in aquatic environment may pose a risk to the non-target aquatic organisms. This study provided an integrated evaluation to analyze the toxic stress of sulfamethazine (SMZ) on zebrafish in two lifespan stages (embryo-larval and adult) and three exposure periods (exposure, post-exposure and re-exposure). Zebrafish embryos and adult zebrafish were exposed to SMZ at 0.2, 20 and 2000 μg/L, respectively. The results showed that SMZ at any given concentration inhibited the hatching of embryos at 58-96 hpf (hours post-fertilization). Our result also indicated that two major kinds of the malformation, which was induced by the antibiotic, were edema and spinal curvature. Additionally, the antibiotic stimulated the heartbeat while reduced the body length of the embryo at 72 hpf. Superoxide dismutase (SOD) activities and malondialdehyde (MDA) contents significantly increased at 120 hpf when the embryos were exposed to the lowest concentration (0.2 μg/L) of the antibiotic. On the other hand, the antibiotic induced SOD activities and MDA contents in adult zebrafish in the exposure and re-exposure periods. The MDA contents could recover while SOD activities still increased in 2 d after the exposure. Both SOD activities and MDA contents could recover in 7 d after the exposure. Levels of SOD and MDA in the re-exposure were higher than those in the first exposure. Our results suggested that SMZ had toxic effects on both embryos and adult zebrafish, and provided an integrated evaluation of the toxic effects of SMZ on zebrafish at a new perspective. Copyright © 2017 Elsevier Ltd. All rights reserved.

Myocardial fibrosis induced by exposure to subclinical lipopolysaccharide is associated with decreased miR-29c and enhanced NOX2 expression in mice.

Directory of Open Access Journals (Sweden)

Wilbur Y W Lew

Full Text Available Exposure to subclinical levels of lipopolysaccharide (LPS occurs commonly and is seemingly well tolerated. However, recurrent LPS exposure induces cardiac fibrosis over 2 to 3 months in a murine model, not mediated by the renin-angiotensin system. Subclinical LPS induces cardiac fibrosis by unique mechanisms.In C57/Bl6 mice, LPS (10 mg/kg or saline (control were injected intraperitoneally once a week for 1-4 weeks. Mice showed no signs of distress, change in activity, appetite, or weight loss. Mice were euthanized after 3 days, 1, 2, or 4 weeks to measure cardiac expression of fibrosis-related genes and potential mediators (measured by QRT-PCR, including micro-RNA (miR and NADPH oxidase (NOX. Collagen fraction area of the left ventricle was measured with picrosirius red staining. Cardiac fibroblasts isolated from adult mouse hearts were incubated with 0, 0.1, 1.0 or 10 ng/ml LPS for 48 hours.Cardiac miR expression profiling demonstrated decreased miR-29c after 3 and 7 days following LPS, which were confirmed by QRT-PCR. The earliest changes in fibrosis-related genes and mediators that occurred 3 days after LPS were increased cardiac expression of TIMP-1 and NOX-2 (but not of NOX-4. This persisted at 1 and 2 weeks, with additional increases in collagen Iα1, collagen IIIα1, MMP2, MMP9, TIMP1, TIMP2, and periostin. There was no change in TGF-β or connective tissue growth factor. Collagen fraction area of the left ventricle increased after 2 and 4 weeks of LPS. LPS decreased miR-29c and increased NOX-2 in isolated cardiac fibroblasts.Recurrent exposure to subclinical LPS induces cardiac fibrosis after 2-4 weeks. Early changes 3 days after LPS were decreased miR-29c and increased NOX2 and TIMP1, which persisted at 1 and 2 weeks, along with widespread activation of fibrosis-related genes. Decreased miR-29c and increased NOX2, which induce cardiac fibrosis in other conditions, may uniquely mediate LPS-induced cardiac fibrosis.

In vivo persistence of sister chromatid exchanges (SCE) induced by gamma rays in mouse bone marrow cells

International Nuclear Information System (INIS)

Morales-Ramirez, P.; Vallarino-Kelly, T.; Rodriguez-Reyes, R.

1984-01-01

The sister chromatid exchange (SCE) frequencies induced in bone marrow cells by in vivo irradiation with gamma rays before or after bromodeoxyuridine (BrdUrd) incorporation were compared. The frequency of SCE at different postirradiation times was also measured in bone marrow cells in vivo, irradiated before BrdUrd incorporation. Increased sensitivity to SCE induction by radiation was found in cells after BrdUrd incorporation for one cycle when compared with cells irradiated before BrdUrd incorporation. The increased SCE frequency persisted for at least 72 hr after the initial irradiation, implying that the gamma ray-induced lesion(s) capable of eliciting an SCE are persistent and cannot be easily repaired

Demographics of antibiotic persistence

DEFF Research Database (Denmark)

Kollerova, Silvia; Jouvet, Lionel; Steiner, Ulrich

Persister cells, cells that can survive antibiotic exposure but lack heritable antibiotic resistance, are assumed to play a crucial role for the evolution of antibiotic resistance. Persistence is a stage associated with reduced metabolic activity. Most previous studies have been done on batch...... even play a more prominent role for the evolution of resistance and failures of medical treatment by antibiotics as currently assumed....

Persistent Effects of Developmental Exposure to 17α-Ethinylestradiol on the Zebrafish (Danio rerio Brain Transcriptome and Behavior

Directory of Open Access Journals (Sweden)

Tove Porseryd

2017-04-01

Full Text Available The synthetic estrogen 17α-ethinylestradiol (EE2 is an endocrine disrupting compound of concern due to its persistence and widespread presence in the aquatic environment. Effects of developmental exposure to low concentrations of EE2 in fish on reproduction and behavior not only persisted to adulthood, but have also been observed to be transmitted to several generations of unexposed progeny. To investigate the possible biological mechanisms of the persistent anxiogenic phenotype, we exposed zebrafish embryos for 80 days post fertilization to 0, 3, and 10 ng/L EE2 (measured concentrations 2.14 and 7.34 ng/L. After discontinued exposure, the animals were allowed to recover for 120 days in clean water. Adult males and females were later tested for changes in stress response and shoal cohesion, and whole-brain gene expression was analyzed with RNA sequencing. The results show increased anxiety in the novel tank and scototaxis tests, and increased shoal cohesion in fish exposed during development to EE2. RNA sequencing revealed 34 coding genes differentially expressed in male brains and 62 in female brains as a result of EE2 exposure. Several differences were observed between males and females in differential gene expression, with only one gene, sv2b, coding for a synaptic vesicle protein, that was affected by EE2 in both sexes. Functional analyses showed that in female brains, EE2 had significant effects on pathways connected to the circadian rhythm, cytoskeleton and motor proteins and synaptic proteins. A large number of non-coding sequences including 19 novel miRNAs were also differentially expressed in the female brain. The largest treatment effect in male brains was observed in pathways related to cholesterol biosynthesis and synaptic proteins. Circadian rhythm and cholesterol biosynthesis, previously implicated in anxiety behavior, might represent possible candidate pathways connecting the transcriptome changes to the alterations to behavior

The role of free radicals and stress signalling in persistent genomic instability induced by long wavelength UV light

International Nuclear Information System (INIS)

Phillipson, R.; McMillan, T.J.

2003-01-01

Induction of persistent genomic instability has commonly been investigated with ionising radiation. It has been characterised as a decrease in plating efficiency, and an increase in chromosomal aberrations and mutation frequency in the progeny of cells that survive the initial irradiation. We now present data demonstrating the phenomenon following exposure to long-wavelength solar UV-A (320-400nm) radiation at environmentally relevant doses. Using the spontaneously immortalised human skin keratinocyte line, HaCaT, we observed a significant decrease in plating efficiency (77 +/- 2% of control), and increase in micronuclei (2.5 fold) and mutation frequency (2 fold), 7 days after the initial radiation insult. Modification of UV-A-induced instability by incubation with exogenous catalase implicated reactive oxygen species (ROS), in-particular hydrogen peroxide, in the production and/or maintenance of the phenomenon. Assessment of anti-oxidant enzymes revealed a significant increase in glutathione-s-transferase activity (158 +/- 4% of control) at day 7 in the irradiated cell population, which was inhibited by incubation with exogenous catalase (97 +/- 3%), providing further evidence for an ROS-mediated pathway. Furthermore, inhibition of UV-A-induced micronuclei at day 7 by the flavonoid-containing-protein inhibitor diphenyleneiodonium (DPI) indicates that the NADPH oxidase family of enzymes may be involved in this phenomenon. Measurement of superoxide production by the cytochrome c reduction assay revealed that the irradiated cell population produce 50% more superoxide than the unirradiated controls, and that incubation with DPI led to a preferential reduction in superoxide production in the UV-A treated population at day 7. Finally, NADPH oxidase activity is increased significantly over controls in UV-A-treated cells. These data demonstrate that oxidative stress, analogous to that produced by ionising radiation, induces persistent genomic instability through a

Quantification of image persistence in a digital angiography system

International Nuclear Information System (INIS)

Okkalides, D.P.; Raptou, P.D.

1993-01-01

Image persistence, as a characteristic of video imaging systems affecting the quality of fast moving fluoroscopic images, is shown to vary considerably. A simple quantitative method for measuring image persistence in a digital angiography system is presented, together with a series of image intensifier exposure-response curves. For the Saticon tube, used with the Siemens 3VA Digitron, it was found that persistence increased for low exposure rates and may increase to 31% at a 120 ms interval. In addition, a sharp increase in image persistence, from 8.3% to 33%, was observed within 18 months from installation of the system. (author)

Fluoride exposure abates pro-inflammatory response and induces in vivo apoptosis rendering zebrafish (Danio rerio) susceptible to bacterial infections.

Science.gov (United States)

Singh, Rashmi; Khatri, Preeti; Srivastava, Nidhi; Jain, Shruti; Brahmachari, Vani; Mukhopadhyay, Asish; Mazumder, Shibnath

2017-04-01

The present study describes the immunotoxic effect of chronic fluoride exposure on adult zebrafish (Danio rerio). Zebrafish were exposed to fluoride (71.12 mg/L; 1/10 LC 50 ) for 30 d and the expression of selected genes studied. We observed significant elevation in the detoxification pathway gene cyp1a suggesting chronic exposure to non-lethal concentration of fluoride is indeed toxic to fish. Fluoride mediated pro-oxidative stress is implicated with the downregulation in superoxide dismutase 1 and 2 (sod1/2) genes. Fluoride affected DNA repair machinery by abrogating the expression of the DNA repair gene rad51 and growth arrest and DNA damage inducible beta a gene gadd45ba. The upregulated expression of casp3a coupled with altered Bcl-2 associated X protein/B-cell lymphoma 2 ratio (baxa/bcl2a) clearly suggested chronic fluoride exposure induced the apoptotic cascade in zebrafish. Fluoride-exposed zebrafish when challenged with non-lethal dose of fish pathogen A. hydrophila revealed gross histopathology in spleen, bacterial persistence and significant mortality. We report that fluoride interferes with system-level output of pro-inflammatory cytokines tumour necrosis factor-α, interleukin-1β and interferon-γ, as a consequence, bacteria replicate efficiently causing significant fish mortality. We conclude, chronic fluoride exposure impairs the redox balance, affects DNA repair machinery with pro-apoptotic implications and suppresses pro-inflammatory cytokines expression abrogating host immunity to bacterial infections. Copyright © 2017 Elsevier Ltd. All rights reserved.

Microcystin-LR exposure induces developmental neurotoxicity in zebrafish embryo

International Nuclear Information System (INIS)

Wu, Qin; Yan, Wei; Liu, Chunsheng; Li, Li; Yu, Liqin; Zhao, Sujuan; Li, Guangyu

2016-01-01

Microcystin-LR (MCLR) is a commonly acting potent hepatotoxin and has been pointed out of potentially causing developmental neurotoxicity, but the exact mechanism is little known. In this study, zebrafish embryos were exposed to 0, 0.8, 1.6 or 3.2 mg/L MCLR for 120 h. MCLR exposure through submersion caused serious hatching delay and body length decrease. The content of MCLR in zebrafish larvae was analyzed and the results demonstrated that MCLR can accumulate in zebrafish larvae. The locomotor speed of zebrafish larvae was decreased. Furthermore, the dopamine and acetylcholine (ACh) content were detected to be significantly decreased in MCLR exposure groups. And the acetylcholinesterase (AChE) activity was significantly increased after exposure to 1.6 and 3.2 mg/L MCLR. The transcription pattern of manf, chrnα7 and ache gene was consistent with the change of the dopamine content, ACh content and AChE activity. Gene expression involved in the development of neurons was also measured. α1-tubulin and shha gene expression were down-regulated, whereas mbp and gap43 gene expression were observed to be significantly up-regulated upon exposure to MCLR. The above results indicated that MCLR-induced developmental toxicity might attribute to the disorder of cholinergic system, dopaminergic signaling, and the development of neurons. - Highlights: • MCLR accumulation induces developmental neurotoxicity in zebrafish embryo. • The decrease of dopamine levels might be associated with the MCLR-induced developmental neurotoxicity in zebrafish larvae. • The alternation of cholinergic system might contribute to the change of neurobehavior in zebrafish larvae exposure with MCLR. - MCLR accumulation induces developmental neurotoxicity by affecting cholinergic system, dopaminergic signaling, and the development of neurons in zebrafish embryo.

Developmental programming: postnatal estradiol amplifies ovarian follicular defects induced by fetal exposure to excess testosterone and dihydrotestosterone in sheep.

Science.gov (United States)

Veiga-Lopez, A; Wurst, A K; Steckler, T L; Ye, W; Padmanabhan, V

2014-04-01

Excess of prenatal testosterone (T) induces reproductive defects including follicular persistence. Comparative studies with T and dihydrotestosterone (DHT) have suggested that follicular persistence is programmed via estrogenic actions of T. This study addresses the androgenic and estrogenic contributions in programming follicular persistence. Because humans are exposed to estrogenic environmental steroids from various sources throughout their life span and postnatal insults may also induce organizational and/or activational changes, we tested whether continuous postnatal exposure to estradiol (E) will amplify effects of prenatal steroids on ovarian function. Pregnant sheep were treated with T, DHT, E, or ED (E and DHT) from days 30 to 90 of gestation. Postnatally, a subset of the vehicle (C), T, and DHT females received an E implant. Transrectal ultrasonography was performed in the first breeding season during a synchronized cycle to monitor ovarian follicular dynamics. As expected, number of ≥8 mm follicles was higher in the T versus C group. Postnatal E reduced the number of 4 to 8 mm follicles in the DHT group. Percentage of females bearing luteinized follicles and the number of luteinized follicles differed among prenatal groups. Postnatal E increased the incidence of subluteal cycles in the prenatal T-treated females. Findings from this study confirm previous findings of divergences in programming effects of prenatal androgens and estrogens. They also indicate that some aspects of follicular dynamics are subject to postnatal modulation as well as support the existence of an extended organizational period or the need for a second insult to uncover the previously programmed event.

Persistent barrage firing in cortical interneurons can be induced in vivo and may be important for the suppression of epileptiform activity

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Norimitsu eSuzuki

2014-03-01

Full Text Available Neural circuits are typically maintained in a state of dynamic equilibrium by balanced synaptic excitation and inhibition. However, brain regions that are particularly susceptible to epilepsy may have evolved additional specialized mechanisms for inhibiting overexcitation. Here we identify one such possible mechanism in the cerebral cortex and hippocampus of mice. Recently it was reported that some types of GABAergic interneurons can slowly integrate excitatory inputs until eventually they fire persistently in the absence of the original stimulus. This property, called persistent firing or retroaxonal barrage firing, is of unknown physiological importance. We show that two common types of interneurons in cortical regions, neurogliaform cells and fast-spiking multipolar cells, are unique in exhibiting barrage firing in acute slices (~85% and ~23% success rate for induction, respectively. Barrage firing can also be induced in vivo, although the success rate for induction is lower (~60% in neurogliaform cells. In slices, barrage firing could reliably be triggered by trains of excitatory synaptic input, as well as by exposure to proconvulsant bath solutions (elevated extracellular K+, blockade of GABAA receptors. Using pair recordings in slices, we confirmed that barrage-firing neurogliaform cells can produce synaptic inhibition of nearby pyramidal neurons, and that this inhibition outlasts the original excitation. The ubiquity of neurogliaform and fast-spiking cells, together with their ability to fire persistently following excessive excitation, suggests that these interneurons may function as cortical sentinels, imposing an activity-dependent brake on undesirable neuronal hyperexcitability.

Association between exposure to persistent organohalogen pollutants and epididymal and accessory sex gland function: Multicentre study in Inuit and European populations

DEFF Research Database (Denmark)

Elzanaty, Saad; Rignell-Hydbom, Anna; Jönsson, Bo A.G.

2006-01-01

Exposure to persistent organochlorine pollutants (POPs) may have negative impact on male reproductive function. We, therefore, investigated the association between serum levels of POPs and epididymal and accessory sex gland function. Serum levels of CB-153, p,p′-DDE and seminal markers of epididy......Exposure to persistent organochlorine pollutants (POPs) may have negative impact on male reproductive function. We, therefore, investigated the association between serum levels of POPs and epididymal and accessory sex gland function. Serum levels of CB-153, p,p′-DDE and seminal markers...... with the activity of NAG were found among Greenlandic men (mean difference 7.0 mU/ejaculate, 95% CI 3.0, 34), and in the aggregated cohort (mean difference 4.0 mU/ejaculate, 95% CI -0.2, 8.0). A positive association was observed between CB-153 and PSA as well as zinc among Kharkiv men. In the Swedish cohort...

Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats

International Nuclear Information System (INIS)

Miller, Desinia B.; Snow, Samantha J.; Henriquez, Andres; Schladweiler, Mette C.; Ledbetter, Allen D.; Richards, Judy E.; Andrews, Debora L.; Kodavanti, Urmila P.

2016-01-01

Acute ozone exposure induces a classical stress response with elevated circulating stress hormones along with changes in glucose, protein and lipid metabolism in rats, with similar alterations in ozone-exposed humans. These stress-mediated changes over time have been linked to insulin resistance. We hypothesized that acute ozone-induced stress response and metabolic impairment would persist during subchronic episodic exposure and induce peripheral insulin resistance. Male Wistar Kyoto rats were exposed to air or 0.25 ppm or 1.00 ppm ozone, 5 h/day, 3 consecutive days/week (wk) for 13 wks. Pulmonary, metabolic, insulin signaling and stress endpoints were determined immediately after 13 wk or following a 1 wk recovery period (13 wk + 1 wk recovery). We show that episodic ozone exposure is associated with persistent pulmonary injury and inflammation, fasting hyperglycemia, glucose intolerance, as well as, elevated circulating adrenaline and cholesterol when measured at 13 wk, however, these responses were largely reversible following a 1 wk recovery. Moreover, the increases noted acutely after ozone exposure in non-esterified fatty acids and branched chain amino acid levels were not apparent following a subchronic exposure. Neither peripheral or tissue specific insulin resistance nor increased hepatic gluconeogenesis were present after subchronic ozone exposure. Instead, long-term ozone exposure lowered circulating insulin and severely impaired glucose-stimulated beta-cell insulin secretion. Thus, our findings in young-adult rats provide potential insights into epidemiological studies that show a positive association between ozone exposures and type 1 diabetes. Ozone-induced beta-cell dysfunction may secondarily contribute to other tissue-specific metabolic alterations following chronic exposure due to impaired regulation of glucose, lipid, and protein metabolism. - Highlights: • Subchronic episodic ozone exposure caused pulmonary and metabolic effects. • These

Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats

Energy Technology Data Exchange (ETDEWEB)

Miller, Desinia B. [Curriculum in Toxicology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Snow, Samantha J. [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Henriquez, Andres [Curriculum in Toxicology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina (United States); Schladweiler, Mette C.; Ledbetter, Allen D.; Richards, Judy E.; Andrews, Debora L. [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Kodavanti, Urmila P., E-mail: kodavanti.urmila@epa.gov [Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States)

2016-09-01

Acute ozone exposure induces a classical stress response with elevated circulating stress hormones along with changes in glucose, protein and lipid metabolism in rats, with similar alterations in ozone-exposed humans. These stress-mediated changes over time have been linked to insulin resistance. We hypothesized that acute ozone-induced stress response and metabolic impairment would persist during subchronic episodic exposure and induce peripheral insulin resistance. Male Wistar Kyoto rats were exposed to air or 0.25 ppm or 1.00 ppm ozone, 5 h/day, 3 consecutive days/week (wk) for 13 wks. Pulmonary, metabolic, insulin signaling and stress endpoints were determined immediately after 13 wk or following a 1 wk recovery period (13 wk + 1 wk recovery). We show that episodic ozone exposure is associated with persistent pulmonary injury and inflammation, fasting hyperglycemia, glucose intolerance, as well as, elevated circulating adrenaline and cholesterol when measured at 13 wk, however, these responses were largely reversible following a 1 wk recovery. Moreover, the increases noted acutely after ozone exposure in non-esterified fatty acids and branched chain amino acid levels were not apparent following a subchronic exposure. Neither peripheral or tissue specific insulin resistance nor increased hepatic gluconeogenesis were present after subchronic ozone exposure. Instead, long-term ozone exposure lowered circulating insulin and severely impaired glucose-stimulated beta-cell insulin secretion. Thus, our findings in young-adult rats provide potential insights into epidemiological studies that show a positive association between ozone exposures and type 1 diabetes. Ozone-induced beta-cell dysfunction may secondarily contribute to other tissue-specific metabolic alterations following chronic exposure due to impaired regulation of glucose, lipid, and protein metabolism. - Highlights: • Subchronic episodic ozone exposure caused pulmonary and metabolic effects. • These

Prenatal exposure to persistent organochlorine pollutants is associated with high insulin levels in 5-year-old girls

DEFF Research Database (Denmark)

Tang-Péronard, Jeanett L.; Heitmann, Berit L.; Jensen, Tina K.

2015-01-01

® technology. Insulin and leptin concentrations were transformed from continuous to binary variables, using the 75th percentile as a cut-off point. Multiple logistic regression was used to investigate associations between prenatal POP exposures and non-fasting serum concentrations of insulin and leptin at age......BACKGROUND: Several persistent organochlorine pollutants (POPs) possess endocrine disrupting abilities, thereby potentially leading to an increased risk of obesity and metabolic diseases, especially if the exposure occurs during prenatal life. We have previously found associations between prenatal......-year-old children, thus possibly mediating the association with overweight and obesity at 7 years of age. METHODS: The analyses were based on a prospective Faroese Birth Cohort (n=656), recruited between 1997 and 2000. Major POPs, polychlorinated biphenyls (PCBs), p...

Persistent ER stress induces the spliced leader RNA silencing pathway (SLS, leading to programmed cell death in Trypanosoma brucei.

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Hanoch Goldshmidt

2010-01-01

Full Text Available Trypanosomes are parasites that cycle between the insect host (procyclic form and mammalian host (bloodstream form. These parasites lack conventional transcription regulation, including factors that induce the unfolded protein response (UPR. However, they possess a stress response mechanism, the spliced leader RNA silencing (SLS pathway. SLS elicits shut-off of spliced leader RNA (SL RNA transcription by perturbing the binding of the transcription factor tSNAP42 to its cognate promoter, thus eliminating trans-splicing of all mRNAs. Induction of endoplasmic reticulum (ER stress in procyclic trypanosomes elicits changes in the transcriptome similar to those induced by conventional UPR found in other eukaryotes. The mechanism of up-regulation under ER stress is dependent on differential stabilization of mRNAs. The transcriptome changes are accompanied by ER dilation and elevation in the ER chaperone, BiP. Prolonged ER stress induces SLS pathway. RNAi silencing of SEC63, a factor that participates in protein translocation across the ER membrane, or SEC61, the translocation channel, also induces SLS. Silencing of these genes or prolonged ER stress led to programmed cell death (PCD, evident by exposure of phosphatidyl serine, DNA laddering, increase in reactive oxygen species (ROS production, increase in cytoplasmic Ca(2+, and decrease in mitochondrial membrane potential, as well as typical morphological changes observed by transmission electron microscopy (TEM. ER stress response is also induced in the bloodstream form and if the stress persists it leads to SLS. We propose that prolonged ER stress induces SLS, which serves as a unique death pathway, replacing the conventional caspase-mediated PCD observed in higher eukaryotes.

Pulmonary exposure to carbon black by inhalation or instillation in pregnant mice: Effects on liver DNA strand breaks in dams and offspring

DEFF Research Database (Denmark)

Jackson, Petra; Hougaard, Karin Sørig; Boisen, Anne Mette Zenner

2011-01-01

cells and liver, and in offspring liver. Persistent lung inflammation was observed in exposed mothers. Inhalation exposure induced more DNA strand breaks in the liver of mothers and their offspring, whereas intratracheal instillation did not. Neither inhalation nor instillation affected gestation...... and lactation. Maternal inhalation exposure to Printex 90-induced liver DNA damage in the mothers and the in utero exposed offspring....

Exposure to low infective doses of HCV induces cellular immune responses without consistently detectable viremia or seroconversion in chimpanzees

International Nuclear Information System (INIS)

Shata, Mohamed Tarek; Tricoche, Nancy; Perkus, Marion; Tom, Darley; Brotman, Betsy; McCormack, Patricia; Pfahler, Wolfram; Lee, Dong-Hun; Tobler, Leslie H.; Busch, Michael; Prince, Alfred M.

2003-01-01

In hepatitis C virus (HCV) infection, there is accumulating data suggesting the presence of cellular immune responses to HCV in exposed but seemingly uninfected populations. Some studies have suggested cross-reactive antigens rather than prior HCV exposure as the main reason for the immune responses. In this study we address this question by analyzing the immune response of chimpanzees that have been sequentially exposed to increasing doses of HCV virions. The level of viremia, as well as the immune responses to HCV at different times after virus inoculation, were examined. Our data indicate that HCV infective doses as low as 1-10 RNA (+) virions induce detectable cellular immune responses in chimpanzees without consistently detectable viremia or persistent seroconversion. However, increasing the infective doses of HCV to 100 RNA (+) virions overcame the low-inoculum-induced immune response and produced high-level viremia followed by seroconversion

Persistent wind-induced enhancement of diffusive CO2 transport in a mountain forest snowpack

Science.gov (United States)

D. R. Bowling; W. J. Massman

2011-01-01

Diffusion dominates the transport of trace gases between soil and the atmosphere. Pressure gradients induced by atmospheric flow and wind interacting with topographical features cause a small but persistent bulk flow of air within soil or snow. This forcing, called pressure pumping or wind pumping, leads to a poorly quantified enhancement of gas transport beyond the...

Persistence of yellow fever vaccine-induced antibodies after solid organ transplantation.

Science.gov (United States)

Wyplosz, B; Burdet, C; François, H; Durrbach, A; Duclos-Vallée, J C; Mamzer-Bruneel, M-F; Poujol, P; Launay, O; Samuel, D; Vittecoq, D; Consigny, P H

2013-09-01

Immunization using live attenuated vaccines represents a contra-indication after solid organ transplantation (SOT): consequently, transplant candidates planning to travel in countries where yellow fever is endemic should be vaccinated prior to transplantation. The persistence of yellow fever vaccine-induced antibodies after transplantation has not been studied yet. We measured yellow-fever neutralizing antibodies in 53 SOT recipients vaccinated prior to transplantation (including 29 kidney recipients and 18 liver recipients). All but one (98%) had protective titers of antibodies after a median duration of 3 years (min.: 0.8, max.: 21) after transplantation. The median antibody level was 40 U/L (interquartile range: 40-80). For the 46 patients with a known or estimated date of vaccination, yellow-fever antibodies were still detectable after a median time of 13 years (range: 2-32 years) post-immunization. Our data suggest there is long-term persistence of antibodies to yellow fever in SOT recipients who have been vaccinated prior to transplantation. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.

Will parental exposure to radiation induce tumor in sibling ?

International Nuclear Information System (INIS)

Watanabe, Hiromitsu; Takahashi, Tadateru; Toyota, Kazuhiro; Ito, Akihiro

1991-01-01

There are reports of possible risk of transmission of genetic trait(s) through the germ cell in acquired cancer from parent to sibling. We have confirmed that paternal exposure to 252 Cf neutron irradiation in mice induced sperm abnormality leading to dominant lethals and liver tumors at F 1 offspring. On the other hand, C3H male mice have been known to have high incidence of spontaneous hepatic tumors and increased hepatic tumor risk in F 1 offsprings maybe caused by the genetic transmission of the hepatoma-inducible-trait amplified by 252 Cf neutron irradiation. The present paper describes that paternal exposure to X-ray or chemicals induces heritable characteristics including anomalies and tumors in some special strains of mice and rats. Some possible mechanisms of transmission of genetic trait(s) are also discussed. (author) 52 refs

Persistent effects of prior chronic exposure to corticosterone on reward-related learning and motivation in rodents.

Science.gov (United States)

Olausson, Peter; Kiraly, Drew D; Gourley, Shannon L; Taylor, Jane R

2013-02-01

Repeated or prolonged exposure to stress has profound effects on a wide spectrum of behavioral and neurobiological processes and has been associated with the pathophysiology of depression. The multifaceted nature of this disorder includes despair, anhedonia, diminished motivation, and disrupted cognition, and it has been proposed that depression is also associated with reduced reward-motivated learning. We have previously reported that prior chronic corticosterone exposure to mice produces a lasting depressive-like state that can be reversed by chronic antidepressant treatment. In the present study, we tested the effects of prior chronic exposure to corticosterone (50 μg/ml) administered to rats or to mice in drinking water for 14 days followed by dose-tapering over 9 days. The exposure to corticosterone produced lasting deficits in the acquisition of reward-related learning tested on a food-motivated instrumental task conducted 10-20 days after the last day of full dose corticosterone exposure. Rats exposed to corticosterone also displayed reduced responding on a progressive ratio schedule of reinforcement when tested on day 21 after exposure. Amitriptyline (200 mg/ml in drinking water) exposure for 14 days to mice produced the opposite effect, enhancing food-motivated instrumental acquisition and performance. Repeated treatment with amitriptyline (5 mg/kg, intraperitoneally; bid) subsequent to corticosterone exposure also prevented the corticosterone-induced deficits in rats. These results are consistent with aberrant reward-related learning and motivational processes in depressive states and provide new evidence that stress-induced neuroadaptive alterations in cortico-limbic-striatal brain circuits involved in learning and motivation may play a critical role in aspects of mood disorders.

Persistent Adult Neuroimmune Activation and Loss of Hippocampal Neurogenesis Following Adolescent Ethanol Exposure: Blockade by Exercise and the Anti-inflammatory Drug Indomethacin

Directory of Open Access Journals (Sweden)

Ryan P. Vetreno

2018-03-01

Full Text Available Alcohol abuse and binge drinking are common during adolescence, a developmental period characterized by heightened neuroplasticity. Animal studies reveal that adolescent ethanol exposure decreases hippocampal neurogenesis that persists into adulthood, but the mechanism remains to be fully elucidated. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55, we tested the hypothesis that AIE-induced upregulation of neuroimmune signaling contributes to the loss of hippocampal neurogenesis in adulthood. We found that AIE caused upregulation of multiple proinflammatory Toll-like receptors (TLRs, increased expression of phosphorylated NF-κB p65 (pNF-κB p65 and the cell death marker cleaved caspase 3, and reduced markers of neurogenesis in the adult (P80 hippocampus, which is consistent with persistently increased neuroimmune signaling reducing neurogenesis. We observed a similar increase of pNF-κB p65-immunoreactive cells in the post-mortem human alcoholic hippocampus, an effect that was negatively correlated with age of drinking onset. Voluntary wheel running from P24 to P80 prevented the AIE-induced loss of neurogenesis markers (i.e., nestin and doublecortin in the adult hippocampus that was paralleled by blockade of increased expression of the cell death marker cleaved caspase 3. Wheel running also prevented the AIE-induced increase of hippocampal pNF-κB p65 and induction of neuroimmune NF-κB target genes, including TNFα and IκBα in the adult brain. Administration of the anti-inflammatory drug indomethacin during AIE prevented the loss of neurogenesis markers (i.e., nestin and doublecortin and the concomitant increase of cleaved caspase 3, an effect that was accompanied by blockade of the increase of pNF-κB p65. Similarly, administration of the proinflammatory TLR4 activator lipopolysaccharide resulted in a loss of doublecortin that was paralleled by increased

Differential expression of ozone-induced gene during exposures to ...

African Journals Online (AJOL)

Differential expression of ozone-induced gene during exposures to salt stress in Polygonum sibiricum Laxm leaves, stem and underground stem. ... PcOZI-1 mRNA in untreated plants was detected at low levels in underground stem, leaves and at higher levels in stem. PcOZI-1 mRNA accumulation was transiently induced ...

Chronic oral exposure to the aldehyde pollutant acrolein induces dilated cardiomyopathy

Science.gov (United States)

Ismahil, Mohamed Ameen; Hamid, Tariq; Haberzettl, Petra; Gu, Yan; Chandrasekar, Bysani; Srivastava, Sanjay; Bhatnagar, Aruni

2011-01-01

Environmental triggers of dilated cardiomyopathy are poorly understood. Acute exposure to acrolein, a ubiquitous aldehyde pollutant, impairs cardiac function and cardioprotective responses in mice. Here, we tested the hypothesis that chronic oral exposure to acrolein induces inflammation and cardiomyopathy. C57BL/6 mice were gavage-fed acrolein (1 mg/kg) or water (vehicle) daily for 48 days. The dose was chosen based on estimates of human daily unsaturated aldehyde consumption. Compared with vehicle-fed mice, acrolein-fed mice exhibited significant (P acrolein adduct formation indicative of physical translocation of ingested acrolein to the heart. Acrolein also induced myocyte hypertrophy (∼2.2-fold increased myocyte area, P acrolein-exposed hearts, along with upregulated gene expression of proinflammatory cytokines tumor necrosis factor-α and interleukin-1β. Long-term oral exposure to acrolein, at an amount within the range of human unsaturated aldehyde intake, induces a phenotype of dilated cardiomyopathy in the mouse. Human exposure to acrolein may have analogous effects and raise consideration of an environmental, aldehyde-mediated basis for heart failure. PMID:21908791

IB4(+) nociceptors mediate persistent muscle pain induced by GDNF.

Science.gov (United States)

Alvarez, Pedro; Chen, Xiaojie; Bogen, Oliver; Green, Paul G; Levine, Jon D

2012-11-01

Skeletal muscle is a well-known source of glial cell line-derived neurotrophic factor (GDNF), which can produce mechanical hyperalgesia. Since some neuromuscular diseases are associated with both increased release of GDNF and intense muscle pain, we explored the role of GDNF as an endogenous mediator in muscle pain. Intramuscularly injected GDNF induced a dose-dependent (0.1-10 ng/20 μl) persistent (up to 3 wk) mechanical hyperalgesia in the rat. Once hyperalgesia subsided, injection of prostaglandin E(2) at the site induced a prolonged mechanical hyperalgesia (>72 h) compared with naïve rats (vibration increased muscle GDNF levels at 24 h, a time point where rats also exhibited marked muscle hyperalgesia. Intrathecal antisense oligodeoxynucleotides to mRNA encoding GFRα1, the canonical binding receptor for GDNF, reversibly inhibited eccentric exercise- and mechanical vibration-induced muscle hyperalgesia. Finally, electrophysiological recordings from nociceptors innervating the gastrocnemius muscle in anesthetized rats, revealed significant increase in response to sustained mechanical stimulation after local GDNF injection. In conclusion, these data indicate that GDNF plays a role as an endogenous mediator in acute and induction of chronic muscle pain, an effect likely to be produced by GDNF action at GFRα1 receptors located in IB4(+) nociceptors.

Traumatic brain injury and obesity induce persistent central insulin resistance.

Science.gov (United States)

Karelina, Kate; Sarac, Benjamin; Freeman, Lindsey M; Gaier, Kristopher R; Weil, Zachary M

2016-04-01

Traumatic brain injury (TBI)-induced impairments in cerebral energy metabolism impede tissue repair and contribute to delayed functional recovery. Moreover, the transient alteration in brain glucose utilization corresponds to a period of increased vulnerability to the negative effects of a subsequent TBI. In order to better understand the factors contributing to TBI-induced central metabolic dysfunction, we examined the effect of single and repeated TBIs on brain insulin signalling. Here we show that TBI induced acute brain insulin resistance, which resolved within 7 days following a single injury but persisted until 28 days following repeated injuries. Obesity, which causes brain insulin resistance and neuroinflammation, exacerbated the consequences of TBI. Obese mice that underwent a TBI exhibited a prolonged reduction of Akt (also known as protein kinase B) signalling, exacerbated neuroinflammation (microglial activation), learning and memory deficits, and anxiety-like behaviours. Taken together, the transient changes in brain insulin sensitivity following TBI suggest a reduced capacity of the injured brain to respond to the neuroprotective and anti-inflammatory actions of insulin and Akt signalling, and thus may be a contributing factor for the damaging neuroinflammation and long-lasting deficits that occur following TBI. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Persistence of docetaxel-induced neuropathy and impact on quality of life among breast cancer survivors

DEFF Research Database (Denmark)

Eckhoff, L.; Knoop, A.; Jensen, M. B.

2015-01-01

BACKGROUND: This study evaluates persistence and severity of docetaxel-induced neuropathy (peripheral neuropathy (PN)) and impact on health related quality of life in survivors from early-stage breast cancer. METHODS: One thousand and thirty-one patients with early-stage breast cancer, who received...... at least one cycle of docetaxel and provided information on PN during treatment, completed questionnaires on PN as an outcome (Common Toxicity Criteria (CTC) scores, European Organisation for Research and Treatment of Cancer Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC CIPN20) and EORTC Quality...

Persistently Elevated Somatic Mutation as a Biomarker for Clinically Relevant Exposures in GWI

Science.gov (United States)

2017-10-01

that our approach to environmentally-induced carcinogenesis, to measure the total effect of all genotoxic exposures, as modified by the genetic ...PRINCIPAL INVESTIGATOR: Stephen G. Grant, Ph.D. CONTRACTING ORGANIZATION : Nova Southeastern University, Inc. Fort Lauderdale, FL 33314 REPORT DATE...NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Nova Southeastern

Prenatal and Postnatal Exposure to Persistent Organic Pollutants and Infant Growth: A Pooled Analysis of Seven European Birth Cohorts.

Science.gov (United States)

Iszatt, Nina; Stigum, Hein; Verner, Marc-André; White, Richard A; Govarts, Eva; Murinova, Lubica Palkovicova; Schoeters, Greet; Trnovec, Tomas; Legler, Juliette; Pelé, Fabienne; Botton, Jérémie; Chevrier, Cécile; Wittsiepe, Jürgen; Ranft, Ulrich; Vandentorren, Stéphanie; Kasper-Sonnenberg, Monika; Klümper, Claudia; Weisglas-Kuperus, Nynke; Polder, Anuschka; Eggesbø, Merete

2015-07-01

Infant exposure to persistent organic pollutants (POPs) may contribute to obesity. However, many studies so far have been small, focused on transplacental exposure, used an inappropriate measure to assess postnatal exposure through breastfeeding if any, or did not discern between prenatal and postnatal effects. We investigated prenatal and postnatal exposure to POPs and infant growth (a predictor of obesity). We pooled data from seven European birth cohorts with biomarker concentrations of polychlorinated biphenyl 153 (PCB-153) (n = 2,487), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) (n = 1,864), estimating prenatal and postnatal POPs exposure using a validated pharmacokinetic model. Growth was change in weight-for-age z-score between birth and 24 months. Per compound, multilevel models were fitted with either POPs total exposure from conception to 24 months or prenatal or postnatal exposure. We found a significant increase in growth associated with p,p'-DDE, seemingly due to prenatal exposure (per interquartile increase in exposure, adjusted β = 0.12; 95% CI: 0.03, 0.22). Due to heterogeneity across cohorts, this estimate cannot be considered precise, but does indicate that an association with infant growth is present on average. In contrast, a significant decrease in growth was associated with postnatal PCB-153 exposure (β = -0.10; 95% CI: -0.19, -0.01). To our knowledge, this is the largest study to date of POPs exposure and infant growth, and it contains state-of-the-art exposure modeling. Prenatal p,p'-DDE was associated with increased infant growth, and postnatal PCB-153 with decreased growth at European exposure levels.

Does airborne nickel exposure induce nickel sensitization?

Science.gov (United States)

Mann, Eugen; Ranft, Ulrich; Eberwein, Georg; Gladtke, Dieter; Sugiri, Dorothee; Behrendt, Heidrun; Ring, Johannes; Schäfer, Torsten; Begerow, Jutta; Wittsiepe, Jürgen; Krämer, Ursula; Wilhelm, Michael

2010-06-01

Nickel is one of the most prevalent causes of contact allergy in the general population. This study focuses on human exposure to airborne nickel and its potential to induce allergic sensitization. The study group consisted of 309 children at school-starter age living in the West of Germany in the vicinity of two industrial sources and in a rural town without nearby point sources of nickel. An exposure assessment of nickel in ambient air was available for children in the Ruhr district using routinely monitored ambient air quality data and dispersion modelling. Internal nickel exposure was assessed by nickel concentrations in morning urine samples of the children. The observed nickel sensitization prevalence rates varied between 12.6% and 30.7%. Statistically significant associations were showed between exposure to nickel in ambient air and urinary nickel concentration as well as between urinary nickel concentration and nickel sensitization. Furthermore, an elevated prevalence of nickel sensitization was associated with exposure to increased nickel concentrations in ambient air. The observed associations support the assumption that inhaled nickel in ambient air might be a risk factor for nickel sensitization; further studies in larger collectives are necessary.

Persistence of sister chromatid exchanges and in vitro morphological transformation of Syrian hamster fetal cells by chemical and physical carcinogens

International Nuclear Information System (INIS)

Popescu, N.C.; Amsbaugh, S.C.; DiPaolo, J.A.

1985-01-01

The induction of neoplastic cell transformation is closely associated with DNA alterations which occur shortly after carcinogen exposure. Sister chromatid exchange (SCE) formation is a sensitive indicator of carcinogen-DNA interaction and correlates with the induction of morphological cell transformation. The persistence of lesions generating SCE produced by chemical and physical carcinogens and its relevance to the induction of morphologic transformation was evaluated in coordinated experiments with cultured Syrian hamster fetal cells (HFC). Exponentially growing HFC were exposed for 1 h to benzo[a]pyrene (BP), methyl-methanesulfonate (MMS), cis-platinum (II) diaminedichloride (cis Pt II), N-methyl-N'-nitrosourea (MNU), mitomycin C (MMC), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-acetoxy-2-fluorenyl-acetamide (AcAAF) or u.v. light irradiated. SCE analysis demonstrates that for a period of 48 h after carcinogen exposure, during which time the cells undergo at least four replicative cycles, DNA damage generating SCE induced by all chemical carcinogens either persisted or was partially removed, whereas u.v.-induced lesions were completely removed. An elevated SCE frequency persisted after two additional cell cycles after treatment with BP, AcAAF or MMC without increased cell lethality as compared to other carcinogens whose lesions were completely eliminated during the same period

Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

Science.gov (United States)

Tyler, Christina R.; Solomon, Benjamin R.; Ulibarri, Adam L.; Allan, Andrea M.

2014-01-01

Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism. PMID:24952232

Accumulation of methylglyoxal increases the advanced glycation end-product levels in DRG and contributes to lumbar disk herniation-induced persistent pain.

Science.gov (United States)

Liu, Cui-Cui; Zhang, Xin-Sheng; Ruan, Yu-Ting; Huang, Zhu-Xi; Zhang, Su-Bo; Liu, Meng; Luo, Hai-Jie; Wu, Shao-Ling; Ma, Chao

2017-08-01

Lumbar disk herniation (LDH) with discogenic low back pain and sciatica is a common and complicated musculoskeletal disorder. The underlying mechanisms are poorly understood, and there are no effective therapies for LDH-induced pain. In the present study, we found that the patients who suffered from LDH-induced pain had elevated plasma methylglyoxal (MG) levels. In rats, implantation of autologous nucleus pulposus (NP) to the left lumbar 5 spinal nerve root, which mimicked LDH, induced mechanical allodynia, increased MG level in plasma and dorsal root ganglion (DRG), and enhanced the excitability of small DRG neurons (DRG neurons ex vivo increased the number of action potentials evoked by depolarizing current pulses. Furthermore, inhibition of MG accumulation by aminoguanidine attenuated the enhanced excitability of small DRG neurons and the mechanical allodynia induced by NP implantation. In addition, NP implantation increased levels of advanced glycation end products (AGEs) in DRG, and intrathecal injection of MG-derived AGEs induced the mechanical allodynia and DRG neuronal hyperactivity. Intrathecal injection of MG also significantly increased the expression of AGEs in DRG. Importantly, scavenging of MG by aminoguanidine also attenuated the increase in AGEs induced by NP implantation. These results suggested that LDH-induced MG accumulation contributed to persistent pain by increasing AGE levels. Thus generation of AGEs from MG may represent a target for treatment of LDH-induced pain. NEW & NOTEWORTHY Our study demonstrates that methylglyoxal accumulation via increasing advanced glycation end-product levels in dorsal root ganglion contributes to the persistent pain induced by lumbar disk herniation, which proposed potential targets for the treatment of lumbar disk herniation-induced persistent pain. Copyright © 2017 the American Physiological Society.

Repeated restraint stress exposure during early withdrawal accelerates incubation of cue-induced cocaine craving.

Science.gov (United States)

Glynn, Ryan M; Rosenkranz, J Amiel; Wolf, Marina E; Caccamise, Aaron; Shroff, Freya; Smith, Alyssa B; Loweth, Jessica A

2018-01-01

A major challenge for treating cocaine addiction is the propensity for abstinent users to relapse. Two important triggers for relapse are cues associated with prior drug use and stressful life events. To study their interaction in promoting relapse during abstinence, we used the incubation model of craving and relapse in which cue-induced drug seeking progressively intensifies ('incubates') during withdrawal from extended-access cocaine self-administration. We tested rats for cue-induced cocaine seeking on withdrawal day (WD) 1. Rats were then subjected to repeated restraint stress or control conditions (seven sessions held between WD6 and WD14). All rats were tested again for cue-induced cocaine seeking on WD15, 1 day after the last stress or control session. Although controls showed a time-dependent increase in cue-induced cocaine seeking (incubation), rats exposed to repeated stress in early withdrawal exhibited a more robust increase in seeking behavior between WD1 and WD15. In separate stressed and control rats, equivalent cocaine seeking was observed on WD48. These results indicate that repeated stress in early withdrawal accelerates incubation of cocaine craving, although craving plateaus at the same level were observed in controls. However, 1 month after the WD48 test, rats subjected to repeated stress in early withdrawal showed enhanced cue-induced cocaine seeking following acute (24 hours) food deprivation stress. Together, these data indicate that chronic stress exposure enhances the initial rate of incubation of craving during early withdrawal, resulting in increased vulnerability to cue-induced relapse during this period, and may lead to a persistent increase in vulnerability to the relapse-promoting effects of stress. © 2016 Society for the Study of Addiction.

Haematogical changes induced by subchronic glyphosate exposure ...

African Journals Online (AJOL)

The aim of this study was to determine the haematological changes induced by subchronic glyphosate exposure in Wistar rats and the ameliorative effect of zinc. Sixty adult male and female Wistar rats were used for the study. Twelve of them were used for the LD50 which was evaluated to be 3750 mg kg-1 with clinical ...

Persistence of unstable and stable chromosome aberrations in lymphocytes of cancer patients treated with radiotherapy

Energy Technology Data Exchange (ETDEWEB)

Di Giorgio, M.; Vallerga, M.B.; Taja, M.R. [Autoridad Regulatoria Nuclear, Buenos Aires (Argentina); Sardi, M. [Hospital Italiano - Mevaterapia, Buenos Aires (Argentina)

2006-07-01

Background: Radiation-induced DNA damage in human lymphocytes has equal probability of producing both stable or unstable chromosome aberrations (C.A.). Reports of its in vivo persistence show considerable variations. The quantification of unstable C.A. (dicentrics) in peripheral blood lymphocytes (P.B.L.) is the most reliable biological method for estimating whole-body doses of recent overexposures to ionizing radiation. Given that during the division of T cell precursors, proliferative death of cells containing dicentrics reduces the number of such lymphocytes in peripheral blood, dicentric methodology should be modified to account for past exposures. Micronuclei (M.N.) in cytokinesis-blocked human P.B.L. are well established bio markers for assessing radiation damage in vivo. However, persistence of radiation induced M.N. is limited. Unlike dicentrics and M.N., stable C.A. (translocations) identified at present by the FISH technique, seem to be an adequate indicator for the dosimetric evaluation of past exposures, since translocations are not selected against during mitotic division in the haematopoietic stem cells compartment. Nevertheless, for partial -body exposures with high dose there is some evidence that the decline with time of dicentrics causes some reduction in the yield of translocations. Purpose: To assess the persistence along time of dicentrics, M.N. and translocations in lymphocytes of cancer patients after radiotherapy in order to model changes in C.A. frequencies with partial-body exposures. Materials and methods: 22 cancer patients with different tumor sites, treated with radiotherapy, were evaluated through dicentric chromosome, M.N. and FISH techniques with a follow-up time of up to 90 months after the end of radiotherapy. Regression analysis were performed: 1) for dicentric and for M.N. frequencies in relation to time after the end of radiotherapy and total tumor dose; 2) for the percentage of uns table cells in relation to time after the end

Sex differences in visuospatial abilities persist during induced hypogonadism.

Science.gov (United States)

Guerrieri, Gioia M; Wakim, Paul G; Keenan, P A; Schenkel, Linda A; Berlin, Kate; Gibson, Carolyn J; Rubinow, David R; Schmidt, Peter J

2016-01-29

Despite well-established sex differences in the performance on tests of several cognitive domains (e.g., visuospatial ability), few studies in humans have evaluated if these sex differences are evident both in the presence of circulating sex hormones and during sex steroid hormonal suppression. Sex differences identified in the relative absence of circulating levels of estradiol and testosterone suggest that differences in brain structure or function exist independent of current hormonal environment and are more likely a reflection of differing developmental exposures and/or genetic substrates. To evaluate cognitive performance in healthy eugonadal men and women before and again during GnRH agonist-induced hypogonadism. Men (n=16) and women (n=15) without medical or psychiatric illness were matched for IQ. Cognitive tests were performed at baseline (when eugonadal) and after 6-8 weeks of GnRH agonist-induced gonadal suppression. The test batteries included measures of verbal and spatial memory, spatial ability, verbal fluency, motor speed/dexterity, and attention/concentration. Data were analyzed using repeated-measures models. During both eugonadism and hypogonadism, men performed significantly better than women on several measures of visuospatial performance including mental rotation, line orientation, Money Road Map, Porteus maze, and complex figure drawing. Although some test performances showed an effect of hormone treatment, the majority of these differences reflected an improved performance during hypogonadism compared with baseline (and probably reflected practice effects). The well-documented male advantage in visuospatial performance, which we observed during eugonadal conditions, was maintained in the context of short-term suppression of gonadal function in both men and women. These findings suggest that, in humans, sex differences in visuospatial performance are not merely dependent on differences in the current circulating sex steroid environment. Thus

Radiation-induced genomic instability and bystander effects: inter-related inflammatory-type non-targeted effects of exposure to ionizing radiation

Energy Technology Data Exchange (ETDEWEB)

Wright, E.G. (Molecular and Cellular Pathology Laboratories, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, Dundee, Scotland (United Kingdom))

2008-12-15

The dogma that genetic alterations are restricted to directly irradiated cells has been challenged by observations in which effects of ionizing radiation, characteristically associated with the consequences of energy deposition in the cell nucleus, arise in non-irradiated cells. These, so called, untargeted effects are demonstrated in cells that are the descendants of irradiated cells (radiation-induced genomic instability) or in cells that have communicated with neighbouring irradiated cells (radiation-induced bystander effects). There are also reports of long-range signals in vivo, known as clastogenic factors, with the capacity to induce damage in unirradiated cells. Clastogenic factors may be related to the inflammatory responses that have been implicated in some of the pathological consequences of radiation exposures. The phenotypic expression of untargeted effects reflects a balance between the type of signals produced and the responses of cell populations to such signals, both of which may be significantly influenced by cell type and genotype. There is accumulating evidence that untargeted effects in vitro involve inter-cellular signalling, production of cytokines and free radical generation. These are also features of inflammatory responses in vivo that are known to have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. At present it is far from clear how untargeted effects contribute to overall cellular radiation responses and in vivo consequences but it is possible that the various untargeted effects may reflect inter-related aspects of a non-specific inflammatory-type response to radiation-induced stress and injury and be involved in a variety of the pathological consequences of radiation exposures. (orig.)

Radiation-induced genomic instability and bystander effects: inter-related inflammatory-type non-targeted effects of exposure to ionizing radiation

International Nuclear Information System (INIS)

Wright, E.G.

2008-01-01

The dogma that genetic alterations are restricted to directly irradiated cells has been challenged by observations in which effects of ionizing radiation, characteristically associated with the consequences of energy deposition in the cell nucleus, arise in non-irradiated cells. These, so called, untargeted effects are demonstrated in cells that are the descendants of irradiated cells (radiation-induced genomic instability) or in cells that have communicated with neighbouring irradiated cells (radiation-induced bystander effects). There are also reports of long-range signals in vivo, known as clastogenic factors, with the capacity to induce damage in unirradiated cells. Clastogenic factors may be related to the inflammatory responses that have been implicated in some of the pathological consequences of radiation exposures. The phenotypic expression of untargeted effects reflects a balance between the type of signals produced and the responses of cell populations to such signals, both of which may be significantly influenced by cell type and genotype. There is accumulating evidence that untargeted effects in vitro involve inter-cellular signalling, production of cytokines and free radical generation. These are also features of inflammatory responses in vivo that are known to have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. At present it is far from clear how untargeted effects contribute to overall cellular radiation responses and in vivo consequences but it is possible that the various untargeted effects may reflect inter-related aspects of a non-specific inflammatory-type response to radiation-induced stress and injury and be involved in a variety of the pathological consequences of radiation exposures. (orig.)

Hurricane-Related Exposure Experiences and Stressors, Other Life Events, and Social Support: Concurrent and Prospective Impact on Children's Persistent Posttraumatic Stress Symptoms

Science.gov (United States)

La Greca, Annette M.; Silverman, Wendy K.; Lai, Betty; Jaccard, James

2010-01-01

Objective: We investigated the influence of hurricane exposure, stressors occurring during the hurricane and recovery period, and social support on children's persistent posttraumatic stress (PTS). Method: Using a 2-wave, prospective design, we assessed 384 children (54% girls; mean age = 8.74 years) 9 months posthurricane, and we reassessed 245…

Does occupational exposure to ionizing radiation induce adaptation

International Nuclear Information System (INIS)

Djurovic, B.; Selakovic, V.; Radjen, S.; Radakovic, S.; Spasic-Jokic, V.

2008-01-01

Full text: Even the most of personnel occupationally exposed (OE) to ionizing radiation (IR) is exposed to very low doses (LD), some harmful effects can be noticed. IR can affect the cell structure in two ways: directly and indirectly-inducing radiolysis of water and production of reactive oxygen species (ROS) similar to endogenously induced. In the low- LET exposure almost 70 % of absorbed energy is spent for ROS production. Over-production of ROS can cause oxidative stress. DNA is the main target of induced ROS. It is also experimentally showed that many important cell protective mechanisms, such is adaptation, are dependent of ROS concentration produced by low doses. The aim of this paper is to investigate if occupational exposure to LD induce over-production of ROS, and influence the activity of protective enzymes and radiosensitivity as well as induce adaptation. Our subjects were medical workers occupationally exposed to IR (44) and not-exposed (33), matched in gender, age, habits-dietary, alcohol consumption, smoking. Occupational exposure was calculated on the basis of individual TL-dose records. Besides the standard medical examination, micronucleus test, superoxide production and lipid peroxidation index, expressed as malonaldehyde (MDA) production, were performed by standard procedures as well as measurements of activity of the superoxide dismutase (SOD) and glutathione (GSH). Half of each sample were put in a sterile plastic test-tube placed in a plexiglas container 15 x 15 cm, and irradiated by 60 Co source of γ-ray at room temperature. Employed radiation dose was 2 Gy, dose-rate 0.45 Gy/min and distance from the source 74 cm. All blood samples were frozen at -70 C degrees, and kept till analyses which were performed at the same time. Our results confirm: significantly higher incidence of micronuclei in OE (.31±10 vs 17±8, p=0.00) with significant increase after irradiation in each group and lack of differences in radiosensitivity between groups

Radiation-induced taste aversion: effects of radiation exposure level and the exposure-taste interval

International Nuclear Information System (INIS)

Spector, A.C.; Smith, J.C.; Hollander, G.R.

1986-01-01

Radiation-induced taste aversion has been suggested to possibly play a role in the dietary difficulties observed in some radiotherapy patients. In rats, these aversions can still be formed even when the radiation exposure precedes the taste experience by several hours. This study was conducted to examine whether increasing the radiation exposure level could extend the range of the exposure-taste interval that would still support the formation of a taste aversion. Separate groups of rats received either a 100 or 300 R gamma-ray exposure followed 1, 3, 6, or 24 h later by a 10-min saccharin (0.1% w/v) presentation. A control group received a sham exposure followed 1 h later by a 10-min saccharin presentation. Twenty-four hours following the saccharin presentation all rats received a series of twelve 23-h two-bottle preference tests between saccharin and water. The results indicated that the duration of the exposure-taste interval plays an increasingly more important role in determining the initial extent of the aversion as the dose decreases. The course of recovery from taste aversion seems more affected by dose than by the temporal parameters of the conditioning trial

Persistence and vulnerability: retaining biodiversity in the landscape ...

Indian Academy of Sciences (India)

Unknown

An objective of biodiversity conservation activities is to minimize the exposure of biodiversity features to threatening processes and to ensure, as far as possible, that biodiversity persists in the landscape. We discuss how issues of vulnerability and persistence can and should be addressed at all stages of the conservation.

Formation and Stabilization of Environmentally Persistent Free Radicals Induced by the Interaction of Anthracene with Fe(III)-Modified Clays.

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Jia, Hanzhong; Nulaji, Gulimire; Gao, Hongwei; Wang, Fu; Zhu, Yunqing; Wang, Chuanyi

2016-06-21

Environmentally persistent free radicals (EPFRs) are occasionally detected in Superfund sites but the formation of EPFRs induced by polycyclic aromatic hydrocarbons (PAHs) is not well understood. In the present work, the formation of EPFRs on anthracene-contaminated clay minerals was quantitatively monitored via electron paramagnetic resonance (EPR) spectroscopy, and surface/interface-related environmental influential factors were systematically explored. The obtained results suggest that EPFRs are more readily formed on anthracene-contaminated Fe(III)-montmorillonite than in other tested systems. Depending on the reaction condition, more than one type of organic radicals including anthracene-based radical cations with g-factors of 2.0028-2.0030 and oxygenic carbon-centered radicals featured by g-factors of 2.0032-2.0038 were identified. The formed EPFRs are stabilized by their interaction with interlayer surfaces, and such surface-bound EPFRs exhibit slow decay with 1/e-lifetime of 38.46 days. Transformation pathway and possible mechanism are proposed on the basis of experimental results and quantum mechanical simulations. Overall, the formation of EPFRs involves single-electron-transfer from anthracene to Fe(III) initially, followed by H2O addition on formed aromatic radical cation. Because of their potential exposure in soil and atmosphere, such clay surface-associated EPFRs might induce more serious toxicity than PAHs and exerts significant impacts on human health.

IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study

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Kurukulaaratchy Ramesh

2008-01-01

Full Text Available Abstract Background Tobacco smoke and genetic susceptibility are risk factors for asthma and wheezing. The aim of this study was to investigate whether there is a combined effect of interleukin-13 gene (IL13 polymorphisms and tobacco smoke on persistent childhood wheezing and asthma. Methods In the Isle of Wight birth cohort (UK, 1989–1999, five IL13 single nucleotide polymorphisms (SNPs: rs1800925 (-1112C/T, rs2066960, rs1295686, rs20541 (R130Q and rs1295685 were genotyped. Parents were asked whether their children had wheezed in the last 12 months at ages 1, 2, 4 and 10 years. Children who reported wheeze in the first 4 years of life and also had wheezing at age 10 were classified as early-onset persistent wheeze phenotype; non-wheezers never wheezed up to age 10. Persistent asthma was defined as having a diagnosis of asthma both during the first four years of life and at age 10. Logistic regression methods were used to analyze data on 791 children with complete information. Potential confounders were gender, birth weight, duration of breast feeding, and household cat or dog present during pregnancy. Results Maternal smoking during pregnancy was associated with early-onset persistent wheeze (OR 2.93, p IL13 were not (OR 1.15, p = 0.60 for the common haplotype pair. However, the effect of maternal smoking during pregnancy was stronger in children with the common IL13 haplotype pair compared to those without it (OR 5.58 and OR 1.29, respectively; p for interaction = 0.014. Single SNP analysis revealed a similar statistical significance for rs20541 (p for interaction = 0.02. Comparable results were observed for persistent childhood asthma (p for interaction = 0.03. Conclusion This is the first report that shows a combined effect of in utero exposure to smoking and IL13 on asthma phenotypes in childhood. The results emphasize that genetic studies need to take environmental exposures into account, since they may explain contradictory findings.

Carboplatin enhances the production and persistence of radiation-induced DNA single-strand breaks

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Yang, L.; Douple, E.B.; O'Hara, J.A.; Wang, H.J.

1995-01-01

Fluorometric analysis of DNA unwinding and alkaline elution were used to investigate the production and persistence of DNA single-strand breaks (SSBs) in Chinese hamster V79 and xrs-5 cells treated with the chemotherapeutic agent carboplatin in combination with radiation. Carboplatin was administered to cells before irradiation in hypoxic conditions, or the drug was added immediately after irradiation during the postirradiation recovery period in air. The results of DNA unwinding studies suggest that carboplatin enhances the production of radiation-induced SSBs in hypoxic V79 cells and xrs-5 cells by a factor of 1.86 and 1.83, respectively, when combined with radiation compared to the SSBs produced by irradiation alone. Carboplatin alone did not produce a measureable number of SSBs. Alkaline elution profiles also indicated that the rate of elution of SSBs was higher in cells treated with the carboplatin is present after irradiation and during the postirradiation recovery period, the rejoining of radiation-induced SSBs by a factor of 1.46 in V79 cells with 20 Gy irradiation and by a factor of 2.02 in xrs-5 cells with 20 Gy irradiation. When carboplatin is present after irradiation and during the postirradiation recovery period, the rejoining of radiation-induced SSBs is inhibited during this postirradiation incubation period (radiopotentiation) with a relative inhibition factor at 1 h postirradiation of 1.25 in V79 cells and 1.15 in xrs-5 cells. An increased production and persistence of SSBs resulting from the interaction of carboplatin with radiation may be an important step in the mechanism responsible for the potentiated cell killing previously from studies in animal tumors and in cultured cells. 31 refs., 7 figs

Chronic corticosterone exposure persistently elevates the expression of memory-related genes in the lateral amygdala and enhances the consolidation of a Pavlovian fear memory.

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Melissa S Monsey

Full Text Available Chronic exposure to stress has been widely implicated in the development of anxiety disorders, yet relatively little is known about the long-term effects of chronic stress on amygdala-dependent memory formation. Here, we examined the effects of a history of chronic exposure to the stress-associated adrenal steroid corticosterone (CORT on the consolidation of a fear memory and the expression of memory-related immediate early genes (IEGs in the lateral nucleus of the amygdala (LA. Rats received chronic exposure to CORT (50 μg/ml in their drinking water for 2 weeks and were then titrated off the CORT for an additional 6 days followed by a 2 week 'wash-out' period consisting of access to plain water. Rats were then either sacrificed to examine the expression of memory-related IEG expression in the LA or given auditory Pavlovian fear conditioning. We show that chronic exposure to CORT leads to a persistent elevation in the expression of the IEGs Arc/Arg3.1 and Egr-1 in the LA. Further, we show that rats with a history of chronic CORT exposure exhibit enhanced consolidation of a fear memory; short-term memory (STM is not affected, while long-term memory (LTM is significantly enhanced. Treatment with the selective serotonin reuptake inhibitor (SSRI fluoxetine following the chronic CORT exposure period was observed to effectively reverse both the persistent CORT-related increases in memory-related IEG expression in the LA and the CORT-related enhancement in fear memory consolidation. Our findings suggest that chronic exposure to CORT can regulate memory-related IEG expression and fear memory consolidation processes in the LA in a long-lasting manner and that treatment with fluoxetine can reverse these effects.

Chronic corticosterone exposure persistently elevates the expression of memory-related genes in the lateral amygdala and enhances the consolidation of a Pavlovian fear memory.

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Monsey, Melissa S; Boyle, Lara M; Zhang, Melinda L; Nguyen, Caroline P; Kronman, Hope G; Ota, Kristie T; Duman, Ronald S; Taylor, Jane R; Schafe, Glenn E

2014-01-01

Chronic exposure to stress has been widely implicated in the development of anxiety disorders, yet relatively little is known about the long-term effects of chronic stress on amygdala-dependent memory formation. Here, we examined the effects of a history of chronic exposure to the stress-associated adrenal steroid corticosterone (CORT) on the consolidation of a fear memory and the expression of memory-related immediate early genes (IEGs) in the lateral nucleus of the amygdala (LA). Rats received chronic exposure to CORT (50 μg/ml) in their drinking water for 2 weeks and were then titrated off the CORT for an additional 6 days followed by a 2 week 'wash-out' period consisting of access to plain water. Rats were then either sacrificed to examine the expression of memory-related IEG expression in the LA or given auditory Pavlovian fear conditioning. We show that chronic exposure to CORT leads to a persistent elevation in the expression of the IEGs Arc/Arg3.1 and Egr-1 in the LA. Further, we show that rats with a history of chronic CORT exposure exhibit enhanced consolidation of a fear memory; short-term memory (STM) is not affected, while long-term memory (LTM) is significantly enhanced. Treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine following the chronic CORT exposure period was observed to effectively reverse both the persistent CORT-related increases in memory-related IEG expression in the LA and the CORT-related enhancement in fear memory consolidation. Our findings suggest that chronic exposure to CORT can regulate memory-related IEG expression and fear memory consolidation processes in the LA in a long-lasting manner and that treatment with fluoxetine can reverse these effects.

Persistence of gamma-H2AX and 53BP1 foci in proliferating and nonproliferating human mammary epithelial cells after exposure to gamma-rays or iron ions

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Groesser, Torsten; Chang, Hang; Fontenay, Gerald; Chen, James; Costes, Sylvain V.; Barcellos-Hoff, Mary Helen; Parvin, Bahram; Rydberg, Bjorn

2010-12-22

To investigate {gamma}-H2AX (phosphorylated histone H2AX) and 53BP1 (tumour protein 53 binding protein No. 1) foci formation and removal in proliferating and non-proliferating human mammary epithelial cells (HMEC) after exposure to sparsely and densely ionizing radiation under different cell culture conditions. HMEC cells were grown either as monolayers (2D) or in extracellular matrix to allow the formation of acinar structures in vitro (3D). Foci numbers were quantified by image analysis at various time points after exposure. Our results reveal that in non-proliferating cells under 2D and 3D cell culture conditions, iron-ion induced {gamma}-H2AX foci were still present at 72 h after exposure, although 53BP1 foci returned to control levels at 48 h. In contrast in proliferating HMEC, both {gamma}-H2AX and 53BP1 foci decreased to control levels during the 24-48 h time interval after irradiation under 2D conditions. Foci numbers decreased faster after {gamma}-ray irradiation and returned to control levels by 12 h regardless of marker, cell proliferation status, and cell culture condition. Conclusions: The disappearance of radiation induced {gamma}-H2AX and 53BP1 foci in HMEC have different dynamics that depend on radiation quality and proliferation status. Notably, the general patterns do not depend on the cell culture condition (2D versus 3D). We speculate that the persistent {gamma}-H2AX foci in iron-ion irradiated non-proliferating cells could be due to limited availability of double strand break (DSB) repair pathways in G0/G1-phase, or that repair of complex DSB requires replication or chromatin remodeling.

Dietary exposure to persistent organic pollutants and metals among Inuit and Chukchi in Russian Arctic Chukotka

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Alexey A. Dudarev

2012-07-01

Full Text Available Objectives. The general aim was to assess dietary exposure to selected persistent organic pollutants (POPs and metals among Eskimo (Inuit and Chukchi of the Chukotka Peninsula of the Russian Arctic, and to establish recommendations for exposure risk reduction. Study design. A cross-sectional evaluation of nutritional patterns of coastal and inland indigenous peoples of the Chukotka Autonomous Okrug (in 2001–2003; assessment of the levels of persistent toxic substances (PTSs in traditional foods and their comparison to Russian food safety limits; the identification of local sources of food contamination; and the recommendation and implementation of risk management measures. Methods. Community-based dietary survey of self reported food frequencies (453 persons, chemical analyses (POPs and metals of local foods and indoor matters (397 samples, substantiation of recommendations for daily (weekly, monthly intakes of traditional food. Results. POPs in traditional food items are generally below the Russian food safety limits except marine mammal fat, while Hg and Cd are high mainly in mammal viscera. Lead is relatively low in tissues of all animals studied. For the Chukotka coastal communities, seals constitute the principal source of the whole suite of PTSs considered. Consumption restrictions are recommended for marine and freshwater fish, some wild meats (waterfowl and seal, fats (whale and seal, liver (most animals and kidney (reindeer, walrus and seal. Evidence is presented that contamination of foodstuffs may be significantly increased during storing/processing/cooking of food due to indoor and outdoor environmental conditions. Conclusions. Based on the analytical findings and the local PTSs sources identified, guidelines on food safety are suggested, as well as measures to reduce food contamination and domestic and local sources. Important and urgent remedial actions are recommended to minimize PTSs environmental and domestic contamination

Piracetam prevents memory deficit induced by postnatal propofol exposure in mice.

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Wang, Yuan-Lin; Li, Feng; Chen, Xin

2016-05-15

Postnatal propofol exposure impairs hippocampal synaptic development and memory. However, the effective agent to alleviate the impairments was not verified. In this study, piracetam, a positive allosteric modulator of AMPA receptor was administered following a seven-day propofol regime. Two months after propofol administration, hippocampal long-term potentiation (LTP) and long-term memory decreased, while intraperitoneal injection of piracetam at doses of 100mg/kg and 50mg/kg following last propofol exposure reversed the impairments of memory and LTP. Mechanically, piracetam reversed propofol exposure-induced decrease of BDNF and phosphorylation of mTor. Similar as piracetam, BDNF supplementary also ameliorated propofol-induced abnormalities of synaptic plasticity-related protein expressions, hippocampal LTP and long-term memory. These results suggest that piracetam prevents detrimental effects of propofol, likely via activating BDNF synthesis. Copyright © 2016 Elsevier B.V. All rights reserved.

Arsenic exposure induces the Warburg effect in cultured human cells

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Zhao, Fei; Severson, Paul; Pacheco, Samantha; Futscher, Bernard W.; Klimecki, Walter T., E-mail: klimecki@pharmacy.arizona.edu

2013-08-15

Understanding how arsenic exacts its diverse, global disease burden is hampered by a limited understanding of the particular biological pathways that are disrupted by arsenic and underlie pathogenesis. A reductionist view would predict that a small number of basic pathways are generally perturbed by arsenic, and manifest as diverse diseases. Following an initial observation that arsenite-exposed cells in culture acidify their media more rapidly than control cells, the report here shows that low level exposure to arsenite (75 ppb) is sufficient to induce aerobic glycolysis (the Warburg effect) as a generalized phenomenon in cultured human primary cells and cell lines. Expanded studies in one such cell line, the non-malignant pulmonary epithelial line, BEAS-2B, established that the arsenite-induced Warburg effect was associated with increased accumulation of intracellular and extracellular lactate, an increased rate of extracellular acidification, and inhibition by the non-metabolized glucose analog, 2-deoxy-D-glucose. Associated with the induction of aerobic glycolysis was a pathway-wide induction of glycolysis gene expression, as well as protein accumulation of an established glycolysis master-regulator, hypoxia-inducible factor 1A. Arsenite-induced alteration of energy production in human cells represents the type of fundamental perturbation that could extend to many tissue targets and diseases. - Highlights: • Chronic arsenite exposure induces aerobic glycolysis, dubbed the “Warburg effect”. • Arsenite-induced Warburg effect is a general phenomenon in cultured human cells. • HIF-1A may mediate arsenite induced Warburg effect.

Arsenic exposure induces the Warburg effect in cultured human cells

International Nuclear Information System (INIS)

Zhao, Fei; Severson, Paul; Pacheco, Samantha; Futscher, Bernard W.; Klimecki, Walter T.

2013-01-01

Understanding how arsenic exacts its diverse, global disease burden is hampered by a limited understanding of the particular biological pathways that are disrupted by arsenic and underlie pathogenesis. A reductionist view would predict that a small number of basic pathways are generally perturbed by arsenic, and manifest as diverse diseases. Following an initial observation that arsenite-exposed cells in culture acidify their media more rapidly than control cells, the report here shows that low level exposure to arsenite (75 ppb) is sufficient to induce aerobic glycolysis (the Warburg effect) as a generalized phenomenon in cultured human primary cells and cell lines. Expanded studies in one such cell line, the non-malignant pulmonary epithelial line, BEAS-2B, established that the arsenite-induced Warburg effect was associated with increased accumulation of intracellular and extracellular lactate, an increased rate of extracellular acidification, and inhibition by the non-metabolized glucose analog, 2-deoxy-D-glucose. Associated with the induction of aerobic glycolysis was a pathway-wide induction of glycolysis gene expression, as well as protein accumulation of an established glycolysis master-regulator, hypoxia-inducible factor 1A. Arsenite-induced alteration of energy production in human cells represents the type of fundamental perturbation that could extend to many tissue targets and diseases. - Highlights: • Chronic arsenite exposure induces aerobic glycolysis, dubbed the “Warburg effect”. • Arsenite-induced Warburg effect is a general phenomenon in cultured human cells. • HIF-1A may mediate arsenite induced Warburg effect

Persistence of radiation-induced chromosome aberrations in a long-term cell culture.

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Duran, Assumpta; Barquinero, Joan Francesc; Caballín, María Rosa; Ribas, Montserrat; Barrios, Leonardo

2009-04-01

The aim of the present study was to evaluate the persistence of chromosome aberrations induced by X rays. FISH painting and mFISH techniques were applied to long-term cultures of irradiated cells. With painting, at 2 Gy the frequency of apparently simple translocations remained almost invariable during all the culture, whereas at 4 Gy a rapid decline was observed between the first and the second samples, followed by a slight decrease until the end of the culture. Apparently simple dicentrics and complex aberrations disappeared after the first sample at 2 and 4 Gy. By mFISH, at 2 Gy the frequency of complete plus one-way translocations remained invariable between the first and last sample, but at 4 Gy a 60% decline was observed. True incomplete simple translocations disappeared at 2 and 4 Gy, indicating that incompleteness could be a factor to consider when the persistence of translocations is analyzed. The analysis by mFISH showed that the frequency of complex aberrations and their complexity increased with dose and tended to disappear in the last sample. Our results indicate that the influence of dose on the decrease in the frequency of simple translocations with time postirradiation cannot be fully explained by the disappearance of true incomplete translocations and complex aberrations. The chromosome involvement was random for radiation-induced exchange aberrations and non-random for total aberrations. Chromosome 7 showed the highest deviations from expected, being less and more involved than expected in the first and last samples, respectively. Some preferential chromosome-chromosome associations were observed, including a coincidence with a cluster from radiogenic chromosome aberrations described in other studies.

Persistence of Breakage in Specific Chromosome Bands 6 Years after Acute Exposure to Oil.

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Alexandra Francés

Full Text Available The identification of breakpoints involved in chromosomal damage could help to detect genes involved in genetic disorders, most notably cancer. Until now, only one published study, carried out by our group, has identified chromosome bands affected by exposure to oil from an oil spill. In that study, which was performed two years after the initial oil exposure in individuals who had participated in clean-up tasks following the wreck of the Prestige, three chromosomal bands (2q21, 3q27, 5q31 were found to be especially prone to breakage. A recent follow-up study, performed on the same individuals, revealed that the genotoxic damage had persisted six years after oil exposure.To determine whether there exist chromosome bands which are especially prone to breakages and to know if there is some correlation with those detected in the previous study. In addition, to investigate if the DNA repair problems detected previously persist in the present study.Follow-up study performed six years after the Prestige oil spill.Fishermen cooperatives in coastal villages.Fishermen highly exposed to oil spill who participated in previous genotoxic study six years after the oil.Chromosome damage in peripheral lymphocytes. For accurate identification of the breakpoints involved in chromosome damage of circulating lymphocytes, a sequential stain/G-banding technique was employed. To determine the most break-prone chromosome bands, two statistical methods, the Fragile Site Multinomial and the chi-square tests (where the bands were corrected by their length were used. To compare the chromosome lesions, structural chromosome alterations and gaps/breaks between two groups of individuals we used the GEE test which takes into account a possible within-individual correlation. Dysfunctions in DNA repair mechanisms, expressed as chromosome damage, were assessed in cultures with aphidicolin by the GEE test.Cytogenetic analyses were performed in 47 exposed individuals. A total of

Do effects of mercury in larval amphibians persist after metamorphosis?

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Todd, Brian D; Willson, John D; Bergeron, Christine M; Hopkins, William A

2012-01-01

Despite widespread concern about the role of environmental contaminants in global amphibian declines, and evidence that post-metamorphic life stages contribute disproportionately to amphibian population dynamics, most studies in amphibian ecotoxicology focus on larval life stages. Studies that focus solely on early life stages may miss important effects of contaminant exposure, such as latent effects that manifest some time after previous exposure. Moreover, it is often assumed that effects observed in amphibian larvae will persist to affect survival or reproduction later in life. We used terrestrial enclosures to determine whether exposure to mercury (Hg) through maternal transfer and/or larval diet had any adverse effects in post-metamorphic American toads (Bufo americanus). We found a 5% difference in size at metamorphosis that was attributed to maternal Hg exposure persisted for 1 year in the terrestrial environment, resulting in a 7% difference at the conclusion of the study. Although patterns of survival differed among treatments through time, we found no overall difference in survival after 1 year. We also found no evidence of emergent latent effects in the terrestrial toads that could be attributed to earlier exposure. Our results indicate that adverse effects of maternal Hg exposure that were observed in larval amphibians may persist to affect later terrestrial life stages but that no novel adverse effects developed when animals were raised in a semi-natural environment. Moreover, we found no evidence of persistent effects of dietary Hg exposure in larvae, highlighting a need for greater focus on maternal effects in amphibian ecotoxicology. Finally, we suggest an increase in the use of longitudinal studies to better understand contaminant impacts to amphibian populations via effects in both aquatic and terrestrial life stages.

Acrylonitrile potentiates hearing loss and cochlear damage induced by moderate noise exposure in rats

International Nuclear Information System (INIS)

Pouyatos, BenoIt; Gearhart, Caroline A.; Fechter, Laurence D.

2005-01-01

The diversity of chemical and drugs that can potentiate noise-induced hearing loss (NIHL) has impeded efforts to predict such interactions. We have hypothesized that chemical contaminants that disrupt intrinsic antioxidant defenses hold significant risk for potentiating NIHL. If this is true, then acrylonitrile (ACN) would be expected to potentiate NIHL. ACN, one of the 50 most commonly used chemicals in the United States, is metabolized via two pathways that are likely to disrupt intrinsic reactive oxygen species (ROS) buffering systems: (1) it conjugates glutathione, depleting this important antioxidant rapidly; (2) a second pathway involves the formation of cyanide, which can inhibit superoxide dismutase. We hypothesized that moderate noise exposure, that does not produce permanent hearing loss by itself, could initiate oxidative stress and that ACN could render the inner ear more sensitive to noise by disrupting intrinsic antioxidant defenses. Temporary and persistent effects of ACN alone (50 mg/kg, sc 5 days), noise alone (95 or 97 dB octave band noise, 4 h/day for 5 days), or ACN in combination with noise were determined using distortion product otoacoustic emissions (DPOAEs) and compound action potential (CAP) amplitudes. Histopathological damage to hair cells resulting from these treatments was also investigated using surface preparations of the organ of Corti. Individually, neither ACN nor noise exposures caused any permanent hearing or hair cell loss; only a reversible temporary threshold shift was measured in noise-exposed animals. However, when given in combination, ACN and noise induced permanent threshold shifts (13-16 dB between 7 and 40 kHz) and a decrease in DPOAE amplitudes (up to 25 dB at 19 kHz), as well as significant outer hair cell (OHC) loss (up to 20% in the first row between 13 and 47 kHz). This investigation demonstrates that ACN can potentiate NIHL at noise levels that are realistic in terms of human exposure, and that the OHCs are the

Intermittent cold exposure enhances fat accumulation in mice.

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Hyung Sun Yoo

Full Text Available Due to its high energy consuming characteristics, brown adipose tissue (BAT has been suggested as a key player in energy metabolism. Cold exposure is a physiological activator of BAT. Intermittent cold exposure (ICE, unlike persistent exposure, is clinically feasible. The main objective of this study was to investigate whether ICE reduces adiposity in C57BL/6 mice. Surprisingly, we found that ICE actually increased adiposity despite enhancing Ucp1 expression in BAT and inducing beige adipocytes in subcutaneous white adipose tissue. ICE did not alter basal systemic insulin sensitivity, but it increased liver triglyceride content and secretion rate as well as blood triglyceride levels. Gene profiling further demonstrated that ICE, despite suppressing lipogenic gene expression in white adipose tissue and liver during cold exposure, enhanced lipogenesis between the exposure periods. Together, our results indicate that despite enhancing BAT recruitment, ICE in mice increases fat accumulation by stimulating de novo lipogenesis.

Mobility-induced persistent chimera states

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Petrungaro, Gabriela; Uriu, Koichiro; Morelli, Luis G.

2017-12-01

We study the dynamics of mobile, locally coupled identical oscillators in the presence of coupling delays. We find different kinds of chimera states in which coherent in-phase and antiphase domains coexist with incoherent domains. These chimera states are dynamic and can persist for long times for intermediate mobility values. We discuss the mechanisms leading to the formation of these chimera states in different mobility regimes. This finding could be relevant for natural and technological systems composed of mobile communicating agents.

Recurring ethanol exposure induces disinhibited courtship in Drosophila.

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Hyun-Gwan Lee

Full Text Available Alcohol has a strong causal relationship with sexual arousal and disinhibited sexual behavior in humans; however, the physiological support for this notion is largely lacking and thus a suitable animal model to address this issue is instrumental. We investigated the effect of ethanol on sexual behavior in Drosophila. Wild-type males typically court females but not males; however, upon daily administration of ethanol, they exhibited active intermale courtship, which represents a novel type of behavioral disinhibition. The ethanol-treated males also developed behavioral sensitization, a form of plasticity associated with addiction, since their intermale courtship activity was progressively increased with additional ethanol experience. We identified three components crucial for the ethanol-induced courtship disinhibition: the transcription factor regulating male sex behavior Fruitless, the ABC guanine/tryptophan transporter White and the neuromodulator dopamine. fruitless mutant males normally display conspicuous intermale courtship; however, their courtship activity was not enhanced under ethanol. Likewise, white males showed negligible ethanol-induced intermale courtship, which was not only reinstated but also augmented by transgenic White expression. Moreover, inhibition of dopamine neurotransmission during ethanol exposure dramatically decreased ethanol-induced intermale courtship. Chronic ethanol exposure also affected a male's sexual behavior toward females: it enhanced sexual arousal but reduced sexual performance. These findings provide novel insights into the physiological effects of ethanol on sexual behavior and behavioral plasticity.

Long-term changes in amphetamine-induced reinforcement and aversion in rats following exposure to 56Fe particle

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Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.

Exposing rats to heavy particles produces alterations in the functioning of dopaminergic neurons and in the behaviors that depend upon the integrity of the dopaminergic system. Two of these dopamine-dependent behaviors include amphetamine-induced reinforcement, measure using the conditioned place preference procedure, and amphetamine-induced reinforcement, measured using the conditioned place preference procedure, and amphetamine-induced aversion, measured using the conditioned taste aversion. Previous research has shown that exposing rats to 1.0 Gy of 1GeV/n 56Fe particles produced a disruption of an amphetamine-induced taste aversion 3 days following exposure, but produced an apparent enhancement of the aversion 112 days following exposure. The present experiments were designed to provide a further evaluation of these results by examining taste aversion learning 154 days following exposure to 1.0Gy 56Fe particles and to establish the convergent validity of the taste aversion results by looking at the effects of exposure on the establishment of an amphetamine-induced conditioned place preference 3, 7, and 16 weeks following irradiation. The taste aversion results failed to confirm the apparent enhancement of the amphetamine-induced CTA observed in the prior experiment. However, exposure to 56Fe particles prevented the acquisition of amphetamine-induced place preference at all three-time intervals. The results are interpreted as indicating that exposure to heavy particles can produce long-term changes in behavioral functioning.

Quantifying the persistence of pro-smoking media effects on college students' smoking risk.

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Setodji, Claude M; Martino, Steven C; Scharf, Deborah M; Shadel, William G

2014-04-01

To quantify the persistence of pro-smoking media exposure effects on college students' intentions to smoke and smoking refusal self-efficacy. A total of 134 college students (ages 18-24 years) were enrolled in an ecological momentary assessment study in which they carried handheld data collection devices for 3 weeks and reported their exposures to pro-smoking media as they occurred in the real world. Smoking intentions and smoking refusal self-efficacy were assessed after each exposure to pro-smoking media and at random prompts during each day of the 3-week assessment period. A generalized additive model was used to determine how long the effect of an exposure to pro-smoking media persisted. The effect of pro-smoking media exposures persisted for 7 days. After exposure, smoking intentions immediately increased (.56; 95% confidence interval [CI]: [.26, .87]) and then steadily decreased (-.12; 95% CI: [-.19, -.05]) each day for 7 days, while smoking refusal self-efficacy immediately decreased (-.42; 95% CI: [-.75, -.10]) and then steadily increased (.09; 95% CI: [.02, .16]) each day for 7 days. Daily changes occurring after 7 days were not statistically significant, suggesting that smoking intentions and refusal self-efficacy had stabilized and were no longer affected by pro-smoking media exposure. Exposures to pro-smoking media may have strong implications for emerging young adults smoking risk as the impact of an individual exposure appears to persist for at least a week. Copyright © 2014 Society for Adolescent Health and Medicine. All rights reserved.

Ozone Therapy in the Management of Persistent Radiation-Induced Rectal Bleeding in Prostate Cancer Patients

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Bernardino Clavo

2015-01-01

Full Text Available Introduction. Persistent radiation-induced proctitis and rectal bleeding are debilitating complications with limited therapeutic options. We present our experience with ozone therapy in the management of such refractory rectal bleeding. Methods. Patients (n=12 previously irradiated for prostate cancer with persistent or severe rectal bleeding without response to conventional treatment were enrolled to receive ozone therapy via rectal insufflations and/or topical application of ozonized-oil. Ten (83% patients had Grade 3 or Grade 4 toxicity. Median follow-up after ozone therapy was 104 months (range: 52–119. Results. Following ozone therapy, the median grade of toxicity improved from 3 to 1 (p<0.001 and the number of endoscopy treatments from 37 to 4 (p=0.032. Hemoglobin levels changed from 11.1 (7–14 g/dL to 13 (10–15 g/dL, before and after ozone therapy, respectively (p=0.008. Ozone therapy was well tolerated and no adverse effects were noted, except soft and temporary flatulence for some hours after each session. Conclusions. Ozone therapy was effective in radiation-induced rectal bleeding in prostate cancer patients without serious adverse events. It proved useful in the management of rectal bleeding and merits further evaluation.

Glufosinate aerogenic exposure induces glutamate and IL-1 receptor dependent lung inflammation.

Science.gov (United States)

Maillet, Isabelle; Perche, Olivier; Pâris, Arnaud; Richard, Olivier; Gombault, Aurélie; Herzine, Ameziane; Pichon, Jacques; Huaux, Francois; Mortaud, Stéphane; Ryffel, Bernhard; Quesniaux, Valérie F J; Montécot-Dubourg, Céline

2016-11-01

Glufosinate-ammonium (GLA), the active component of an herbicide, is known to cause neurotoxicity. GLA shares structural analogy with glutamate. It is a powerful inhibitor of glutamine synthetase (GS) and may bind to glutamate receptors. Since these potentials targets of GLA are present in lung and immune cells, we asked whether airway exposure to GLA may cause lung inflammation in mice. A single GLA exposure (1 mg/kg) induced seizures and inflammatory cell recruitment in the broncho-alveolar space, and increased myeloperoxidase (MPO), inducible NO synthase (iNOS), interstitial inflammation and disruption of alveolar septae within 6-24 h. Interleukin 1β (IL-1β) was increased and lung inflammation depended on IL-1 receptor 1 (IL-1R1). We demonstrate that glutamate receptor pathway is central, since the N-methyl-D-aspartate (NMDA) receptor inhibitor MK-801 prevented GLA-induced lung inflammation. Chronic exposure (0.2 mg/kg 3× per week for 4 weeks) caused moderate lung inflammation and enhanced airway hyperreactivity with significant increased airway resistance. In conclusion, GLA aerosol exposure causes glutamate signalling and IL-1R-dependent pulmonary inflammation with airway hyperreactivity in mice. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Chronic Exposure to Particulate Nickel Induces Neoplastic Transformation in Human Lung Epithelial Cells

Directory of Open Access Journals (Sweden)

Amie L. Holmes

2013-11-01

Full Text Available Nickel is a well-known human lung carcinogen with the particulate form being the most potent; however, the carcinogenic mechanism remains largely unknown. Few studies have investigated the genotoxicity and carcinogenicity of nickel in its target cell, human bronchial epithelial cells. Thus, the goal of this study was to investigate the effects of particulate nickel in human lung epithelial cells. We found that nickel subsulfide induced concentration- and time-dependent increases in both cytotoxicity and genotoxicity in human lung epithelial cells (BEP2D. Chronic exposure to nickel subsulfide readily induced cellular transformation, inducing 2.55, 2.9 and 2.35 foci per dish after exposure to 1, 2.5 and 5 μg/cm2 nickel subsulfide, respectively. Sixty-one, 100 and 70 percent of the foci isolated from 1, 2.5, and 5 μg/cm2 nickel subsulfide treatments formed colonies in soft agar and the degree of soft agar colony growth increased in a concentration-dependent manner. Thus, chronic exposure to particulate nickel induces genotoxicity and cellular transformation in human lung epithelial cells.

RNAi dynamics in Juvenile Fasciola spp. Liver flukes reveals the persistence of gene silencing in vitro.

Directory of Open Access Journals (Sweden)

Paul McVeigh

2014-09-01

Full Text Available Fasciola spp. liver fluke cause pernicious disease in humans and animals. Whilst current control is unsustainable due to anthelmintic resistance, gene silencing (RNA interference, RNAi has the potential to contribute to functional validation of new therapeutic targets. The susceptibility of juvenile Fasciola hepatica to double stranded (dsRNA-induced RNAi has been reported. To exploit this we probe RNAi dynamics, penetrance and persistence with the aim of building a robust platform for reverse genetics in liver fluke. We describe development of standardised RNAi protocols for a commercially-available liver fluke strain (the US Pacific North West Wild Strain, validated via robust transcriptional silencing of seven virulence genes, with in-depth experimental optimisation of three: cathepsin L (FheCatL and B (FheCatB cysteine proteases, and a σ-class glutathione transferase (FheσGST.Robust transcriptional silencing of targets in both F. hepatica and Fasciola gigantica juveniles is achievable following exposure to long (200-320 nt dsRNAs or 27 nt short interfering (siRNAs. Although juveniles are highly RNAi-susceptible, they display slower transcript and protein knockdown dynamics than those reported previously. Knockdown was detectable following as little as 4h exposure to trigger (target-dependent and in all cases silencing persisted for ≥25 days following long dsRNA exposure. Combinatorial silencing of three targets by mixing multiple long dsRNAs was similarly efficient. Despite profound transcriptional suppression, we found a significant time-lag before the occurrence of protein suppression; FheσGST and FheCatL protein suppression were only detectable after 9 and 21 days, respectively.In spite of marked variation in knockdown dynamics, we find that a transient exposure to long dsRNA or siRNA triggers robust RNAi penetrance and persistence in liver fluke NEJs supporting the development of multiple-throughput phenotypic screens for control

The importance of diet on exposure to and effects of persistent organic pollutants on human health in the Arctic

DEFF Research Database (Denmark)

Odland, Jon Øyvind; Deutch, Bente; Hansen, Jens C.

2003-01-01

AIM: To describe the importance of diet on exposure to and possible health effects of persistent organic pollutants (POPs) in the Arctic. METHODS: The study is based on a literature review. RESULTS: Minor decreases in POPs and minor increases in Hg levels in Arctic populations in Greenland, Eastern...... of the dietary components is sustained. CONCLUSIONS: To improve our understanding of the health effects associated with exposure to contaminants in the Arctic, we recommend that circumpolar epidemiological studies should be implemented on a larger scale. MeHg- and POPs-related effects are still the key issues...... to decline marginally by 2030. Estimating the effects on the basis of current knowledge is difficult, but the combination of improved methodology and selection of risk groups will be a progressive step in the process. Any strategies based on traditional food substitution should ensure that the value...

Perinatal exposure to a mixture of persistent pollutants based on blood profiles of Arctic populations affects bone parameters in 35 days old rats

Energy Technology Data Exchange (ETDEWEB)

Stern, N.; Trossvik, C.; Hakansson, H. [Inst. of Environmental Medicine, Karolinska Inst., Stockholm (Sweden); Bowers, W.; Nakai, J.S.; Chu, I. [Environmental and Occupational Toxicology Div., Environmental Health Sciences Bureau, Health Canada, Ottawa (Canada)

2004-09-15

Environmental pollution of Arctic regions is a public concern. Arctic inhabitants are a high-risk group regarding health effects of environmental toxicants because of their high consumption of contaminated fish and wildlife. Developing fetuses and newborn infants may be particularly vulnerable to the effects of exposure to persistent organic pollutants (POPs) and toxic metals. Developmental exposure to environmental pollutants affects a wide range of clinical and biochemical parameters. Disturbance in skeletal growth, an integral component of somatic development, is a novel area in the toxicity of POPs. Low-dose prenatal exposure to TCDD caused a variety of harmful effects in rat long bones. In adult rats, TCDD exposure caused inhibited bone growth and lowered biomechanical properties of tibia and exposure to the dioxin-like PCBcongener 3,3,4,4,5-pentachlorobiphenyl has been associated with a decreased strength and collagen concentration of humerus. The aim of this study was to investigate effects of perinatal exposure to a mixture of PCBs, organochlorines and methyl mercury based on blood levels of Canadian Arctic populations on skeletal development in rat pups.

Effects of the swimming exercise on the consolidation and persistence of auditory and contextual fear memory.

Science.gov (United States)

Faria, Rodolfo Souza; Gutierres, Luís Felipe Soares; Sobrinho, Fernando César Faria; Miranda, Iris do Vale; Reis, Júlia Dos; Dias, Elayne Vieira; Sartori, Cesar Renato; Moreira, Dalmo Antonio Ribeiro

2016-08-15

Exposure to negative environmental events triggers defensive behavior and leads to the formation of aversive associative memory. Cellular and molecular changes in the central nervous system underlie this memory formation, as well as the associated behavioral changes. In general, memory process is established in distinct phases such as acquisition, consolidation, evocation, persistence, and extinction of the acquired information. After exposure to a particular event, early changes in involved neural circuits support the memory consolidation, which corresponds to the short-term memory. Re-exposure to previously memorized events evokes the original memory, a process that is considered essential for the reactivation and consequent persistence of memory, ensuring that long-term memory is established. Different environmental stimuli may modulate the memory formation process, as well as their distinct phases. Among the different environmental stimuli able of modulating memory formation is the physical exercise which is a potent modulator of neuronal activity. There are many studies showing that physical exercise modulates learning and memory processes, mainly in the consolidation phase of the explicit memory. However, there are few reports in the literature regarding the role of physical exercise in implicit aversive associative memory, especially at the persistence phase. Thus, the present study aimed to investigate the relationship between swimming exercise and the consolidation and persistence of contextual and auditory-cued fear memory. Male Wistar rats were submitted to sessions of swimming exercise five times a week, over six weeks. After that, the rats were submitted to classical aversive conditioning training by a pairing tone/foot shock paradigm. Finally, rats were evaluated for consolidation and persistence of fear memory to both auditory and contextual cues. Our results demonstrate that classical aversive conditioning with tone/foot shock pairing induced

Exposure to Gulf War Illness chemicals induces functional muscarinic receptor maladaptations in muscle nociceptors.

Science.gov (United States)

Cooper, B Y; Johnson, R D; Nutter, T J

2016-05-01

Chronic pain is a component of the multisymptom disease known as Gulf War Illness (GWI). There is evidence that pain symptoms could have been a consequence of prolonged and/or excessive exposure to anticholinesterases and other GW chemicals. We previously reported that rats exposed, for 8 weeks, to a mixture of anticholinesterases (pyridostigmine bromide, chlorpyrifos) and a Nav (voltage activated Na(+) channel) deactivation-inhibiting pyrethroid, permethrin, exhibited a behavior pattern that was consistent with a delayed myalgia. This myalgia-like behavior was accompanied by persistent changes to Kv (voltage activated K(+)) channel physiology in muscle nociceptors (Kv7, KDR). In the present study, we examined how exposure to the above agents altered the reactivity of Kv channels to a muscarinic receptor (mAChR) agonist (oxotremorine-M). Comparisons between muscle nociceptors harvested from vehicle and GW chemical-exposed rats revealed that mAChR suppression of Kv7 activity was enhanced in exposed rats. Yet in these same muscle nociceptors, a Stromatoxin-insensitive component of the KDR (voltage activated delayed rectifier K(+) channel) exhibited decreased sensitivity to activation of mAChR. We have previously shown that a unique mAChR-induced depolarization and burst discharge (MDBD) was exaggerated in muscle nociceptors of rats exposed to GW chemicals. We now provide evidence that both muscle and vascular nociceptors of naïve rats exhibit MDBD. Examination of the molecular basis of the MDBD in naïve animals revealed that while the mAChR depolarization was independent of Kv7, the action potential burst was modulated by Kv7 status. mAChR depolarizations were shown to be dependent, in part, on TRPA1. We argue that dysfunction of the MDBD could be a functional convergence point for maladapted ion channels and receptors consequent to exposure to GW chemicals. Copyright © 2016 Elsevier Inc. All rights reserved.

In Vivo Lipopolysaccharide Exposure of Human Blood Leukocytes Induces Cross-Tolerance to Multiple TLR Ligands

NARCIS (Netherlands)

de Vos, Alex F.; Pater, Jennie M.; van den Pangaart, Petra S.; de Kruif, Martijn D.; van 't Veer, Cornelis; van der Poll, Tom

2009-01-01

In vitro and in vivo experiments in mice have shown that exposure of cells to the TLR4 ligand LPS induces tolerance toward a second exposure to LPS and induces cross-tolerance to certain other TLR ligands. Recently, we found that LPS tolerance in experimental human endotoxemia and Gram-negative

Acrolein exposure suppresses antigen-induced pulmonary inflammation

Science.gov (United States)

2013-01-01

Background Adverse health effects of tobacco smoke arise partly from its influence on innate and adaptive immune responses, leading to impaired innate immunity and host defense. The impact of smoking on allergic asthma remains unclear, with various reports demonstrating that cigarette smoke enhances asthma development but can also suppress allergic airway inflammation. Based on our previous findings that immunosuppressive effects of smoking may be largely attributed to one of its main reactive electrophiles, acrolein, we explored the impact of acrolein exposure in a mouse model of ovalbumin (OVA)-induced allergic asthma. Methods C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection with the adjuvant aluminum hydroxide on days 0 and 7, and challenged with aerosolized OVA on days 14–16. In some cases, mice were also exposed to 5 ppm acrolein vapor for 6 hrs/day on days 14–17. Lung tissues or brochoalveolar lavage fluids (BALF) were collected either 6 hrs after a single initial OVA challenge and/or acrolein exposure on day 14 or 48 hrs after the last OVA challenge, on day 18. Inflammatory cells and Th1/Th2 cytokine levels were measured in BALF, and lung tissue samples were collected for analysis of mucus and Th1/Th2 cytokine expression, determination of protein alkylation, cellular thiol status and transcription factor activity. Results Exposure to acrolein following OVA challenge of OVA-sensitized mice resulted in markedly attenuated allergic airway inflammation, demonstrated by decreased inflammatory cell infiltrates, mucus hyperplasia and Th2 cytokines. Acrolein exposure rapidly depleted lung tissue glutathione (GSH) levels, and induced activation of the Nrf2 pathway, indicated by accumulation of Nrf2, increased alkylation of Keap1, and induction of Nrf2-target genes such as HO-1. Additionally, analysis of inflammatory signaling pathways showed suppressed activation of NF-κB and marginally reduced activation of JNK in acrolein

Persistence of urinary excretion products of benzo(a)pyrene

International Nuclear Information System (INIS)

Uziel, M.; Haglund, R.; White, D.A.

1988-01-01

Persistence of DNA-adducts has been observed in a variety of experimental circumstances and has been suggested as one potential mechanism for explaining the long-term delay before expression of proliferative disease. In this concept, a stable DNA-adduct, which is a remnant of a prior exposure in a nondividing cell, would not express the genotoxic effect until the cells were stimulated to divide, and thus explain the long-term delay in expression of cancer. An alternative view of the observation of persistent DNA-adducts, described in this communication, is the continuing replenishment of DNA adducts by formation and turnover of these adducts from exposure to a constant supply of the ultimate carcinogenic species derived from a prior exposure. It is of interest to note that virtually all experiments where ''persistent'' adducts have been observed have been high dose exposures. During the course of experiments designed to develop improved methods for detection of DNA adducts and related derivatives derived from polynuclear aromatic hydrocarbons (PAH), we observed that there was a continuous excretion of urinary derivatives of the injected benzo(a)pyrene (BaP) beyond the initial burst of detoxification. This report describes the time dependent distribution of those derivatives in blood, urine, feces, and at the site of injection. 11 refs., 5 figs., 4 tabs

Lithium prevents long-term neural and behavioral pathology induced by early alcohol exposure.

Science.gov (United States)

Sadrian, B; Subbanna, S; Wilson, D A; Basavarajappa, B S; Saito, M

2012-03-29

Fetal alcohol exposure can cause developmental defects in offspring known as fetal alcohol spectrum disorder (FASD). FASD symptoms range from obvious facial deformities to changes in neuroanatomy and neurophysiology that disrupt normal brain function and behavior. Ethanol exposure at postnatal day 7 in C57BL/6 mice induces neuronal cell death and long-lasting neurobehavioral dysfunction. Previous work has demonstrated that early ethanol exposure impairs spatial memory task performance into adulthood and perturbs local and interregional brain circuit integrity in the olfacto-hippocampal pathway. Here we pursue these findings to examine whether lithium prevents anatomical, neurophysiological, and behavioral pathologies that result from early ethanol exposure. Lithium has neuroprotective properties that have been shown to prevent ethanol-induced apoptosis. Here we show that mice co-treated with lithium on the same day as ethanol exposure exhibit dramatically reduced acute neurodegeneration in the hippocampus and retain hippocampal-dependent spatial memory as adults. Lithium co-treatment also blocked ethanol-induced disruption in synaptic plasticity in slice recordings of hippocampal CA1 in the adult mouse brain. Moreover, long-lasting dysfunctions caused by ethanol in olfacto-hippocampal networks, including sensory-evoked oscillations and resting state coherence, were prevented in mice co-treated with lithium. Together, these results provide behavioral and physiological evidence that lithium is capable of preventing or reducing immediate and long-term deleterious consequences of early ethanol exposure on brain function. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Biomarkers of exposure, effect, and susceptibility of arsenic-induced health hazards in Taiwan

International Nuclear Information System (INIS)

Chen, C.-J.; Hsu, L.-I; Wang, C.-H.

2005-01-01

Long-term exposure to inorganic arsenic from drinking water has been documented to induce cancers and vascular diseases in a dose-response relationship. A series of molecular environmental epidemiological studies have been carried out to elucidate biomarkers of exposure, effect, and susceptibility for arsenic-related health hazards in Taiwan. Arsenic levels in urine, hair, and nail are biomarkers for short-term (<1 year) internal dose, skin hyperpigmentation and palmoplantar hyperkeratosis are for long-term (many years) internal dose, and percentage of monomethylarsonic acid in total metabolites of inorganic arsenic in urine may be considered as an exposure marker for biologically effective dose. The biomarkers of early biological effects of ingested inorganic arsenic included blood levels of reactive oxidants and anti-oxidant capacity, genetic expression of inflammatory molecules, as well as cytogenetic changes including sister chromatid exchange, micronuclei, and chromosome aberrations of peripheral lymphocytes. Both mutation type and hot spots of p53 gene were significantly different in arsenic-induced and non-arsenic-induced TCCs. The frequency of chromosomal imbalances analyzed by comparative genomic hybridization and the frequency of loss of heterozygosity were significantly higher in arsenic-induced TCC than non-arsenic-induced TCC at specific sites. Biomarkers of susceptibility to arsenic-induced health hazards included genetic polymorphisms of enzymes involved in xenobiotic metabolism, DNA repair, and oxidative stress, as well as serum level of carotenoids. Gene-gene and gene-environment interactions are involved in arsenic-induced health hazards through toxicological mechanisms including genomic instability and oxidative stress

Comparative proteomic analysis reveals heart toxicity induced by chronic arsenic exposure in rats

International Nuclear Information System (INIS)

Huang, Qingyu; Xi, Guochen; Alamdar, Ambreen; Zhang, Jie; Shen, Heqing

2017-01-01

Arsenic is a widespread metalloid in the environment, which poses a broad spectrum of adverse effects on human health. However, a global view of arsenic-induced heart toxicity is still lacking, and the underlying molecular mechanisms remain unclear. By performing a comparative quantitative proteomic analysis, the present study aims to investigate the alterations of proteome profile in rat heart after long-term exposure to arsenic. As a result, we found that the abundance of 81 proteins were significantly altered by arsenic treatment (35 up-regulated and 46 down-regulated). Among these, 33 proteins were specifically associated with cardiovascular system development and function, including heart development, heart morphology, cardiac contraction and dilation, and other cardiovascular functions. It is further proposed that the aberrant regulation of 14 proteins induced by arsenic would disturb cardiac contraction and relaxation, impair heart morphogenesis and development, and induce thrombosis in rats, which is mediated by the Akt/p38 MAPK signaling pathway. Overall, these findings will augment our knowledge of the involved mechanisms and develop useful biomarkers for cardiotoxicity induced by environmental arsenic exposure. - Highlights: • Arsenic exposure has been associated with a number of adverse health effects. • The molecular mechanisms involved in arsenic-induced cardiotoxicity remain unclear. • Differential proteins were identified in arsenic-exposed rat heart by proteomics. • Arsenic induces heart toxicity through the Akt/p38 MAPK signaling pathway. - Label-free quantitative proteomic analysis of rat heart reveals putative mechanisms and biomarkers for arsenic-induced cardiotoxicity.

Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle During Adulthood

Directory of Open Access Journals (Sweden)

Fiona B Mcdonald

2016-03-01

Full Text Available Intermittent hypoxia is a feature of apnea of prematurity, chronic lung disease and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH during postnatal development (pCIH causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 hours of delivery, pups and their respective dams were exposed to CIH: 90s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 hrs per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH, where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

Early life exposure to chronic intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during adulthood.

LENUS (Irish Health Repository)

McDonald, Fiona B

2016-03-01

Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and\\/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

Chlamydia trachomatis responds to heat shock, penicillin induced persistence, and IFN-gamma persistence by altering levels of the extracytoplasmic stress response protease HtrA

Directory of Open Access Journals (Sweden)

Mathews Sarah A

2008-11-01

Full Text Available Abstract Background Chlamydia trachomatis, an obligate intracellular human pathogen, is the most prevalent bacterial sexually transmitted infection worldwide and a leading cause of preventable blindness. HtrA is a virulence and stress response periplasmic serine protease and molecular chaperone found in many bacteria. Recombinant purified C. trachomatis HtrA has been previously shown to have both activities. This investigation examined the physiological role of Chlamydia trachomatis HtrA. Results The Chlamydia trachomatis htrA gene complemented the lethal high temperature phenotype of Escherichia coli htrA- (>42°C. HtrA levels were detected to increase by western blot and immunofluorescence during Chlamydia heat shock experiments. Confocal laser scanning microscopy revealed a likely periplasmic localisation of HtrA. During penicillin induced persistence of Chlamydia trachomatis, HtrA levels (as a ratio of LPS were initially less than control acute cultures (20 h post infection but increased to more than acute cultures at 44 h post infection. This was unlike IFN-γ persistence where lower levels of HtrA were observed, suggesting Chlamydia trachomatis IFN-γ persistence does not involve a broad stress response. Conclusion The heterologous heat shock protection for Escherichia coli, and increased HtrA during cell wall disruption via penicillin and heat shock, indicates an important role for HtrA during high protein stress conditions for Chlamydia trachomatis.

Persistent symptoms in agricultural workers exposed to organophosphate pesticides

Directory of Open Access Journals (Sweden)

Martha E. Palacios N

2011-07-01

Full Text Available Objective: to evaluate the prevalence of these symptoms and their relationship with pesticide exposure and the cholinesterase levels in agricultural workers. Methodology: an analytical cross-sectional study conducted in Mexico. Cholinesterase concentration and symptom frequency were assessed for 106 agricultural workers. Exposure was defined with a composed index of 15 variables. Results: symptom prevalence was 52 out of 100 workers. 31% of workers had 1 to 3 of the symptoms, 16% had 4 to 9 of them and 5% had 10 or more of the symptoms. There was an association, p = 0.03, between days of exposure and persistent symptoms. Likewise, there was an association between exposure level and the presence of probable and specific symptoms. Patients with the highest exposure level had 20% more chances of exhibiting symptoms. Cholinesterase concentration ranges were normal. Anemia was detected in 28% of the population. It was three times as frequent in females as in males (p < 0.001. Conclusions: it was possible to identify the increase of persistent symptoms in workers with cholinesterase levels that are usually considered to be normal.

Literature review on induced exposure models, Task 2 HS-270

Science.gov (United States)

1982-02-01

Sections 1, 2 and 3 of this report describe the development of : induced exposure models, together with d discussion of questions : of validity. These Sections focus on the most important and : relevant results from the literature, while Appendix A c...

An Exposure Assessment of Polybrominated Diphenyl Ethers ...

Science.gov (United States)

EPA announced the availability of the final report, An Exposure Assessment of Polybrominated Diphenyl Ethers. This report provides a comprehensive assessment of the exposure of Americans to this class of persistent organic pollutants. Individual chapters in this document address: the production, use, and lifecycle of PBDEs; environmental fate; environmental levels; and human exposure. This final report addresses the exposure assessment needs identified in the OPBDE Workgroup project plan. It provides a comprehensive assessment of the exposure of Americans to this class of persistent organic pollutants. Individual chapters in this document address: the production, use, and lifecycle of PBDEs; environmental fate; environmental levels; and human exposure.

Treatment of phobophobia by exposure to CO2-induced anxiety symptoms.

Science.gov (United States)

Griez, E; van den Hout, M A

1983-08-01

It is argued that fear of fear, or phobophobia, can be an important maintaining factor in cases of seemingly free-floating anxiety with periodic panic attacks and that effective treatment consists of exposure to the feared neurovegetative sensations. The case history presented suggests that inhalation of CO2-O2 mixtures induces the phobic interoceptive sensations and that it can be used in the exposure treatment of phobophobia.

Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice.

Science.gov (United States)

La Merrill, Michele A; Sethi, Sunjay; Benard, Ludovic; Moshier, Erin; Haraldsson, Borje; Buettner, Christoph

2016-11-01

Dichlorodiphenyltrichloroethane (DDT) was used extensively to control malaria, typhus, body lice, and bubonic plague worldwide, until countries began restricting its use in the 1970s. However, the use of DDT to control vector-borne diseases continues in developing countries. Prenatal DDT exposure is associated with elevated blood pressure in humans. We hypothesized that perinatal DDT exposure causes hypertension in adult mice. DDT was administered to C57BL/6J dams from gestational day 11.5 to postnatal day 5. Blood pressure (BP) and myocardial wall thickness were measured in male and female adult offspring. Adult mice were treated with an angiotensin converting enzyme (ACE) inhibitor, captopril, to evaluate sensitivity to amelioration of DDT-associated hypertension by ACE inhibition. We further assessed the influence of DDT exposure on the expression of mRNAs that regulate BP through renal ion transport. Adult mice perinatally exposed to DDT exhibited chronically increased systolic BP, increased myocardial wall thickness, and elevated expression of mRNAs of several renal ion transporters. Captopril completely reversed hypertension in mice perinatally exposed to DDT. These data demonstrate that perinatal exposure to DDT causes hypertension and cardiac hypertrophy in adult offspring. A key mechanism underpinning this hypertension is an overactivated renin angiotensin system because ACE inhibition reverses the hypertension induced by perinatal DDT exposure. Citation: La Merrill M, Sethi S, Benard L, Moshier E, Haraldsson B, Buettner C. 2016. Perinatal DDT exposure induces hypertension and cardiac hypertrophy in adult mice. Environ Health Perspect 124:1722-1727; http://dx.doi.org/10.1289/EHP164.

Persistence of external signs in Pacific herring Clupea pallasii Valenciennes with ichthyophoniasis

Science.gov (United States)

Hart, Lucas M.; Conway, Carla M.; Elliott, Diane G.; Hershberger, Paul K.

2016-01-01

The progression of external signs of Ichthyophonus infection in Pacific herring Clupea pallasii Valenciennes was highly variable and asynchronous after intraperitoneal injection with pure parasite preparations; however, external signs generally persisted through the end of the study (429 days post-exposure). Observed signs included papules, erosions and ulcers. The prevalence of external signs plateaued 35 days post-exposure and persisted in 73–79% of exposed individuals through the end of the first experiment (147 days post-exposure). Among a second group of infected herring, external signs completely resolved in only 10% of the fish after 429 days. The onset of mortality preceded the appearance of external signs. Histological examination of infected skin and skeletal muscle tissues indicated an apparent affinity of the parasite for host red muscle. Host responses consisted primarily of granulomatous inflammation, fibrosis and necrosis in the skeletal muscle and other tissues. The persistence and asynchrony of external signs and host response indicated that they were neither a precursor to host mortality nor did they provide reliable metrics for hindcasting on the date of exposure. However, the long-term persistence of clinical signs in Pacific herring may be useful in ascertaining the population-level impacts of ichthyophoniasis in regularly observed populations.

Persisting nutritional neuropathy amongst former war prisoners.

OpenAIRE

Gill, G V; Bell, D R

1982-01-01

Of 898 former Far East prisoners of war, assessed between 1968 and 1981, 49 (5.5%) had evidence of persisting symptomatic neurological disease dating back to their periods of malnutrition in captivity. The commonest syndromes were peripheral neuropathy (often of "burning foot" type), optic atrophy, and sensori-neural deafness. Though nutritional neuropathies disappeared soon after release in most ex-Far East prisoners of war, in some they have persisted up to 36 years since exposure to the nu...

The Role of Musk in Relieving the Neurodegenerative Changes Induced After Exposure to Chronic Stress.

Science.gov (United States)

Abd El Wahab, Manal Galal; Ali, Soad Shaker; Ayuob, Nasra Naeim

2018-06-01

This study aimed to evaluate the effect induced by musk on Alzheimer's disease-such as neurodegenerative changes in mice exposed to chronic unpredictable mild stress (CUMS). Forty male Swiss albino mice were divided into 4 groups (n = 10); control, CUMS, CUMS + fluoxetine, CUMS + musk. At the end of the experiment, behavior of the mice was assessed. Serum corticosterone level, hippocampal protein level of the glucocorticoid receptors, and brain-derived neurotropic factor were also assessed. Hippocampus was histopathologically examined. Musk improved depressive status induced after exposure to CUMS as evidenced by the forced swimming and open field tests and improved the short-term memory as evidenced by the elevated plus maze test. Musk reduced both corticosterone levels and the hippocampal neurodegenerative changes observed after exposure to CUMS. These improvements were comparable to those induced by fluoxetine. Musk alleviated the memory impairment and neurodegenerative changes induced after exposure to the chronic stress.

Country-specific chemical signatures of persistent environmental compounds in breast milk

DEFF Research Database (Denmark)

Krysiak-Baltyn, Konrad; Toppari, J.; Skakkebaek, N.E.

2010-01-01

for exposure of the foetus to such agents. Therefore, we undertook a comprehensive ecological study of 121 EDCs, including the persistent compounds dioxins, polychlorinated biphenyls (PCBs), pesticides and flame retardants, and non-persistent phthalates, in 68 breast milk samples from Denmark and Finland...

Persistence in the WFC3 IR Detector: An Area Dependent Model

Science.gov (United States)

Long, Knox S.; Baggett, Sylvia M.

2018-05-01

When the IR detector on WFC3 is exposed to a bright source or sources, the sources not only appear in the original exposure, but can appear as afterimages in later exposures, a phenomenon known as persistence. The magnitude and duration of persistence for a fixed stimulus varies somewhat across the face of the detector. Our previous attempts to characterize this variation were limited to a correction that captures only the variation in the magnitude. Here we describe a simple model which allows for variations both in the magnitude and the duration of the persistence, and then evaluate quantitatively how much improvement this model provides. We conclude that while this was a useful experiment, it does not result in a marked improvement in our ability to predict persistence in the WFC3/IR array. We discuss why this was the case, and possible paths forward.

Glucose administration attenuates spatial memory deficits induced by chronic low-power-density microwave exposure.

Science.gov (United States)

Lu, Yonghui; Xu, Shangcheng; He, Mindi; Chen, Chunhai; Zhang, Lei; Liu, Chuan; Chu, Fang; Yu, Zhengping; Zhou, Zhou; Zhong, Min

2012-07-16

Extensive evidence indicates that glucose administration attenuates memory deficits in rodents and humans, and cognitive impairment has been associated with reduced glucose metabolism and uptake in certain brain regions including the hippocampus. In the present study, we investigated whether glucose treatment attenuated memory deficits caused by chronic low-power-density microwave (MW) exposure, and the effect of MW exposure on hippocampal glucose uptake. We exposed Wistar rats to 2.45 GHz pulsed MW irradiation at a power density of 1 mW/cm(2) for 3 h/day, for up to 30 days. MW exposure induced spatial learning and memory impairments in rats. Hippocampal glucose uptake was also reduced by MW exposure in the absence or presence of insulin, but the levels of blood glucose and insulin were not affected. However, these spatial memory deficits were reversed by systemic glucose treatment. Our results indicate that glucose administration attenuates the spatial memory deficits induced by chronic low-power-density MW exposure, and reduced hippocampal glucose uptake may be associated with cognitive impairment caused by MW exposure. Copyright © 2012 Elsevier Inc. All rights reserved.

Preconception paternal bisphenol A exposure induces sex-specific anxiety and depression behaviors in adult rats.

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Ying Fan

Full Text Available Bisphenol A (BPA, an environmental endocrine-disrupting compound, has drawn a great attention for its adverse effect on behavioral development. Maternal exposure to this compound has been reported to induce anxiety and depression in offspring, but the effect of its paternal exposure is rarely discussed. This study investigated whether preconception paternal BPA exposure can affect the emotions of male rats and their offspring. Eighteen adult male rats (F0 received either a vehicle or 50 μg/kg/day BPA diet for 21 weeks and were then mated with non-exposed females to produce offspring (F1. The affective behaviors of F0 and F1 rats were evaluated in the open-field test, the elevated-plus maze and the forced swimming test, and their serum corticosterone were then examined. BPA exposure induced increased anxiety behaviors along with increased serum corticosterone in F0 rats. This paternal exposure also led to increased anxiety behaviors in F1 females and aggravated depression behaviors in both sexes of F1 rats. Furthermore, only F1 females exhibited increased serum corticosterone. Overall, these data indicate that preconception paternal exposure to a low dose of BPA may induce transgenerational sex-specific impairments in the affection of adult rats.

Long-lasting neurobehavioral effects of prenatal exposure to xylene in rats

DEFF Research Database (Denmark)

Hass, Ulla; Lund, S. P.; Simonsen, L.

1997-01-01

The persistence of neurobehavioral effects in female rats (Mol:WIST) exposed to 500 ppm technical xylene (dimethylbenzene, GAS-no 1330-20-7) for 6 hours per day on days 7-20 of prenatal development was studied. The dose level was selected so as not to induce maternal toxicity or decreased viabili...... are planned to investigate whether neurobehavioral effects resulting from prenatal xylene exposure can interact with neurophysiological aging processes. (C) 1997 Inter Press, Inc....

Environmental Arsenic Exposure and Microbiota in Induced Sputum

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Allison G. White

2014-02-01

Full Text Available Arsenic exposure from drinking water is associated with adverse respiratory outcomes, but it is unknown whether arsenic affects pulmonary microbiota. This exploratory study assessed the effect of exposure to arsenic in drinking water on bacterial diversity in the respiratory tract of non-smokers. Induced sputum was collected from 10 subjects with moderate mean household water arsenic concentration (21.1 ± 6.4 ppb and 10 subjects with low household water arsenic (2.4 ± 0.8 ppb. To assess microbiota in sputum, the V6 hypervariable region amplicons of bacterial 16s rRNA genes were sequenced using the Ion Torrent Personal Genome Machine. Microbial community differences between arsenic exposure groups were evaluated using QIIME and Metastats. A total of 3,920,441 sequence reads, ranging from 37,935 to 508,787 per sample for 316 chips after QIIME quality filtering, were taxonomically classified into 142 individual genera and five phyla. Firmicutes (22%, Proteobacteria (17% and Bacteriodetes (12% were the main phyla in all samples, with Neisseriaceae (15%, Prevotellaceae (12% and Veillonellacea (7% being most common at the genus level. Some genera, including Gemella, Lactobacillales, Streptococcus, Neisseria and Pasteurellaceae were elevated in the moderate arsenic exposure group, while Rothia, Prevotella, Prevotellaceae Fusobacterium and Neisseriaceae were decreased, although none of these differences was statistically significant. Future studies with more participants and a greater range of arsenic exposure are needed to further elucidate the effects of drinking water arsenic consumption on respiratory microbiota.

Transposon mutagenesis identifies novel genes associated with Staphylococcus aureus persister formation

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Wang ewenjie

2015-12-01

Full Text Available Pathogenic bacterial persisters are responsible for the recalcitrance of chronic and persistent infections to antimicrobial therapy. Although the mechanisms of persister formation and survival have been widely studied in Escherichia coli, persistence mechanisms in S. aureus remain largely unknown. Here, we screened a transposon mutant library of a clinical methicillin-resistant Staphylococcus aureus（MRSA）strain, USA500 (ST8, under antibiotic pressure and identified 13 genes whose insertion mutations resulted in a defect in persistence. These candidate genes were further confirmed by evaluating the survival of the mutants upon exposure to levofloxacin and several other stress conditions. We found 13 insertion mutants with significantly lower persister numbers under several stress conditions, including sdhA, sdhB, ureG, mnhG1, fbaA, ctaB, clpX, parE, HOU_0223, HOU_0587, HOU_2091, HOU_2315 and HOU_2346, which mapped into pathways of oxidative phosphorylation, TCA cycle, glycolysis, cell cycle and ABC transporters, suggesting that these genes and pathways may play an important role in persister formation and survival. The newly constructed knockout strains of ureG, sdhA and sdhB and their complemented strains were also tested for defect in persisters following exposure to levofloxacin and several other stress conditions. The results from these experiments were consistent with the screening results, which indicated that deletion of these genes in MRSA USA500 leads to persister defect. These findings provide novel insights into the mechanisms of persister formation and survival in S. aureus and offer new targets for the development of persister-directed antibiotics for the improved treatment of chronic and persistent infections.

Amorphous nanosilicas induce consumptive coagulopathy after systemic exposure

Science.gov (United States)

Nabeshi, Hiromi; Yoshikawa, Tomoaki; Matsuyama, Keigo; Nakazato, Yasutaro; Arimori, Akihiro; Isobe, Masaaki; Tochigi, Saeko; Kondoh, Sayuri; Hirai, Toshiro; Akase, Takanori; Yamashita, Takuya; Yamashita, Kohei; Yoshida, Tokuyuki; Nagano, Kazuya; Abe, Yasuhiro; Yoshioka, Yasuo; Kamada, Haruhiko; Imazawa, Takayoshi; Itoh, Norio; Kondoh, Masuo; Yagi, Kiyohito; Mayumi, Tadanori; Tsunoda, Shin-ichi; Tsutsumi, Yasuo

2012-02-01

We previously reported that well-dispersed amorphous nanosilicas with particle size 70 nm (nSP70) penetrate skin and produce systemic exposure after topical application. These findings underscore the need to examine biological effects after systemic exposure to nanosilicas. The present study was designed to examine the biological effects. BALB/c mice were intravenously injected with amorphous nanosilicas of sizes 70, 100, 300, 1000 nm and then assessed for survival, blood biochemistry, and coagulation. As a result, injection of nSP70 caused fatal toxicity, liver damage, and platelet depletion, suggesting that nSP70 caused consumptive coagulopathy. Additionally, nSP70 exerts procoagulant activity in vitro associated with an increase in specific surface area, which increases as diameter reduces. In contrast, nSP70-mediated procoagulant activity was absent in factor XII-deficient plasma. Collectively, we revealed that interaction between nSP70 and intrinsic coagulation factors such as factor XII, were deeply related to nSP70-induced harmful effects. In other words, it is suggested that if interaction between nSP70 and coagulation factors can be suppressed, nSP70-induced harmful effects may be avoided. These results would provide useful information for ensuring the safety of nanomaterials (NMs) and open new frontiers in biological fields by the use of NMs.

BEAM-BASED MEASUREMENTS OF PERSISTENT CURRENT DECAY IN RHIC

International Nuclear Information System (INIS)

FISCHER, W.; JAIN, A.; TEPIKIAN, S.

2001-01-01

The two RHIC rings are equipped with superconducting dipole magnets. At injection, induced persistent currents in these magnets lead to a sextupole component. As the persistent currents decay with time, the horizontal and vertical chromaticities change. From magnet measurements of persistent current decays, chromaticity changes in the machine are estimated and compared with chromaticity measurements

Neonatal Persistent Exposure to 6-Propyl-2-thiouracil, a Thyroid-Disrupting Chemical, Differentially Modulates Expression of Hepatic Catalase and C/EBP-β in Adult Rats.

Science.gov (United States)

Bunker, Suresh Kumar; Dandapat, Jagneshwar; Sahoo, Sunil Kumar; Roy, Anita; Chainy, Gagan B N

2016-02-01

Persistent exposure of rats to 6-propyl-2-thiouracil (PTU) from birth resulted in decreases in plasma thyroid hormone (TH) levels and hepatic expression of catalase and CCAAT enhancer binding protein β (C/EBP-β). Catalase promoter region (-185 to +52) that contains binding sites for C/EBP-β showed an augmentation in the methylation level along with a change in methylation pattern of CpG islands in response to PTU treatment. PTU withdrawal on 30 days of birth restored TH levels and C/EBP-β to control rats in adulthood. Although catalase expression was restored to some extent in adult rats in response to PTU withdrawal, a permanent change in its promoter CpG methylation pattern was recorded. The results suggest that downregulation of adult hepatic catalase gene in response to persistent neonatal PTU exposure may not solely be attributed to thyroid-disrupting properties of PTU. It is possible that besides thyroid-disrupting behavior, PTU may impair expression of hepatic catalase by altering methylation pattern of its promoter. © 2015 Wiley Periodicals, Inc.

Human B cells fail to secrete type I interferons upon cytoplasmic DNA exposure.

Science.gov (United States)

Gram, Anna M; Sun, Chenglong; Landman, Sanne L; Oosenbrug, Timo; Koppejan, Hester J; Kwakkenbos, Mark J; Hoeben, Rob C; Paludan, Søren R; Ressing, Maaike E

2017-11-01

Most cells are believed to be capable of producing type I interferons (IFN I) as part of an innate immune response against, for instance, viral infections. In macrophages, IFN I is potently induced upon cytoplasmic exposure to foreign nucleic acids. Infection of these cells with herpesviruses leads to triggering of the DNA sensors interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP (cGAMP) synthase (cGAS). Thereby, the stimulator of interferon genes (STING) and the downstream molecules TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) are sequentially activated culminating in IFN I secretion. Human gamma-herpesviruses, such as Epstein-Barr virus (EBV), exploit B cells as a reservoir for persistent infection. In this study, we investigated whether human B cells, similar to macrophages, engage the cytoplasmic DNA sensing pathway to induce an innate immune response. We found that the B cells fail to secrete IFN I upon cytoplasmic DNA exposure, although they express the DNA sensors cGAS and IFI16 and the signaling components TBK1 and IRF3. In primary human B lymphocytes and EBV-negative B cell lines, this deficiency is explained by a lack of detectable levels of the central adaptor protein STING. In contrast, EBV-transformed B cell lines did express STING, yet both these lines as well as STING-reconstituted EBV-negative B cells did not produce IFN I upon dsDNA or cGAMP stimulation. Our combined data show that the cytoplasmic DNA sensing pathway is dysfunctional in human B cells. This exemplifies that certain cell types cannot induce IFN I in response to cytoplasmic DNA exposure providing a potential niche for viral persistence. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Persistent Skin Reactions and Aluminium Hypersensitivity Induced by Childhood Vaccines.

Science.gov (United States)

Salik, Elaha; Løvik, Ida; Andersen, Klaus E; Bygum, Anette

2016-11-02

There is increasing awareness of reactions to vaccination that include persistent skin reactions. We present here a retrospective investigation of long-lasting skin reactions and aluminium hypersensitivity in children, based on medical records and questionnaires sent to the parents. In the 10-year period 2003 to 2013 we identified 47 children with persistent skin reactions caused by childhood vaccinations. Most patients had a typical presentation of persisting pruritic subcutaneous nodules. Five children had a complex diagnostic process involving paediatricians, orthopaedics and plastic surgeons. Two patients had skin biopsies performed from their skin lesions, and 2 patients had the nodules surgically removed. Forty-two children had a patch-test performed with 2% aluminium chloride hexahydrate in petrolatum and 39 of them (92%) had a positive reaction. The persistent skin reactions were treated with potent topical corticosteroids and disappeared slowly. Although we advised families to continue vaccination of their children, one-third of parents omitted or postponed further vaccinations.

Persisting nutritional neuropathy amongst former war prisoners.

Science.gov (United States)

Gill, G V; Bell, D R

1982-01-01

Of 898 former Far East prisoners of war, assessed between 1968 and 1981, 49 (5.5%) had evidence of persisting symptomatic neurological disease dating back to their periods of malnutrition in captivity. The commonest syndromes were peripheral neuropathy (often of "burning foot" type), optic atrophy, and sensori-neural deafness. Though nutritional neuropathies disappeared soon after release in most ex-Far East prisoners of war, in some they have persisted up to 36 years since exposure to the nutritional insult. PMID:6292369

Repeated Exposure of Epithelial Cells to Apoptotic Cells Induces the Specific Selection of an Adaptive Phenotype: Implications for Tumorigenesis.

Science.gov (United States)

Feng, Lanfei; Vujicic, Snezana; Dietrich, Michael E; Litbarg, Natalia; Setty, Suman; Antoni, Angelika; Rauch, Joyce; Levine, Jerrold S

2018-05-16

The consequences of apoptosis extend beyond mere death of the cell. We have shown that receptor-mediated recognition of apoptotic target cells by viable kidney proximal tubular epithelial cells (PTECs) inhibits PTEC proliferation, growth, and survival. Here we tested the hypothesis that continual exposure to apoptotic targets can induce a phenotypic change in responding PTECs, as in other instances of natural selection. In particular, we demonstrate that repeated exposure to apoptotic targets leads to emergence of a PTEC line (denoted BU.MPT SEL ) resistant to apoptotic target-induced death. Resistance is exquisitely specific. Not only are BU.MPT SEL responders fully resistant to apoptotic target-induced death (~85% survival versus exposure in selected versus non-selected responders indicated that the acquired resistance of BU.MPT SEL cells lies in a regulatory step affecting the generation of the pro-apoptotic protein, truncated BH3 interacting-domain death agonist (tBID), most likely at the level of BID cleavage by caspase-8. This specific adaptation has especial relevance for cancer, in which the prominence and persistence of cell death entail magnification of the post-mortem effects of apoptotic cells. Just as cancer cells acquire specific resistance to chemotherapeutic agents, we propose that cancer cells may also adapt to their ongoing exposure to apoptotic targets. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Adolescent, but not adult, binge ethanol exposure leads to persistent global reductions of choline acetyltransferase expressing neurons in brain.

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Ryan P Vetreno

Full Text Available During the adolescent transition from childhood to adulthood, notable maturational changes occur in brain neurotransmitter systems. The cholinergic system is composed of several distinct nuclei that exert neuromodulatory control over cognition, arousal, and reward. Binge drinking and alcohol abuse are common during this stage, which might alter the developmental trajectory of this system leading to long-term changes in adult neurobiology. In Experiment 1, adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P] 25 to P55 treatment led to persistent, global reductions of choline acetyltransferase (ChAT expression. Administration of the Toll-like receptor 4 agonist lipopolysaccharide to young adult rats (P70 produced a reduction in ChAT+IR that mimicked AIE. To determine if the binge ethanol-induced ChAT decline was unique to the adolescent, Experiment 2 examined ChAT+IR in the basal forebrain following adolescent (P28-P48 and adult (P70-P90 binge ethanol exposure. Twenty-five days later, ChAT expression was reduced in adolescent, but not adult, binge ethanol-exposed animals. In Experiment 3, expression of ChAT and vesicular acetylcholine transporter expression was found to be significantly reduced in the alcoholic basal forebrain relative to moderate drinking controls. Together, these data suggest that adolescent binge ethanol decreases adult ChAT expression, possibly through neuroimmune mechanisms, which might impact adult cognition, arousal, or reward sensitivity.

Persistent Skin Reactions and Aluminium Hypersensitivity Induced by Childhood Vaccines

DEFF Research Database (Denmark)

Salik, Elaha; Løvik, Ida; Andersen, Klaus E

2016-01-01

There is increasing awareness of reactions to vaccination that include persistent skin reactions. We present here a retrospective investigation of long-lasting skin reactions and aluminium hypersensitivity in children, based on medical records and questionnaires sent to the parents. In the 10-year...... period 2003 to 2013 we identified 47 children with persistent skin reactions caused by childhood vaccinations. Most patients had a typical presentation of persisting pruritic subcutaneous nodules. Five children had a complex diagnostic process involving paediatricians, orthopaedics and plastic surgeons...... treated with potent topical corticosteroids and disappeared slowly. Although we advised families to continue vaccination of their children, one-third of parents omitted or postponed further vaccinations....

Low-dose cadmium exposure exacerbates polyhexamethylene guanidine-induced lung fibrosis in mice.

Science.gov (United States)

Kim, Min-Seok; Kim, Sung-Hwan; Jeon, Doin; Kim, Hyeon-Young; Han, Jin-Young; Kim, Bumseok; Lee, Kyuhong

2018-01-01

Cadmium (Cd) is a toxic metal present in tobacco smoke, air, food, and water. Inhalation is an important route of Cd exposure, and lungs are one of the main target organs for metal-induced toxicity. Cd inhalation is associated with an increased risk of pulmonary diseases. The present study aimed to assess the effects of repeated exposure to low-dose Cd in a mouse model of polyhexamethylene guanidine (PHMG)-induced lung fibrosis. Mice were grouped into the following groups: vehicle control (VC), PHMG, cadmium chloride (CdCl 2 ), and PHMG + CdCl 2 . Animals in the PHMG group exhibited increased numbers of total cells and inflammatory cells in the bronchoalveolar lavage fluid (BALF) accompanied by inflammation and fibrosis in lung tissues. These parameters were exacerbated in mice in the PHMG + CdCl 2 group. In contrast, mice in the CdCl 2 group alone displayed only minimal inflammation in pulmonary tissue. Expression of inflammatory cytokines and fibrogenic mediators was significantly elevated in lungs of mice in the PHMG group compared with that VC. Further, expression of these cytokines and mediators was enhanced in pulmonary tissue in mice administered PHMG + CdCl 2 . Data demonstrate that repeated exposure to low-dose Cd may enhance the development of PHMG-induced pulmonary fibrosis.

Adaptive response induced by occupational exposures to ionizing radiation

International Nuclear Information System (INIS)

Barquinero, J.F.; Caballin, M.R.; Barrios, L.; Egozcue, J.; Miro, R.; Ribas, M.

1997-01-01

We have found a significant decreased sensitivity to the cytogenetic effects of both ionizing radiation (IR) (2 Gy of γ rays) and bleomycin (BLM, 0,03 U/ml), in lymphocytes from individuals occupationally exposed to IR when compared with controls. These results suggest that occupational exposures to IR can induce adaptive response that can be detected by a subsequent treatment either by IR or by BLM. When a comparison is made between the cytogenetic effects of both treatments, no correlation was observed at the individual level. On the other hand, the individual frequencies of chromosome aberrations induced by a challenge dose of IR were negatively correlated with the occupationally received doses during the last three years. This correlation was not observed after the challenge treatment of BLM. Moreover, the individual frequencies of chromosome aberrations induced by IR treatment were homogeneous. This is not the case of the individual frequencies of chromatid aberrations induced by BLM, where a great heterogeneity was observed. (authors)

Early embryonic androgen exposure induces transgenerational epigenetic and metabolic changes.

Science.gov (United States)

Xu, Ning; Chua, Angela K; Jiang, Hong; Liu, Ning-Ai; Goodarzi, Mark O

2014-08-01

Androgen excess is a central feature of polycystic ovary syndrome (PCOS), which affects 6% to 10% of young women. Mammals exposed to elevated androgens in utero develop PCOS-like phenotypes in adulthood, suggesting fetal origins of PCOS. We hypothesize that excess androgen exposure during early embryonic development may disturb the epigenome and disrupt metabolism in exposed and unexposed subsequent generations. Zebrafish were used to study the underlying mechanism of fetal origins. Embryos were exposed to androgens (testosterone and dihydrotestosterone) early at 26 to 56 hours post fertilization or late at 21 to 28 days post fertilization. Exposed zebrafish (F0) were grown to adults and crossed to generate unexposed offspring (F1). For both generations, global DNA methylation levels were examined in ovaries using a luminometric methylation assay, and fasting and postprandial blood glucose levels were measured. We found that early but not late androgen exposure induced changes in global methylation and glucose homeostasis in both generations. In general, F0 adult zebrafish exhibited altered global methylation levels in the ovary; F1 zebrafish had global hypomethylation. Fasting blood glucose levels were decreased in F0 but increased in F1; postprandial glucose levels were elevated in both F0 and F1. This androgenized zebrafish study suggests that transient excess androgen exposure during early development can result in transgenerational alterations in the ovarian epigenome and glucose homeostasis. Current data cannot establish a causal relationship between epigenetic changes and altered glucose homeostasis. Whether transgenerational epigenetic alteration induced by prenatal androgen exposure plays a role in the development of PCOS in humans deserves study.

Persistent estrus rat models of polycystic ovary disease: an update.

Science.gov (United States)

Singh, Krishna B

2005-10-01

To critically review published articles on polycystic ovary (PCO) disease in rat models, with a focus on delineating its pathophysiology. Review of the English-language literature published from 1966 to March 2005 was performed through PubMed search. Keywords or phrases used were persistent estrus, chronic anovulation, polycystic ovary, polycystic ovary disease, and polycystic ovary syndrome. Articles were also located via bibliographies of published literature. University Health Sciences Center. Articles on persistent estrus and PCO in rats were selected and reviewed regarding the methods for induction of PCO disease. Changes in the reproductive cycle, ovarian morphology, hormonal parameters, and factors associated with the development of PCO disease in rat models were analyzed. Principal methods for inducing PCO in the rat include exposure to constant light, anterior hypothalamic and amygdaloidal lesions, and the use of androgens, estrogens, antiprogestin, and mifepristone. The validated rat PCO models provide useful information on morphologic and hormonal disturbances in the pathogenesis of chronic anovulation in this condition. These studies have aimed to replicate the morphologic and hormonal characteristics observed in the human PCO syndrome. The implications of these studies to human condition are discussed.

The Differences in Serum Quantitative Specific IgE Levels Induced by Dermatophagoides pteronyssinus, Dermatophagoides farinae and Blomia tropicalis Sensitization in Intermittent and Persistent Allergic Asthma

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Agus Joko Susanto

2018-01-01

Full Text Available Background: house dust mites (HDM are an important inhalant allergen in allergic asthma. However, molecular diagnostic study of specific IgE to HDM allergens has not been done in Indonesia. In addition, the association of quantitative specific IgE measurement with asthma severity has not been investigatedd. This study aimed to investigate the difference of serum quantitative specific IgE levels induced by Dermatophagoides (D. pteronyssinus, D. farinae and Blomia tropicalis sensitization in intermittent and persistent allergic asthma. Methods: this was a cross-sectional study on adult allergic asthma patients who were invited for serum specific IgE testing. This study was a part of a larger study within the Division of Allergy and Immunology, Cipto Mangunkusumo Hospital. Asthma severity was defined based on Global Initiative on Asthma (GINA 2015 criteria and were grouped as intermittent or persistent. Quantitative specific IgE testing was done on blood serum using a multiple allergosorbent test (Polycheck Allergy, Biocheck GmbH, Munster, Germany. The HDM allergens tested were D. pteronyssinus, D. farinae, and Blomia tropicalis. Difference between two groups were analyze using Mann-Whitney test. Results: a total of 87 subjects were enrolled in this study; 69 (79.3% were women. Mean patients’ age was 40, 2 years. Sixty-three (72.4% subjects had asthma and allergic rhinitis. Fifty-eight (66.7% subjects were classified as persistent asthma. The prevalence of sensitization was 62.1% for D. farinae, 51.7% for D. pteronyssinus, and 48.3% for Blomia tropicalis. The median of specific IgE levels were significantly higher in persistent asthma compares to intermittent asthma induced by D. farinae (median 1.30 vs. 0.0 kU/L; p=0.024 and B. tropicalis (median 0.57 vs. 0.0 kU/L; p=0.015 sensitization. Level of Specific IgE  D. pteronyssinus was also to be higher in persistent asthma than the level measured in intermittent asthma (0.67 vs. 0.00 kU/L; p=0

Persistent depletion of plasma gelsolin (pGSN) after exposure of mice to heavy silicon ions

Science.gov (United States)

Rithidech, Kanokporn Noy; Reungpatthanaphong, Paiboon; Tungjai, Montree; Jangiam, Witawat; Honikel, Louise; Whorton, Elbert B.

2018-05-01

Little is known about plasma proteins that can be used as biomarkers for early and late responses to radiation. The purpose of this study was to determine a link between depletion of plasma gelsolin (pGSN) and cell-death as well as inflammatory responses in the lung (one of the tissues known to be radiosensitive) of the same exposed CBA/CaJ mice after exposure to heavy silicon (28Si) ions. To prevent the development of multiple organ dysfunctions, pGSN (an important component of the extracellular actin-scavenging system) is responsible for the removal of actin that is released into the circulation during inflammation and from dying cells. We evaluated the levels of pGSN in plasma collected from groups of mice (5 mice in each) at 1 week (wk) and 1 month (1 mo) after exposure whole body to different doses of 28Si ions, i.e. 0, 0.1, 0.25, or 0.5 Gy (2 fractionated exposures, 15 days apart that totaled each selected dose). In the same mouse, the measurements of pGSN levels were coupled with the quantitation of injuries in the lung, determined by (a) the levels of cleaved poly (ADP-ribose) polymerase (cleaved-PARP), a marker of apoptotic cell-death, (b) the levels of activated nuclear factor-kappa B (NF-κB) and selected cytokines, i.e. tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6, from tissue-lysates of the lung. Further, the ratio of neutrophils and lymphocytes (N/L) was determined in the same mouse. Our data indicated: (i) the magnitude of pGSN depletion was dependent to radiation dose at both harvest times, (ii) a persistent depletion of pGSN up to 1 mo post-exposure to 0.25 or 0.5 Gy of 28Si ions, (iii) an inverse-correlation between pGSN depletion and increased levels of cleaved-PARP, including activated NF-κB/pro-inflammatory cytokines in the lung, and (iv) at both harvest times, statistically significant increases in the N/L ratio in groups of mice exposed to 0.5 Gy only. Our findings suggested that depletion in pGSN levels

Amorphous nanosilicas induce consumptive coagulopathy after systemic exposure

International Nuclear Information System (INIS)

Nabeshi, Hiromi; Yoshikawa, Tomoaki; Matsuyama, Keigo; Nakazato, Yasutaro; Arimori, Akihiro; Isobe, Masaaki; Tochigi, Saeko; Kondoh, Sayuri; Hirai, Toshiro; Akase, Takanori; Yamashita, Takuya; Yamashita, Kohei; Yoshida, Tokuyuki; Itoh, Norio; Nagano, Kazuya; Abe, Yasuhiro; Yoshioka, Yasuo; Kamada, Haruhiko; Imazawa, Takayoshi; Kondoh, Masuo

2012-01-01

We previously reported that well-dispersed amorphous nanosilicas with particle size 70 nm (nSP70) penetrate skin and produce systemic exposure after topical application. These findings underscore the need to examine biological effects after systemic exposure to nanosilicas. The present study was designed to examine the biological effects. BALB/c mice were intravenously injected with amorphous nanosilicas of sizes 70, 100, 300, 1000 nm and then assessed for survival, blood biochemistry, and coagulation. As a result, injection of nSP70 caused fatal toxicity, liver damage, and platelet depletion, suggesting that nSP70 caused consumptive coagulopathy. Additionally, nSP70 exerts procoagulant activity in vitro associated with an increase in specific surface area, which increases as diameter reduces. In contrast, nSP70-mediated procoagulant activity was absent in factor XII-deficient plasma. Collectively, we revealed that interaction between nSP70 and intrinsic coagulation factors such as factor XII, were deeply related to nSP70-induced harmful effects. In other words, it is suggested that if interaction between nSP70 and coagulation factors can be suppressed, nSP70-induced harmful effects may be avoided. These results would provide useful information for ensuring the safety of nanomaterials (NMs) and open new frontiers in biological fields by the use of NMs. (paper)

Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

Directory of Open Access Journals (Sweden)

Chia-Yu Chang

2015-01-01

Full Text Available Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM and open field test (OFT in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST and forced swimming test (FST in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

Does acute tobacco smoking prevent cue-induced craving?

Science.gov (United States)

Schlagintweit, Hera E; Barrett, Sean P

2016-05-01

Smoking cessation aids appear to be limited in their ability to prevent craving triggered by exposure to smoking-associated stimuli; however, the extent to which cue-induced cravings persist following denicotinized or nicotine-containing tobacco smoking is not known. Thirty (17 male) ⩾12-hour abstinent dependent smokers completed two sessions during which they smoked a nicotine-containing or denicotinized cigarette. Instructions regarding the nicotine content of the cigarette varied across sessions, and all participants were exposed to a neutral cue followed by a smoking cue after cigarette consumption. Craving was assessed before and after cigarette consumption and cue exposure. Reduced intentions to smoke were associated with both nicotine expectancy (pSmoking-associated stimuli increased craving regardless of nicotine expectancy or administration (p-valuessmoking, neither smoking-related nicotine administration nor expectation prevents increases in craving following exposure to smoking-associated stimuli. These findings suggest that cue-induced craving may be resistant to various pharmacological and psychological interventions. © The Author(s) 2016.

Prenatal exposure to persistent organochlorine pollutants is associated with high insulin levels in 5-year-old girls.

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Tang-Péronard, Jeanett L; Heitmann, Berit L; Jensen, Tina K; Vinggaard, Anne M; Madsbad, Sten; Steuerwald, Ulrike; Grandjean, Philippe; Weihe, Pál; Nielsen, Flemming; Andersen, Helle R

2015-10-01

Several persistent organochlorine pollutants (POPs) possess endocrine disrupting abilities, thereby potentially leading to an increased risk of obesity and metabolic diseases, especially if the exposure occurs during prenatal life. We have previously found associations between prenatal POP exposures and increased BMI, waist circumference and change in BMI from 5 to 7 years of age, though only among girls with overweight mothers. In the same birth cohort, we investigated whether prenatal POP exposure was associated with serum concentrations of insulin and leptin among 5-year-old children, thus possibly mediating the association with overweight and obesity at 7 years of age. The analyses were based on a prospective Faroese Birth Cohort (n=656), recruited between 1997 and 2000. Major POPs, polychlorinated biphenyls (PCBs), p,p'-dichlorodiphenyldichloroethylene (DDE) and hexachlorobenzene (HCB), were measured in maternal pregnancy serum and breast milk. Children were followed-up at the age of 5 years where a non-fasting blood sample was drawn; 520 children (273 boys and 247 girls) had adequate serum amounts available for biomarker analyses by Luminex® technology. Insulin and leptin concentrations were transformed from continuous to binary variables, using the 75th percentile as a cut-off point. Multiple logistic regression was used to investigate associations between prenatal POP exposures and non-fasting serum concentrations of insulin and leptin at age 5 while taking into account confounders. Girls with highest prenatal POP exposure were more likely to have high non-fasting insulin levels (PCBs 4th quartile: OR=3.71; 95% CI: 1.36, 10.01. DDE 4th quartile: OR=2.75; 95% CI: 1.09, 6.90. HCB 4th quartile: OR=1.98; 95% CI: 1.06, 3.69) compared to girls in the lowest quartile. No significant associations were observed with leptin, or among boys. A mediating effect of insulin or leptin on later obesity was not observed. These findings suggest, that for girls, prenatal

Whole body exposure of mice to secondhand smoke induces dose-dependent and persistent promutagenic DNA adducts in the lung

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Kim, Sang-In; Arlt, Volker M.; Yoon, Jae-In; Cole, Kathleen J.; Pfeifer, Gerd P.; Phillips, David H.; Besaratinia, Ahmad

2011-01-01

Secondhand smoke (SHS) exposure is a known risk factor for lung cancer in lifelong nonsmokers. However, the underlying mechanism of action of SHS in lung carcinogenesis remains elusive. We have investigated, using the 32 P-postlabeling assay, the genotoxic potential of SHS in vivo by determining the formation and kinetics of repair of DNA adducts in the lungs of mice exposed whole body to SHS for 2 or 4 months (5 h/day, 5 days/week), and an ensuing one-month recovery period. We demonstrate that exposure of mice to SHS elicits a significant genotoxic response as reflected by the elevation of DNA adduct levels in the lungs of SHS-exposed animals. The increases in DNA adduct levels in the lungs of SHS-exposed mice are dose-dependent as they are related to the intensity and duration of SHS exposure. After one month of recovery in clean air, the levels of lung DNA adducts in the mice exposed for 4 months remain significantly higher than those in the mice exposed for 2 months (P < 0.0005), levels in both groups being significantly elevated relative to controls (P < 0.00001). Our experimental findings accord with the epidemiological data showing that exposure to smoke-derived carcinogens is a risk factor for lung cancer; not only does the magnitude of risk depend upon carcinogen dose, but it also becomes more irreversible with prolonged exposure. The confirmation of epidemiologic data by our experimental findings is of significance because it strengthens the case for the etiologic involvement of SHS in nonsmokers' lung cancer. Identifying the etiologic factors involved in the pathogenesis of lung cancer can help define future strategies for prevention, early detection, and treatment of this highly lethal malignancy.

Cryotherapy-Induced Persistent Vasoconstriction After Cutaneous Cooling: Hysteresis Between Skin Temperature and Blood Perfusion

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Khoshnevis, Sepideh; Craik, Natalie K.; Matthew Brothers, R.; Diller, Kenneth R.

2016-01-01

The goal of this study was to investigate the persistence of cold-induced vasoconstriction following cessation of active skin-surface cooling. This study demonstrates a hysteresis effect that develops between skin temperature and blood perfusion during the cooling and subsequent rewarming period. An Arctic Ice cryotherapy unit (CTU) was applied to the knee region of six healthy subjects for 60 min of active cooling followed by 120 min of passive rewarming. Multiple laser Doppler flowmetry perfusion probes were used to measure skin blood flow (expressed as cutaneous vascular conductance (CVC)). Skin surface cooling produced a significant reduction in CVC (P cryotherapy. PMID:26632263

Persistence of a hyperthermic sign-reversal during nitrous oxide inhalation despite cue-exposure treatment with and without a drug-onset cue.

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Kaiyala, Karl J; Woods, Stephen C; Ramsay, Douglas S

2014-01-01

We asked whether chronic tolerance and the hyperthermic sign-reversal induced by repeated 60% N 2 O exposures could be extinguished using a cue-exposure paradigm. Rats received 18 N 2 O administrations in a total calorimetry system that simultaneously measures core temperature (Tc), metabolic heat production (HP), and body heat loss (HL). Each exposure entailed a 2-h baseline period followed by a 1.5-h N 2 O exposure. The 18 drug exposures induced a robust intra-administration hyperthermia in which the initial hypothermic effect of N 2 O inverted to a significant hyperthermic sign-reversal during N 2 O inhalation due primarily to an acquired robust increase in HP. The rats were then randomized to one of three extinction procedures (n=8/procedure) over a 20-d interval: 1) a N 2 O-abstinent home-cage group (HC) that received only the usual animal care; 2) a cue-exposure group (CEXP) in which the animals were placed in the calorimeter 8 times but received no N 2 O; and 3) a drug-onset-cue group (DOC) in which animals received a brief N 2 O exposure in the calorimeter that mimicked the first 3 min of an actual 60% N 2 O trial. Following the extinction sessions, all rats received a 60% N 2 O test trial and Tc, HP and HL were assessed. The hyperthermic sign-reversal remained fully intact during the test trial, with no significant differences observed among groups in any post-baseline change in any thermal outcome. These data suggest that cue exposure may not be an efficacious strategy to reduce sign-reversals that develop with chronic drug use.

Burden of higher lead exposure in African-Americans starts in utero and persists into childhood.

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Cassidy-Bushrow, Andrea E; Sitarik, Alexandra R; Havstad, Suzanne; Park, Sung Kyun; Bielak, Lawrence F; Austin, Christine; Johnson, Christine Cole; Arora, Manish

2017-11-01

of lead exposure is vertically transmitted (i.e., mother-to-child) to African-American children before they are born and persists into early childhood. Our results suggest that testing women for lead during pregnancy (or in pre-conception planning), may be needed to identify the risk to their future offspring, particularly for African-American women. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect decomposition in the presence of an exposure-induced mediator-outcome confounder

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VanderWeele, Tyler J.; Vansteelandt, Stijn; Robins, James M.

2014-01-01

Methods from causal mediation analysis have generalized the traditional approach to direct and indirect effects in the epidemiologic and social science literature by allowing for interaction and non-linearities. However, the methods from the causal inference literature have themselves been subject to a major limitation in that the so-called natural direct and indirect effects that are employed are not identified from data whenever there is a variable that is affected by the exposure, which also confounds the relationship between the mediator and the outcome. In this paper we describe three alternative approaches to effect decomposition that give quantities that can be interpreted as direct and indirect effects, and that can be identified from data even in the presence of an exposure-induced mediator-outcome confounder. We describe a simple weighting-based estimation method for each of these three approaches, illustrated with data from perinatal epidemiology. The methods described here can shed insight into pathways and questions of mediation even when an exposure-induced mediator-outcome confounder is present. PMID:24487213

Alkylation Induced DNA Repair and Mutagenesis in Escherichia coli.

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1987-11-23

unrepaired 3-methyladenine in DNA 29 2.4.1 Cytotoxic effects of persisting m3A in DNA 30 2.4.2 Mutagenic bypass synthesis of depurinat ,d DNA 30 3 CONCLUDING...induced by a single exposure to the ca’rcinogen N- methyl-N- nitrosourea (MNU) due to activation of the malignant Ha-ras-i locus. Analysis of the induced...ing CO:A uolymerase I for repair synthesis . Since DNA polymerase I would be required to complete repair after the in~uial activity of TagII, we tested

Predictive features of persistent activity emergence in regular spiking and intrinsic bursting model neurons.

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Kyriaki Sidiropoulou

Full Text Available Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC, which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS and an intrinsic bursting (IB model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli, in both model cells. In addition, the action potential (AP latency and the first few inter-spike-intervals of the neuronal response can be used to reliably detect inducing vs. non-inducing inputs, suggesting a potential mechanism by which downstream neurons can rapidly decode the upcoming emergence of persistent activity. While the two model neurons did not differ in the coding features of persistent activity emergence, the properties of persistent activity, such as the firing pattern and the duration of temporally-restricted persistent activity were distinct. Collectively, our results pinpoint to specific features of the neuronal response to a given

Histopathological effects of chlorpyrifos on the gills, hepatopancreas and gonads of the freshwater crab Zilchiopsis collastinensis. Persistent effects after exposure.

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Negro, C L; Collins, P

2017-06-01

Sublethal effects of the pesticide chlorpyrifos were evaluated in the crab Zilchiopsis collastinensis (Decapoda, Trichodactylidae). Crabs were exposed to high concentrations of chlorpyrifos at the beginning of the experiment and controlled dilution, under natural light and temperature conditions. A control and three concentrations (22.4, 41.25 and 61.4µg chlorpyrifos L -1 ) were evaluated in triplicate. Nine crabs per concentration and day were used. The gills, hepatopancreas and ovaries were sampled before pesticide exposure (day 0) and 8, 15 and 22 days later, when concentrations were diluted and below the detection limits. The histopathological effects and their variations in time were observed and quantified. In gills, hyperplasias were observed in several cases, mainly in crabs exposed to chlorpyrifos. The number of collapsed lamellae and the number of affected lamellae quickly increased in exposed crabs, as effects were observed on day 8 and remained until day 22. In hepatopancreas there was an increase in the number of F and B -cells and affected tubules, especially after 22 days of exposure (p<0.05). In ovaries, there were no effects on gonadosomatic indexes or oocyte volume, but there was a significant increase in the atretic oocyte proportion related to pesticide exposure (p<0.05). The histopathological effects on the gills, hepatopancreas and ovaries were observed after exposure and persist even after dilution, and might be related to earlier exposures. Thus, these histopathological effects might be used as pesticide biomarkers even after the pesticide is not detected by chemical methods. Copyright © 2017 Elsevier Inc. All rights reserved.

NH125 kills methicillin-resistant Staphylococcus aureus persisters by lipid bilayer disruption.

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Kim, Wooseong; Fricke, Nico; Conery, Annie L; Fuchs, Beth Burgwyn; Rajamuthiah, Rajmohan; Jayamani, Elamparithi; Vlahovska, Petia M; Ausubel, Frederick M; Mylonakis, Eleftherios

2016-01-01

NH125, a known WalK inhibitor kills MRSA persisters. However, its precise mode of action is still unknown. The mode of action of NH125 was investigated by comparing its spectrum of antimicrobial activity and its effects on membrane permeability and giant unilamellar vesicles (GUVs) with walrycin B, a WalR inhibitor and benzyldimethylhexadecylammonium chloride (16-BAC), a cationic surfactant. NH125 killed persister cells of a variety of Staphylococcus aureus strains. Similar to 16-BAC, NH125 killed MRSA persisters by inducing rapid membrane permeabilization and caused the rupture of GUVs, whereas walrycin B did not kill MRSA persisters or induce membrane permeabilization and did not affect GUVs. NH125 kills MRSA persisters by interacting with and disrupting membranes in a detergent-like manner.

Persistent attenuation and enhancement of the earthworm main muscle contraction generator response induced by repeated stimulation of a peripheral neuron

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Y.C. Chang

1998-10-01

Full Text Available Responses evoked in the earthworm, Amynthas hawayanus, main muscle contraction generator M-2 (postsynaptic mechanical-stimulus-sensitive neuron by threshold mechanical stimuli in 2-s intertrial intervals (ITI were used as the control or unconditioned responses (UR. Their attenuation induced by decreasing these intervals in non-associative conditioning and their enhancement induced by associating the unconditioned stimuli (US to a train of short (0.1 s hyperpolarizing electrical substitutive conditioning stimuli (SCS in the Peri-Kästchen (PK neuron were measured in four parameters, i.e., peak numbers (N and amplitude (averaged from 120 responses, sum of these amplitudes (SAMP and the highest peak amplitude (V over a period of 4 min. Persistent attenuation similar to habituation was induced by decreasing the control ITI to 0.5 s and 2.0 s in non-associative conditioning within less than 4 min. Dishabituation was induced by randomly pairing one of these habituated US to an electrical stimulus in the PK neuron. All four parameters of the UR were enhanced by forward (SCS-US, but not backward (US-SCS, association of the US with 25, 100 and 250-Hz trains of SCS with 40-ms interstimulus intervals (ISI for 4 min and persisted for another 4 min after turning off the SCS. The enhancement of these parameters was proportional to the SCS frequencies in the train. No UR was evoked by the SCS when the US was turned off after 4 min of classical conditioning.

Dose-responsiveness and persistence of microRNA expression alterations induced by cigarette smoke in mouse lung

International Nuclear Information System (INIS)

Izzotti, Alberto; Larghero, Patrizia; Longobardi, Mariagrazia; Cartiglia, Cristina; Camoirano, Anna; Steele, Vernon E.; De Flora, Silvio

2011-01-01

Our previous studies demonstrated that exposure to cigarette smoke (CS), either mainstream or environmental, results in a remarkable downregulation of microRNA expression in the lung of both mice and rats. The goals of the present study were to evaluate the dose responsiveness to CS and the persistence of microRNA alterations after smoking cessation. ICR (CD-1) neonatal mice were exposed whole-body to mainstream CS, at the doses of 119, 292, 438, and 631 mg/m 3 of total particulate matter. Exposure started within 12 h after birth and continued daily for 4 weeks. The levels of bulky DNA adducts and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) were measured by 32 P postlabeling procedures, and the expression of 697 mouse microRNAs was analyzed by microarray. The highest CS dose was lethal. Exposure to CS caused a dose-dependent increase of DNA alterations. DNA adducts and, even more sharply, 8-oxodGuo were reverted 1 and 4 weeks after smoking cessation. Exposure to CS resulted in an evident dysregulation of microRNA expression profiles, mainly in the sense of downregulation. The two lowest doses were not particularly effective, while the highest nonlethal dose produced extensive microRNA alterations. The expression of most downregulated microRNAs, including among others 7 members of the let-7 family, was restored one week after smoking cessation. However, the recovery was incomplete for a limited array of microRNAs, including mir-34b, mir-345, mir-421, mir-450b, mir-466, and mir-469. Thus, it appears that microRNAs mainly behave as biomarkers of effect and that exposure to high-dose, lasting for an adequate period of time, is needed to trigger the CS-related carcinogenesis process in the experimental animal model used.

Radiation-induced irreparable heritable changes in cells promoting their tumoral transformation

International Nuclear Information System (INIS)

Kuzin, A.M.; Vagabova, M.Eh.; Yurov, S.S.

1988-01-01

In experiments with model plant tumors (Kalanchoe-ti plasmid Agrobat. tumefaciens C-58D) it was shown that exposure of the recepient plant to low-level γ-radiation of Gy induced changes in cells that were not repaired over two months promoting tumoral transformations in them. Those changes were shown to persist in the offspring of the exposed somatic cells

Impairment induced by chronic occupational cadmium exposure during brazing process

International Nuclear Information System (INIS)

Anwar, S.M.; Aly, M.M.

2002-01-01

Cadmium (CD) is considered a metal of the 20 th century to which all inhabitants of develop societies are exposed. Long-term occupational and environmental exposure to CD often results in renal dysfunction as the kidney is considered the critical target organ. The aim of this work was to evalutate both resporatory and renal manifestations induced by occupational exposure to CD compounds during brazing process, and suggesting a protocol for prevention and control for CD- induced health effects. This study was conducted on 20 males occupationally exposed workers. They are divided into two groups: Group-1 included (10) exposed smokers and group-2 included (10) exposed non-smokers. Results of both groups were compared with those of 10 healthy age and sex matched non-smokers. All subjects were subjected to detailed history taking and laboratory investigations including blood and urinary CD, liver profile (SGOT, SGPT and alkline phosphates), kindey function tests (blood urea, creatinine and urinary beta 2 - microglobulin). The level of Cd in the atmosphere of the work plase air was also assessed to detect the degree of exposure as it was about 6 times greater than thesave level (1 mu /m 3 ). (1) This study demonstrated elevation levels of blood CD, urea, creatinine and urinary CD and beta 2 -microglobulin for both exposed worker groups than the controls. In additions no appreciable were noted for liver function tests, although the levels fell within normal range

Effects of dopamine D2 receptor (DRD2) and transporter (SLC6A3) polymorphisms on smoking cue-induced cigarette craving among African-American smokers.

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Erblich, J; Lerman, C; Self, D W; Diaz, G A; Bovbjerg, D H

2005-04-01

Cue-induced craving for addictive substances has long been known to contribute to the problem of persistent addiction in humans. Research in animals over the past decade has solidly established the central role of dopamine in cue-induced craving for addictive substances, including nicotine. Analogous studies in humans, however, are lacking, especially among African-American smokers, who have lower quit rates than Caucasian smokers. Based on the animal literature, the study's objective was to test the hypothesis that smokers carrying specific variants in dopamine-related genes previously associated with risk for addictive behaviors would exhibit heightened levels of cigarette craving following laboratory exposure to cues. To this end, cigarette craving was induced in healthy African-American smokers (n=88) through laboratory exposure to smoking cues. Smokers carrying either the DRD2 (D2 dopamine receptor gene) TaqI A1 RFLP or the SLC6A3 (dopamine transporter gene) 9-repeat VNTR polymorphisms had stronger cue-induced cravings than noncarriers (Ps cue-induced craving in humans, and suggest a possible genetic risk factor for persistent smoking behavior in African-American smokers.

Modelling the exposure induced by a criticality excursion in solution

International Nuclear Information System (INIS)

Kerouanton, David; Delgovea, Laure; Castaniera, Eric; Raimondia, Nicolas

2008-01-01

During a criticality accident, significant exposure is generated by 4 radiation origins: radiation directly induced by fissions (prompt neutrons and gamma), gamma radiations induced by (n, γ) reactions in crossed materials (capture gamma) and gamma radiations emitted by fission products. Due to boiling of the solution, a fraction of fissions products is airborne and is deposited in the ventilation shafts. 5.10 18 fissions are considered in a dissolution tank containing uranyl nitrate by using the deterministic ATTILA radiation transport code. Instantaneous radiations rates are evaluated as a function of the distance and compared with data available in the literature. Dose rates induced behind various shielding materials such as concrete, steel or glass are assessed. In all cases, relative contributions of prompt or capture radiations is detailed. (author)

Assessment of the mode of action for hexavalent chromium-induced lung cancer following inhalation exposures

International Nuclear Information System (INIS)

Proctor, Deborah M.; Suh, Mina; Campleman, Sharan L.; Thompson, Chad M.

2014-01-01

Highlights: • No published or well recognized MOA for Cr(VI)-induced lung tumors exists. • MOA analysis for Cr(VI)-induced lung cancer was conducted to inform risk assessment. • Cr(VI) epidemiologic, toxicokinetic, toxicological, mechanistic data were evaluated. • Weight of evidence does not support a mutagenic MOA for Cr(VI)-induced lung cancer. • Non-linear approaches should be considered for evaluating Cr(VI) lung cancer risk. - Abstract: Inhalation of hexavalent chromium [Cr(VI)] is associated with increased lung cancer risk among workers in several industries, most notably chromate production workers exposed to high concentrations of Cr(VI) (≥100 μg/m 3 ), for which clear exposure–response relationships and respiratory irritation and tissue damage have been reported. Data from this industry are used to assess lung cancer risk associated with environmental and current occupational exposures, occurring at concentrations that are significantly lower. There is considerable uncertainty in the low dose extrapolation of historical occupational epidemiology data to assess risk at current exposures because no published or well recognized mode of action (MOA) for Cr(VI)-induced lung tumors exists. We conducted a MOA analysis for Cr(VI)-induced lung cancer evaluating toxicokinetic and toxicological data in humans and rodents and mechanistic data to assess plausibility, dose–response, and temporal concordance for potential MOAs. Toxicokinetic data support that extracellular reduction of Cr(VI), which limits intracellular absorption of Cr(VI) and Cr(VI)-induced toxicity, can be overwhelmed at high exposure levels. In vivo genotoxicity and mutagenicity data are mostly negative and do not support a mutagenic MOA. Further, both chronic bioassays and the epidemiologic literature support that lung cancer occurs at exposures that cause tissue damage. Based on this MOA analysis, the overall weight of evidence supports a MOA involving deposition and accumulation

Adaptive response induced by occupational exposures to ionizing radiation

International Nuclear Information System (INIS)

Barquinero, J.F.; Caballin, M.R.; Barrios, L.; Murtra, P.; Egozcue, J.; Miro, R.; Ribas, M.

1997-01-01

We have found a significant decreased sensitivity to the cytogenetic effects of ionizing radiation (IR) and bleomycin (BLM) in lymphocytes from individuals occupationally exposed to IR when compared with a control population. These results suggest that occupational exposures to IR can induce adaptive response that can be detected by a subsequent treatment by IR or by BLM. However, no correlation between the results obtained with both treatments was observed. A great heterogeneity in the frequencies of chromatid aberrations induced by BLM was observed. The study of the influence of different harvesting times showed that there was no correlation with the frequencies of chromatid breaks. Our results indicate that the use of BLM to detect adaptive response has several difficulties at the individual level. (author)

Persistence of smoking-induced dysregulation of miRNA expression in the small airway epithelium despite smoking cessation.

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Guoqing Wang

Full Text Available Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD and lung cancer remains significantly higher compared to healthy nonsmokers. Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE, we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 9 healthy nonsmokers and 10 healthy smokers, before and after they quit smoking for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy nonsmokers (p1.5, with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway being the top identified enriched pathway of the target genes of the persistent dysregulated miRNAs. In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammatory diseases or lung cancer, it is likely that persistent smoking-related changes in SAE miRNAs play a role in the subsequent development of these disorders.

PRENATAL ETHANOL EXPOSURE LEADS TO GREATER ETHANOL-INDUCED APPETITIVE REINFORCEMENT

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Pautassi, Ricardo M.; Nizhnikov, Michael E.; Spear, Norman E.; Molina, Juan C.

2012-01-01

Prenatal ethanol significantly heightens later alcohol consumption, but the mechanisms that underlie this phenomenon are poorly understood. Little is known about the basis of this effect of prenatal ethanol on the sensitivity to ethanol’s reinforcing effects. One possibility is that prenatal ethanol exposure makes subjects more sensitive to the appetitive effects of ethanol or less sensitive to ethanol’s aversive consequences. The present study assessed ethanol-induced second-order conditioned place preference (CPP) and aversion and ethanol-induced conditioned taste aversion (CTA) in infant rats prenatally exposed to ethanol (2.0 g/kg) or vehicle (water) or left untreated. The involvement of the κ opioid receptor system in ethanol-induced CTA was also explored. When place conditioning occurred during the ascending limb of the blood-ethanol curve (Experiment 1), the pups exposed to ethanol in utero exhibited greater CPP than untreated controls, with a shift to the right of the dose-response curve. Conditioning during a later phase of intoxication (30–45 min post-administration; Experiment 2) resulted in place aversion in control pups exposed to vehicle during late gestation but not in pups that were exposed to ethanol in utero. Ethanol induced a reliable and similar CTA (Experiment 3) in the pups treated with vehicle or ethanol during gestation, and CTA was insensitive to κ antagonism. These results suggest that brief exposure to a moderate ethanol dose during late gestation promotes ethanol-mediated reinforcement and alters the expression of conditioned aversion by ethanol. This shift in the motivational reactivity to ethanol may be an underlying basis of the effect of prenatal ethanol on later ethanol acceptance. PMID:22698870

Persistent Hiccups Following Stapedectomy

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Aidonis I

2010-10-01

Full Text Available Objective: We report a case of a 37 year-old man who developed persistent hiccups after elective stapedectomy. Method and Results: The diagnostic approach is discussed as well as the non-pharmacologic and pharmacologic treatments and overall management. The aim is to stress that there is a variety of potential factors that can induce hiccups perioperatively and in cases like this a step by step approach must be taken. Conclusion: Persistent hiccups are very rare following stapedectomy, control of them is crucial for the successful outcome. The trigger may be more than one factors and the good response to treatment may be due to dealing successfully with more than one thing.

Persistent increased PKMζ in long-term and remote spatial memory.

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Hsieh, Changchi; Tsokas, Panayiotis; Serrano, Peter; Hernández, A Iván; Tian, Dezhi; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

2017-02-01

PKMζ is an autonomously active PKC isoform that is thought to maintain both LTP and long-term memory. Whereas persistent increases in PKMζ protein sustain the kinase's action in LTP, the molecular mechanism for the persistent action of PKMζ during long-term memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1day to 1month after training. Therefore, if the mechanisms of PKMζ's persistent action in LTP maintenance and long-term memory were similar, persistent increases in PKMζ would last for the duration of the memory, far longer than most other learning-induced gene products. Here we find that spatial conditioning by aversive active place avoidance or appetitive radial arm maze induces PKMζ increases in dorsal hippocampus that persist from 1day to 1month, coinciding with the strength and duration of memory retention. Suppressing the increase by intrahippocampal injections of PKMζ-antisense oligodeoxynucleotides prevents the formation of long-term memory. Thus, similar to LTP maintenance, the persistent increase in the amount of autonomously active PKMζ sustains the kinase's action during long-term and remote spatial memory maintenance. Copyright © 2016. Published by Elsevier Inc.

Exercise Prevents Memory Impairment Induced by Arsenic Exposure in Mice: Implication of Hippocampal BDNF and CREB.

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Bao-Fei Sun

Full Text Available High concentrations of arsenic, which can be occasionally found in drinking water, have been recognized as a global health problem. Exposure to arsenic can disrupt spatial memory; however, the underlying mechanism remains unclear. In the present study, we tested whether exercise could interfere with the effect of arsenic exposure on the long-term memory (LTM of object recognition in mice. Arsenic (0, 1, 3, and 10 mg/ kg, i.g. was administered daily for 12 weeks. We found that arsenic at dosages of 1, 3, and 10 mg/kg decreased body weight and increased the arsenic content in the brain. The object recognition LTM (tested 24 h after training was disrupted by 3 mg/ kg and 10 mg/ kg, but not 1 mg/ kg arsenic exposure. Swimming exercise also prevented LTM impairment induced by 3 mg/ kg, but not with 10 mg/ kg, of arsenic exposure. The expression of brain-derived neurotrophic factor (BDNF and phosphorylated cAMP-response element binding protein (pCREB in the CA1 and dentate gyrus areas (DG of the dorsal hippocampus were decreased by 3 mg/ kg and 10 mg/ kg, but not by 1 mg/ kg, of arsenic exposure. The decrease in BDNF and pCREB in the CA1 and DG induced by 3 mg/ kg, but not 10 mg/ kg, of arsenic exposure were prevented by swimming exercise. Arsenic exposure did not affect the total CREB expression in the CA1 or DG. Taken together, these results indicated that swimming exercise prevented the impairment of object recognition LTM induced by arsenic exposure, which may be mediated by BDNF and CREB in the dorsal hippocampus.

Arsenic induced apoptosis in rat liver following repeated 60 days exposure

International Nuclear Information System (INIS)

Bashir, Somia; Sharma, Yukti; Irshad, M.; Nag, T.C.; Tiwari, Monica; Kabra, M.; Dogra, T.D.

2006-01-01

Background: Accumulation of the wide spread environmental toxin arsenic in liver results in hepatotoxcity. Exposure to arsenite and other arsenicals has been previously shown to induce apoptosis in certain tumor cell lines at low (1-3 μM) concentration. Aim: The present study was focused to elucidate the role of free radicals in arsenic toxicity and to investigate the nature of in vivo sodium arsenite induced cell death in liver. Methods: Male wistar rats were exposed to arsenite at three different doses of 0.05, 2.5 and 5 mg/l for 60 days. Oxidative stress in liver was measured by estimating pro-oxidant and antioxidant activity in liver. Histopathological examination of liver was carried out by light and transmission electron microscopy. Analysis of DNA fragmentation by gel electrophoresis was used to identify apoptosis after the exposure. Terminal deoxy-nucleotidyl transferase mediated dUTP Nick end-labeling (TUNEL) assay was used to qualify and quantify apoptosis. Results: A significant increase in cytochrome-P450 and lipid peroxidation accompanied with a significant alteration in the activity of many of the antioxidants was observed, all suggestive of arsenic induced oxidative stress. Histopathological examination under light and transmission electron microscope suggested a combination of ongoing necrosis and apoptosis. DNA-TUNEL showed an increase in apoptotic cells in liver. Agarose gel electrophoresis of DNA of hepatocytes resulted in a characteristic ladder pattern. Conclusion: Chronic arsenic administration induces a specific pattern of apoptosis called post-mitotic apoptosis

Perfluorooctanoic acid exposure induces endoplasmic reticulum stress in the liver and its effects are ameliorated by 4-phenylbutyrate.

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Yan, Shengmin; Zhang, Hongxia; Wang, Jianshe; Zheng, Fei; Dai, Jiayin

2015-10-01

Perfluoroalkyl acids (PFAAs) are a group of widely used anthropogenic compounds. As one of the most dominant PFAAs, perfluorooctanoic acid (PFOA) has been suggested to induce hepatotoxicity and several other toxicological effects. However, details on the mechanisms for PFOA-induced hepatotoxicity still need to be elucidated. In this study, we observed the occurrence of endoplasmic reticulum (ER) stress in mouse livers and HepG2 cells after PFOA exposure using several familiar markers for the unfolded protein response (UPR). ER stress in HepG2 cells after PFOA exposure was not significantly influenced by autophagy inhibition or stimulation. The antioxidant defense system was significantly disturbed in mouse livers after PFOA exposure, and reactive oxygen species (ROS) were increased in cells exposed to PFOA for 24 h. However, N-acetyl-L-cysteine (NAC) pretreatment did not satisfactorily alleviate the UPR in cells exposed to PFOA even though the increase of ROS was less evident. Furthermore, exposure of HepG2 cells to PFOA in the presence of sodium 4-phenylbutyrate (4-PBA), a chemical chaperone and ER stress inhibitor, suggested that 4-PBA alleviated the UPR and autophagosome accumulation induced by PFOA in cells. In addition, several toxicological effects attributed to PFOA exposure, including cell cycle arrest, proteolytic activity impairment, and neutral lipid accumulation, were also improved by 4-PBA cotreatment in cells. In vivo study demonstrated that PFOA-induced lipid metabolism perturbation and liver injury were partially ameliorated by 4-PBA in mice after 28 days of exposure. These findings demonstrated that PFOA-induced ER stress leading to UPR might play an important role in PFOA-induced hepatotoxic effects, and chemical chaperone 4-PBA could ameliorate the effects. Copyright © 2015. Published by Elsevier Inc.

Early life exposure to a rodent carcinogen propiconazole fungicide induces oxidative stress and hepatocarcinogenesis in medaka fish

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Tu, Tzu-Yi; Hong, Chwan-Yang [Department of Agricultural Chemistry, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan (China); Sasado, Takao [Laboratory of Bioresources, National Institute for Basic Biology, Okazaki (Japan); Kashiwada, Shosaku [Research Center for Life and Environmental Sciences, Department of Life Sciences, the Toyo University, Gunma (Japan); Chen, Pei-Jen, E-mail: chenpj@ntu.edu.tw [Department of Agricultural Chemistry, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan (China)

2016-01-15

Highlights: • Propiconazole initiates ROS-induced oxidative stress and damage in medaka fish. • Early life exposure to propiconazole increases incidence of hepatocarcionogensis in p53{sup −/−} medaka. • Oxidative stress and CYP induction involved in p53 regulation are key events in propiconazole-induced hepatotumorigenesis. • Propiconazole-induced toxic response in medaka is compatible with that in rodents. - Abstract: Conazole pollution is an emerging concern to human health and environmental safety because of the broad use of conazole fungicides in agriculture and medicine and their frequent occurrence in aquifers. The agricultural pesticide propiconazole has received much regulatory interest because it is a known rodent carcinogen with evidence of multiple adverse effects in mammals and non-targeted organisms. However, the carcinogenic effect and associated mechanism of propiconazole in fish under microgram-per-liter levels of environmental-relevant exposure remains unclear. To explore whether early life of propiconzaole exposure would induce oxidative stress and latent carcinogenic effects in fish, we continuously exposed larvae of wild type or p53{sup −/−} mutant of medaka fish (Oryzias latipes) to propiconazole (2.5–250 μg/L) for 3, 7, 14 or 28 days and assessed liver histopathology and/or the oxidative stress response and gene expression during exposure and throughout adulthood. Propiconazole dose-dependently induced reactive oxygen species (ROS) level, altered homeostasis of antioxidant superoxide dismutase, catalase and glutathione S-transferase and caused lipid and protein peroxidation during early life exposure in wild type medaka. Such exposure also significantly upregulated gene expression of the cytochrome P450 CYP1A, but marginally suppressed that of tumor suppressor p53 in adults. Furthermore, histopathology revealed that p53{sup −/−} mutant medaka with early life exposure to propiconazole showed increased incidence of

Early life exposure to a rodent carcinogen propiconazole fungicide induces oxidative stress and hepatocarcinogenesis in medaka fish

International Nuclear Information System (INIS)

Tu, Tzu-Yi; Hong, Chwan-Yang; Sasado, Takao; Kashiwada, Shosaku; Chen, Pei-Jen

2016-01-01

Highlights: • Propiconazole initiates ROS-induced oxidative stress and damage in medaka fish. • Early life exposure to propiconazole increases incidence of hepatocarcionogensis in p53"−"/"− medaka. • Oxidative stress and CYP induction involved in p53 regulation are key events in propiconazole-induced hepatotumorigenesis. • Propiconazole-induced toxic response in medaka is compatible with that in rodents. - Abstract: Conazole pollution is an emerging concern to human health and environmental safety because of the broad use of conazole fungicides in agriculture and medicine and their frequent occurrence in aquifers. The agricultural pesticide propiconazole has received much regulatory interest because it is a known rodent carcinogen with evidence of multiple adverse effects in mammals and non-targeted organisms. However, the carcinogenic effect and associated mechanism of propiconazole in fish under microgram-per-liter levels of environmental-relevant exposure remains unclear. To explore whether early life of propiconzaole exposure would induce oxidative stress and latent carcinogenic effects in fish, we continuously exposed larvae of wild type or p53"−"/"− mutant of medaka fish (Oryzias latipes) to propiconazole (2.5–250 μg/L) for 3, 7, 14 or 28 days and assessed liver histopathology and/or the oxidative stress response and gene expression during exposure and throughout adulthood. Propiconazole dose-dependently induced reactive oxygen species (ROS) level, altered homeostasis of antioxidant superoxide dismutase, catalase and glutathione S-transferase and caused lipid and protein peroxidation during early life exposure in wild type medaka. Such exposure also significantly upregulated gene expression of the cytochrome P450 CYP1A, but marginally suppressed that of tumor suppressor p53 in adults. Furthermore, histopathology revealed that p53"−"/"− mutant medaka with early life exposure to propiconazole showed increased incidence of

Exposure to endocrine disruptor induces transgenerational epigenetic deregulation of microRNAs in primordial germ cells.

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Miguel A Brieño-Enríquez

Full Text Available In mammals, germ cell differentiation is initiated in the Primordial Germ Cells (PGCs during fetal development. Prenatal exposure to environmental toxicants such as endocrine disruptors may alter PGC differentiation, development of the male germline and induce transgenerational epigenetic disorders. The anti-androgenic compound vinclozolin represents a paradigmatic example of molecule causing transgenerational effects on germ cells. We performed prenatal exposure to vinclozolin in mice and analyzed the phenotypic and molecular changes in three successive generations. A reduction in the number of embryonic PGCs and increased rate of apoptotic cells along with decrease of fertility rate in adult males were observed in F1 to F3 generations. Blimp1 is a crucial regulator of PGC differentiation. We show that prenatal exposure to vinclozolin deregulates specific microRNAs in PGCs, such as miR-23b and miR-21, inducing disequilibrium in the Lin28/let-7/Blimp1 pathway in three successive generations of males. As determined by global maps of cytosine methylation, we found no evidence for prominent changes in DNA methylation in PGCs or mature sperm. Our data suggest that embryonic exposure to environmental endocrine disruptors induces transgenerational epigenetic deregulation of expression of microRNAs affecting key regulatory pathways of germ cells differentiation.

Modeling Exposure to Persistent Chemicals in Hazard and Risk Assessment

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Cowan-Ellsberry, Christina E.; McLachlan, Michael S.; Arnot, Jon A.; MacLeod, Matthew; McKone, Thomas E.; Wania, Frank

2008-11-01

Fate and exposure modeling has not thus far been explicitly used in the risk profile documents prepared to evaluate significant adverse effect of candidate chemicals for either the Stockholm Convention or the Convention on Long-Range Transboundary Air Pollution. However, we believe models have considerable potential to improve the risk profiles. Fate and exposure models are already used routinely in other similar regulatory applications to inform decisions, and they have been instrumental in building our current understanding of the fate of POP and PBT chemicals in the environment. The goal of this paper is to motivate the use of fate and exposure models in preparing risk profiles in the POP assessment procedure by providing strategies for incorporating and using models. The ways that fate and exposure models can be used to improve and inform the development of risk profiles include: (1) Benchmarking the ratio of exposure and emissions of candidate chemicals to the same ratio for known POPs, thereby opening the possibility of combining this ratio with the relative emissions and relative toxicity to arrive at a measure of relative risk. (2) Directly estimating the exposure of the environment, biota and humans to provide information to complement measurements, or where measurements are not available or are limited. (3) To identify the key processes and chemical and/or environmental parameters that determine the exposure; thereby allowing the effective prioritization of research or measurements to improve the risk profile. (4) Predicting future time trends including how quickly exposure levels in remote areas would respond to reductions in emissions. Currently there is no standardized consensus model for use in the risk profile context. Therefore, to choose the appropriate model the risk profile developer must evaluate how appropriate an existing model is for a specific setting and whether the assumptions and input data are relevant in the context of the application

Exposure to arousal-inducing sounds facilitates visual search.

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Asutay, Erkin; Västfjäll, Daniel

2017-09-04

Exposure to affective stimuli could enhance perception and facilitate attention via increasing alertness, vigilance, and by decreasing attentional thresholds. However, evidence on the impact of affective sounds on perception and attention is scant. Here, a novel aspect of affective facilitation of attention is studied: whether arousal induced by task-irrelevant auditory stimuli could modulate attention in a visual search. In two experiments, participants performed a visual search task with and without auditory-cues that preceded the search. Participants were faster in locating high-salient targets compared to low-salient targets. Critically, search times and search slopes decreased with increasing auditory-induced arousal while searching for low-salient targets. Taken together, these findings suggest that arousal induced by sounds can facilitate attention in a subsequent visual search. This novel finding provides support for the alerting function of the auditory system by showing an auditory-phasic alerting effect in visual attention. The results also indicate that stimulus arousal modulates the alerting effect. Attention and perception are our everyday tools to navigate our surrounding world and the current findings showing that affective sounds could influence visual attention provide evidence that we make use of affective information during perceptual processing.

Differential Immunotoxicity Induced by Two Different Windows of Developmental Trichloroethylene Exposure

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Kathleen M. Gilbert

2014-01-01

Full Text Available Developmental exposure to environmental toxicants may induce immune system alterations that contribute to adult stage autoimmune disease. We have shown that continuous exposure of MRL+/+ mice to trichloroethylene (TCE from gestational day (GD 0 to postnatal day (PND 49 alters several aspects of CD4+ T cell function. This window of exposure corresponds to conception-adolescence/young adulthood in humans. More narrowly defining the window of TCE developmental exposure causes immunotoxicity that would establish the stage at which avoidance and/or intervention would be most effective. The current study divided continuous TCE exposure into two separate windows, namely, gestation only (GD0 to birth (PND0 and early-life only (PND0-PND49. The mice were examined for specific alterations in CD4+ T cell function at PND49. One potentially long-lasting effect of developmental exposure, alterations in retrotransposon expression indicative of epigenetic alterations, was found in peripheral CD4+ T cells from both sets of developmentally exposed mice. Interestingly, certain other effects, such as alterations in thymus cellularity, were only found in mice exposed to TCE during gestation. In contrast, expansion of memory/activation cell subset of peripheral CD4+ T cells were only found in mice exposed to TCE during early life. Different windows of developmental TCE exposure can have different functional consequences.

Rapid Elimination of the Persistent Synergid through a Cell Fusion Mechanism

KAUST Repository

Maruyama, Daisuke

2015-05-01

In flowering plants, fertilization-dependent degeneration of the persistent synergid cell ensures one-on-one pairings of male and female gametes. Here, we report that the fusion of the persistent synergid cell and the endosperm selectively inactivates the persistent synergid cell in Arabidopsis thaliana. The synergid-endosperm fusion causes rapid dilution of pre-secreted pollen tube attractant in the persistent synergid cell and selective disorganization of the synergid nucleus during the endosperm proliferation, preventing attractions of excess number of pollen tubes (polytubey). The synergid-endosperm fusion is induced by fertilization of the central cell, while the egg cell fertilization predominantly activates ethylene signaling, an inducer of the synergid nuclear disorganization. Therefore, two female gametes (the egg and the central cell) control independent pathways yet coordinately accomplish the elimination of the persistent synergid cell by double fertilization. Two female gametes (the egg cell and the central cell) in flowering plants coordinately prevent attractions of excess number of pollen tubes via two mechanisms to inactivate persistent synergid cell. © 2015 Elsevier Inc.

Prioritizing Roads Safety Based on the Quasi-Induced Exposure Method and Utilization of the Analytical Hierarchy Process

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Sajad rezaei

2014-06-01

Full Text Available Safety analysis of the roads through the accident rates which is one of the widely used tools has been resulted from the direct exposure method which is based on the ratio of the vehicle-kilometers traveled and vehicle-travel time. However, due to some fundamental flaws in its theories and difficulties in gaining access to the data required such as traffic volume, distance and duration of the trip, and various problems in determining the exposure in a specific time, place, and individual categories, there is a need for an algorithm for prioritizing the road safety so that with a new exposure method, the problems of the previous approaches would be resolved. In this way, an efficient application may lead to have more realistic comparisons and the new method would be applicable to a wider range of time, place, and individual categories. Therefore, an algorithm was introduced to prioritize the safety of roads using the quasi-induced exposure method and utilizing the analytical hierarchy process. For this research, 11 provinces of Iran were chosen as case study locations. A rural accidents database was created for these provinces, the validity of quasi-induced exposure method for Iran’s accidents database was explored, and the involvement ratio for different characteristics of the drivers and the vehicles was measured. Results showed that the quasi-induced exposure method was valid in determining the real exposure in the provinces under study. Results also showed a significant difference in the prioritization based on the new and traditional approaches. This difference mostly would stem from the perspective of the quasi-induced exposure method in determining the exposure, opinion of experts, and the quantity of accidents data. Overall, the results for this research showed that prioritization based on the new approach is more comprehensive and reliable compared to the prioritization in the traditional approach which is dependent on various

Histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells.

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Semeraro, F; Ammollo, C T; Esmon, N L; Esmon, C T

2014-10-01

Extracellular histones exert part of their prothrombotic activity through the stimulation of blood cells. Besides platelets, histones can bind to red blood cells (RBCs), which are important contributors to thrombogenesis, but little is known about the functional consequences of this interaction. To evaluate the effect of histones on the procoagulant potential of human RBCs with particular regard to the expression of surface phosphatidylserine (PS). PS exposure on human RBCs treated with a natural mixture of histones or recombinant individual histones was evaluated with fluorescein isothiocyanate-annexin-V binding and measured with flow cytometry. Calcium influx in RBCs loaded with the calcium-sensitive fluorophore Fluo-4 AM was assessed with flow cytometry. The procoagulant potential of histone-treated RBCs was evaluated with a purified prothrombinase assay and a one-stage plasma recalcification clotting test. Natural histones induced PS exposure on RBCs in a dose-dependent manner, and neutralization or cleavage of histones by heparin or activated protein C, respectively, abolished PS externalization. H4 was mainly responsible for the stimulating activity of histones, whereas the other subtypes were almost ineffective. Similarly, natural histones and H4 induced influx of calcium into RBCs, whereas the other individual histones did not. Histone-induced exposure of PS on RBCs translated into increased prothrombinase complex-mediated prothrombin activation and accelerated fibrin formation in plasma. Histones induce RBCs to express a procoagulant phenotype through the externalization of PS. This finding provides new insights into the prothrombotic activity of extracellular histones. © 2014 International Society on Thrombosis and Haemostasis.

Environmental risk factors associated with the persistence of conduct difficulties in children with intellectual disabilities and autistic spectrum disorders.

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Emerson, Eric; Blacher, Jan; Einfeld, Stewart; Hatton, Chris; Robertson, Janet; Stancliffe, Roger J

2014-12-01

We investigated the association between exposure to environmental risks in early childhood and the prevalence and persistence of conduct difficulties (CD) in children with intellectual disability (ID) who did not have autistic spectrum disorder (ASD), children with ASD and typically developing (TD) children. Results indicated that: (1) exposure to risk was associated with elevated prevalence of CD at age three and, for TD children and children with ID, increased risk of CD persisting to ages five and seven; (2) at all levels of risk, children with ASD were more likely to show persistent CD than other children; (3) children with ID were no more likely to show persistent CD than TD children at low levels of exposure to environmental risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparative proteomic analysis reveals heart toxicity induced by chronic arsenic exposure in rats.

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Huang, Qingyu; Xi, Guochen; Alamdar, Ambreen; Zhang, Jie; Shen, Heqing

2017-10-01

Arsenic is a widespread metalloid in the environment, which poses a broad spectrum of adverse effects on human health. However, a global view of arsenic-induced heart toxicity is still lacking, and the underlying molecular mechanisms remain unclear. By performing a comparative quantitative proteomic analysis, the present study aims to investigate the alterations of proteome profile in rat heart after long-term exposure to arsenic. As a result, we found that the abundance of 81 proteins were significantly altered by arsenic treatment (35 up-regulated and 46 down-regulated). Among these, 33 proteins were specifically associated with cardiovascular system development and function, including heart development, heart morphology, cardiac contraction and dilation, and other cardiovascular functions. It is further proposed that the aberrant regulation of 14 proteins induced by arsenic would disturb cardiac contraction and relaxation, impair heart morphogenesis and development, and induce thrombosis in rats, which is mediated by the Akt/p38 MAPK signaling pathway. Overall, these findings will augment our knowledge of the involved mechanisms and develop useful biomarkers for cardiotoxicity induced by environmental arsenic exposure. Copyright © 2017 Elsevier Ltd. All rights reserved.

Exposure to mercuric chloride induces developmental damage, oxidative stress and immunotoxicity in zebrafish embryos-larvae.

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Zhang, Qun-Fang; Li, Ying-Wen; Liu, Zhi-Hao; Chen, Qi-Liang

2016-12-01

Mercury (Hg) is a widespread environmental pollutant that can produce severe negative effects on fish even at very low concentrations. However, the mechanisms underlying inorganic Hg-induced oxidative stress and immunotoxicity in the early development stage of fish still need to be clarified. In the present study, zebrafish (Danio rerio) embryos were exposed to different concentrations of Hg 2+ (0, 1, 4 and 16μg/L; added as mercuric chloride, HgCl 2 ) from 2h post-fertilization (hpf) to 168hpf. Developmental parameters and total Hg accumulation were monitored during the exposure period, and antioxidant status and the mRNA expression of genes related to the innate immune system were examined at 168hpf. The results showed that increasing Hg 2+ concentration and time significantly increased total Hg accumulation in zebrafish embryos-larvae. Exposure to 16μg/L Hg 2+ caused developmental damage, including increased mortality and malformation, decreased body length, and delayed hatching period. Meanwhile, HgCl 2 exposure (especially in the 16μg/L Hg 2+ group) induced oxidative stress affecting antioxidant enzyme (CAT, GST and GPX) activities, endogenous GSH and MDA contents, as well as the mRNA levels of genes (cat1, sod1, gstr, gpx1a, nrf2, keap1, hsp70 and mt) encoding antioxidant proteins. Moreover, the transcription levels of several representative genes (il-1β, il-8, il-10, tnfα2, lyz and c3) involved in innate immunity were up-regulated by HgCl 2 exposure, suggesting that inorganic Hg had the potential to induce immunotoxicity. Taken together, the present study provides evidence that waterborne HgCl 2 exposure can induce developmental impairment, oxidative stress and immunotoxicity in the early development stage of fish, which brings insights into the toxicity mechanisms of inorganic Hg in fish. Copyright © 2016 Elsevier B.V. All rights reserved.

Persistent aryl hydrocarbon receptor inducers increase with altitude, and estrogen-like disrupters are low in soils of the Alps.

Science.gov (United States)

Levy, Walkiria; Henkelmann, Bernhard; Bernhöft, Silke; Bovee, Toine; Buegger, Franz; Jakobi, Gert; Kirchner, Manfred; Bassan, Rodolfo; Kräuchi, Norbert; Moche, Wolfgang; Offenthaler, Ivo; Simončič, Primoz; Weiss, Peter; Schramm, Karl-Werner

2011-01-01

Soil samples from remote Alpine areas were analyzed for polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans and polychlorinated biphenyls by high-resolution gas chromatography/high-resolution gas spectrometry. Additionally, the EROD micro-assay and a genetically modified yeast estrogen bioassay were carried out to determine persistent aryl hydrocarbon receptors (AhR) and estrogen receptors (ER) agonists, respectively. Regarding the AhR agonists, the toxicity equivalents of analytical and EROD determined values were compared, targeting both altitude of samples and their soil organic content. The ratio between bioassay derived equivalents and analytical determinations suggested no significant contribution of unknown AhR inducers in these sampling sites and some antagonism in soils with relatively high PCB loading. More CYP1A1 expression was induced at the highest sites or about 1400-1500 m a.s.l. along the altitude profiles. Surprisingly, no clear tendencies with the soil organic content were found for dioxin-like compounds. Mean values obtained in the present study were for ER agonists, 2: 0.37±0.12ng 17ß-estradiol EQ g-1 dry soil [corrected] and 6.1 ± 4.2 pg TCDD-EQ g⁻¹ dry soil for AhR agonists. Low bioassay responses with a higher relative amount of ER disrupters than AhR inducers were detected,indicating the higher abundance of estrogen-like than persistent dioxin-like compounds in these forested areas [corrected].

Current densities in a pregnant woman model induced by simultaneous ELF electric and magnetic field exposure

International Nuclear Information System (INIS)

Cech, R; Leitgeb, N; Pediaditis, M

2008-01-01

The pregnant woman model SILVY was studied to ascertain to what extent the electric current densities induced by 50 Hz homogeneous electric and magnetic fields increase in the case of simultaneous exposure. By vectorial addition of the electric current densities, it could be shown that under worst case conditions the basic restrictions recommended by ICNIRP (International Commission on Non-Ionizing Radiation Protection) guidelines are exceeded within the central nervous system (CNS) of the mother, whereas in sole field exposure they are not. However, within the foetus the induced current densities do not comply with basic restrictions, either from single reference-level electric fields or from simultaneous exposure to electric and magnetic fields. Basic limits were considerably exceeded

The consequence of fetal ethanol exposure and adolescent odor re-exposure on the response to ethanol odor in adolescent and adult rats

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Molina Juan C

2009-01-01

Full Text Available Abstract Background An epidemiologic predictive relationship exists between fetal ethanol exposure and the likelihood for adolescent use. Further, an inverse relationship exists between the age of first experience and the probability of adult abuse. Whether and how the combined effects of prenatal and adolescent ethanol experiences contribute to this progressive pattern remains unknown. Fetal ethanol exposure directly changes the odor attributes of ethanol important for both ethanol odor preference behavior and ethanol flavor perception. These effects persist only to adolescence. Here we tested whether adolescent ethanol odor re-exposure: (Experiment 1 augments the fetal effect on the adolescent behavioral response to ethanol odor; and/or (Experiment 2 perpetuates previously observed adolescent behavioral and neurophysiological responses into adulthood. Methods Pregnant rats received either an ethanol or control liquid diet. Progeny (observers experienced ethanol odor in adolescence via social interaction with a peer (demonstrators that received an intragastric infusion of either 1.5 g/kg ethanol or water. Social interactions were scored for the frequency that observers followed their demonstrator. Whole-body plethysmography evaluated the unconditioned behavioral response of observers to ethanol odor in adolescence (P37 or adulthood (P90. The olfactory epithelium of adults was also examined for its neural response to five odorants, including ethanol. Results Experiment 1: Relative to fetal or adolescent exposure alone, adolescent re-exposure enhanced the behavioral response to ethanol odor in P37 animals. Compared to animals with no ethanol experience, rats receiving a single experience (fetal or adolescent show an enhanced, yet equivalent, ethanol odor response. Fetal ethanol experience also increased olfactory-guided following of an intoxicated peer. Experiment 2: Combined exposure yielded persistence of the behavioral effects only in adult

Visualization of DNA clustered damage induced by heavy ion exposure

International Nuclear Information System (INIS)

Tomita, M.; Yatagai, F.

2003-01-01

Full text: DNA double-strand breaks (DSBs) are the most lethal damage induced by ionizing radiations. Accelerated heavy-ions have been shown to induce DNA clustered damage, which is two or more DNA lesions induced within a few helical turns. Higher biological effectiveness of heavy-ions could be provided predominantly by induction of complex DNA clustered damage, which leads to non-repairable DSBs. DNA-dependent protein kinase (DNA-PK) is composed of catalytic subunit (DNA-PKcs) and DNA-binding heterodimer (Ku70 and Ku86). DNA-PK acts as a sensor of DSB during non-homologous end-joining (NHEJ), since DNA-PK is activated to bind to the ends of double-stranded DNA. On the other hand, NBS1 and histone H2AX are essential for DSB repair by homologous recombination (HR) in higher vertebrate cells. Here we report that phosphorylated H2AX at Ser139 (named γ-H2AX) and NBS1 form large undissolvable foci after exposure to accelerated Fe ions, while DNA-PKcs does not recognize DNA clustered damage. NBS1 and γ-H2AX colocalized with forming discrete foci after exposure to X-rays. At 0.5 h after Fe ion irradiation, NBS1 and γ-H2AX also formed discrete foci. However, at 3-8 h after Fe ion irradiation, highly localized large foci turned up, while small discrete foci disappeared. Large NBS1 and γ-H2AX foci were remained even 16 h after irradiation. DNA-PKcs recognized Ku-binding DSB and formed foci shortly after exposure to X-rays. DNA-PKcs foci were observed 0.5 h after 5 Gy of Fe ion irradiation and were almost completely disappeared up to 8 h. These results suggest that NBS1 and γ-H2AX can be utilized as molecular marker of DNA clustered damage, while DNA-PK selectively recognizes repairable DSBs by NHEJ

Cannabinoid exposure during zebra finch sensorimotor vocal learning persistently alters expression of endocannabinoid signaling elements and acute agonist responsiveness

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Lichtman Aron H

2011-01-01

Full Text Available Abstract Background Previously we have found that cannabinoid treatment of zebra finches during sensorimotor stages of vocal development alters song patterns produced in adulthood. Such persistently altered behavior must be attributable to changes in physiological substrates responsible for song. We are currently working to identify the nature of such physiological changes, and to understand how they contribute to altered vocal learning. One possibility is that developmental agonist exposure results in altered expression of elements of endocannabinoid signaling systems. To test this hypothesis we have studied effects of the potent cannabinoid receptor agonist WIN55212-2 (WIN on endocannabinoid levels and densities of CB1 immunostaining in zebra finch brain. Results We found that late postnatal WIN treatment caused a long-term global disregulation of both levels of the endocannabinoid, 2-arachidonyl glycerol (2-AG and densities of CB1 immunostaining across brain regions, while repeated cannabinoid treatment in adults produced few long-term changes in the endogenous cannabinoid system. Conclusions Our findings indicate that the zebra finch endocannabinoid system is particularly sensitive to exogenous agonist exposure during the critical period of song learning and provide insight into susceptible brain areas.

Antioxidative-related genes expression following perfluorooctane sulfonate (PFOS) exposure in the intertidal mud crab, Macrophthalmus japonicus

Science.gov (United States)

Park, Kiyun; Nikapitiya, Chamilani; Kwak, Tae-Soo; Kwak, Ihn-Sil

2015-09-01

Perfluorooctane sulfonate (PFOS) is a persistent environmental contaminant that is used as a surfactant in various industries and consumer products. The intertidal mud crab, Macrophthalmus japonicus, is one of the most abundant macrobenthic creatures. In this study, we have investigated the effect of PFOS on the molecular transcription of antioxidant and detoxification signaling in M. japonicus crab. The selected stress response genes were superoxide dismutases (CuZnSOD and MnSOD), catalase (CAT), glutathione peroxidase (GPx), phospholipid hydroperoxide glutathione peroxidase (PHGPx), peroxiredoxin (Prx), and thioredoxin reductase (TrxR). Significant up-regulation of SODs and CAT was observed after 24 and 96 h exposure to PFOS at different concentrations. The gene expression levels of GPx, PHGPx, and TrXR were significantly up-regulated after exposure to PFOS for 96 h. The transcript levels of CAT and PHGPx were induced in dose- and time-dependent manners after PFOS treatments. However, Prx gene expression was significantly up-regulated in M. japonicus crabs exposed to 10 and 30 μg L-1 PFOS for 96 h. Additionally, PFOS toxicity in M. japonicus induced reduced survival rates at relatively high concentrations of PFOS exposure. Our findings support the contention that exposures to PFOS induced the response of genes related to oxidative stress and detoxification in M. japonicus crabs.

Cytogenetic adaptive response induced by pre-exposure in human lymphocytes and marrow cells of mice

International Nuclear Information System (INIS)

Zhang Lianzhen; Deng Zhicheng

1993-01-01

The cytogenetic adaptive response induced by pre-exposure in human lymphocytes and marrow cells of mice were studied. The results of this study showed that human lymphocytes in vitro and mouse marrow cells in vivo can become adapted to low-level irradiation from 3 H-TdR or exposure to a low dose of X-or γ-irradiation, so that they become less sensitive to the chromosomal damage effects of subsequent exposures. (4 tabs.)

Perfluorooctanoic acid exposure for 28 days affects glucose homeostasis and induces insulin hypersensitivity in mice

Science.gov (United States)

Yan, Shengmin; Zhang, Hongxia; Zheng, Fei; Sheng, Nan; Guo, Xuejiang; Dai, Jiayin

2015-06-01

Perfluoroalkyl acids (PFAAs) are widely used in many applications due to their unique physical and chemical characteristics. Because of the increasing prevalence of metabolic syndromes, including obesity, dyslipidemia and insulin resistance, concern has arisen about the roles of environmental pollutants in such diseases. Earlier epidemiologic studies showed a potential association between perfluorooctanoic acid (PFOA) and glucose metabolism, but how PFOA influences glucose homeostasis is still unknown. Here, we report on the modulation of the phosphatidylinositol 3-kinase-serine/threonine protein kinase (PI3K-AKT) signaling pathway in the livers of mice after 28 d of exposure to PFOA. Compared with normal mice, PFOA exposure significantly decreased the expression of the phosphatase and tensin homologue (PTEN) protein and affected the PI3K-AKT signaling pathway in the liver. Tolerance tests further indicated that PFOA exposure induced higher insulin sensitivity and glucose tolerance in mice. Biochemical analysis revealed that PFOA exposure reduced hepatic glycogen synthesis, which might be attributed to gluconeogenesis inhibition. The levels of several circulating proteins were altered after PFOA exposure, including proteins potentially related to diabetes and liver disease. Our results suggest that PFOA affected glucose metabolism and induced insulin hypersensitivity in mice.

Persistent renal enhancement after intra-arterial versus intravenous iodixanol administration

International Nuclear Information System (INIS)

Chou, Shinn-Huey; Wang, Zhen J.; Kuo, Jonathan; Cabarrus, Miguel; Fu Yanjun; Aslam, Rizwan; Yee, Judy; Zimmet, Jeffrey M.; Shunk, Kendrick; Elicker, Brett; Yeh, Benjamin M.

2011-01-01

Purpose: To examine the clinical significance of persistent renal enhancement after iodixanol administration. Methods: We retrospectively studied 166 consecutive patients who underwent non-enhanced abdominopelvic CT within 7 days after receiving intra-arterial (n = 99) or intravenous (n = 67) iodixanol. Renal attenuation was measured for each non-enhanced CT scan. Persistent renal enhancement was defined as CT attenuation >55 Hounsfield units (HU). Contrast-induced nephropathy (CIN) was defined as a rise in serum creatinine >0.5 mg/dL within 5 days after contrast administration. Results: While the intensity and frequency of persistent renal enhancement was higher after intra-arterial (mean CT attenuation of 73.7 HU, seen in 54 of 99 patients, or 55%) than intravenous contrast material administration (51.8 HU, seen in 21 of 67, or 31%, p < 0.005), a multivariate regression model showed that the independent predictors of persistent renal enhancement were a shorter time interval until the subsequent non-enhanced CT (p < 0.001); higher contrast dose (p < 0.001); higher baseline serum creatinine (p < 0.01); and older age (p < 0.05). The route of contrast administration was not a predictor of persistent renal enhancement in this model. Contrast-induced nephropathy was noted in 9 patients who received intra-arterial (9%) versus 3 who received intravenous iodixanol (4%), and was more common in patients with persistent renal enhancement (p < 0.01). Conclusion: Persistent renal enhancement at follow-up non-contrast CT suggests a greater risk for contrast-induced nephropathy, but the increased frequency of striking renal enhancement in patients who received intra-arterial rather than intravenous contrast material also reflects the larger doses of contrast and shorter time to subsequent follow-up CT scanning for such patients.

Perfluorooctane sulfonate (PFOS) induces reactive oxygen species (ROS) production in human microvascular endothelial cells: role in endothelial permeability.

Science.gov (United States)

Qian, Yong; Ducatman, Alan; Ward, Rebecca; Leonard, Steve; Bukowski, Valerie; Lan Guo, Nancy; Shi, Xianglin; Vallyathan, Val; Castranova, Vincent

2010-01-01

Perfluorooctane sulfonate (PFOS) is a member of the perfluoroalkyl acids (PFAA) containing an eight-carbon backbone. PFOS is a man-made chemical with carbon-fluorine bonds that are among the strongest in organic chemistry, and PFOS is widely used in industry. Human occupational and environmental exposure to PFOS occurs globally. PFOS is non-biodegradable and is persistent in the human body and environment. In this study, data demonstrated that exposure of human microvascular endothelial cells (HMVEC) to PFOS induced the production of reactive oxygen species (ROS) at both high and low concentrations. Morphologically, it was found that exposure to PFOS induced actin filament remodeling and endothelial permeability changes in HMVEC. Furthermore, data demonstrated that the production of ROS plays a regulatory role in PFOS-induced actin filament remodeling and the increase in endothelial permeability. Our results indicate that the generation of ROS may play a role in PFOS-induced aberrations of the endothelial permeability barrier. The results generated from this study may provide a new insight into the potential adverse effects of PFOS exposure on humans at the cellular level.

Chronic caffeine exposure attenuates blast-induced memory deficit in mice.

Science.gov (United States)

Ning, Ya-Lei; Yang, Nan; Chen, Xing; Zhao, Zi-Ai; Zhang, Xiu-Zhu; Chen, Xing-Yun; Li, Ping; Zhao, Yan; Zhou, Yuan-Guo

2015-01-01

To investigate the effects of three different ways of chronic caffeine administration on blast- induced memory dysfunction and to explore the underlying mechanisms. Adult male C57BL/6 mice were used and randomly divided into five groups: control: without blast exposure, con-water: administrated with water continuously before and after blast-induced traumatic brain injury (bTBI), con-caffeine: administrated with caffeine continuously for 1 month before and after bTBI, pre-caffeine: chronically administrated with caffeine for 1 month before bTBI and withdrawal after bTBI, post-caffeine: chronically administrated with caffeine after bTBI. After being subjected to moderate intensity of blast injury, mice were recorded for learning and memory performance using Morris water maze (MWM) paradigms at 1, 4, and 8 weeks post-blast injury. Neurological deficit scoring, glutamate concentration, proinflammatory cytokines production, and neuropathological changes at 24 h, 1, 4, and 8 weeks post-bTBI were examined to evaluate the brain injury in early and prolonged stages. Adenosine A1 receptor expression was detected using qPCR. All of the three ways of chronic caffeine exposure ameliorated blast-induced memory deficit, which is correlated with the neuroprotective effects against excitotoxicity, inflammation, astrogliosis and neuronal loss at different stages of injury. Continuous caffeine treatment played positive roles in both early and prolonged stages of bTBI; pre-bTBI and post-bTBI treatment of caffeine tended to exert neuroprotective effects at early and prolonged stages of bTBI respectively. Up-regulation of adenosine A1 receptor expression might contribute to the favorable effects of chronic caffeine consumption. Since caffeinated beverages are widely consumed in both civilian and military personnel and are convenient to get, the results may provide a promising prophylactic strategy for blast-induced neurotrauma and the consequent cognitive impairment.

Ecological and spatial factors drive intra- and interspecific variation in exposure of subarctic predatory bird nestlings to persistent organic pollutants.

Science.gov (United States)

Eulaers, Igor; Jaspers, Veerle L B; Bustnes, Jan O; Covaci, Adrian; Johnsen, Trond V; Halley, Duncan J; Moum, Truls; Ims, Rolf A; Hanssen, Sveinn A; Erikstad, Kjell E; Herzke, Dorte; Sonne, Christian; Ballesteros, Manuel; Pinxten, Rianne; Eens, Marcel

2013-07-01

Top predators in northern ecosystems may suffer from exposure to persistent organic pollutants (POPs) as this exposure may synergistically interact with already elevated natural stress in these ecosystems. In the present study, we aimed at identifying biological (sex, body condition), ecological (dietary carbon source, trophic level) and spatial factors (local habitat, regional nest location) that may influence intra- and interspecific variation in exposure of subarctic predatory bird nestlings to polychlorinated biphenyl 153 (CB 153), polybrominated diphenyl ether 47 (BDE 47), dichlorodiphenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB). During three breeding seasons (2008-2010), we sampled body feathers from fully-grown nestlings of three ecologically distinct predatory bird species in subarctic Norway: Northern Goshawk (Accipiter gentilis), White-tailed Eagle (Haliaeetus albicilla) and Golden Eagle (Aquila chrysaetos). The present study analysed, for the first time, body feathers for both POPs and carbon (δ(13)C) and nitrogen (δ(15)N) stable isotopes, thus integrating the dietary carbon source, trophic level and POP exposure for the larger part of the nestling stage. Intraspecific variation in exposure was driven by a combination of ecological and spatial factors, often different for individual compounds. In addition, combinations for individual compounds differed among species. Trophic level and local habitat were the predominant predictors for CB 153, p,p'-DDE and BDE 47, indicating their biomagnification and decreasing levels according to coast>fjord>inland. Variation in exposure may also have been driven by inter-annual variation arisen from primary sources (e.g. p,p'-DDE) and/or possible revolatilisation from secondary sources (e.g. HCB). Interspecific differences in POP exposure were best explained by a combination of trophic level (biomagnification), dietary carbon source (food chain discrimination) and regional nest location (historical POP

Preconception maternal and paternal exposure to persistent organic pollutants and birth size: the LIFE study.

Science.gov (United States)

Robledo, Candace A; Yeung, Edwina; Mendola, Pauline; Sundaram, Rajeshwari; Maisog, Jose; Sweeney, Anne M; Barr, Dana Boyd; Louis, Germaine M Buck

2015-01-01

Persistent organic pollutants (POPs) are developmental toxicants, but the impact of both maternal and paternal exposures on offspring birth size is largely unexplored. We examined associations between maternal and paternal serum concentrations of 63 POPs, comprising five major classes of pollutants, with birth size measures. Parental serum concentrations of 9 organochlorine pesticides, 1 polybrominated biphenyl (PBB), 7 perfluoroalkyl chemicals (PFCs), 10 polybrominated diphenyl ethers (PBDEs), and 36 polychlorinated biphenyls (PCBs) were measured before conception for 234 couples. Differences in birth weight, length, head circumference, and ponderal index were estimated using multiple linear regression per 1-SD increase in natural log-transformed (ln-transformed) chemicals. Models were estimated separately for each parent and adjusted for maternal age, maternal prepregnancy body mass index (kilograms per meter squared) and other confounders, and all models included an interaction term between infant sex and each chemical. Among girls (n = 117), birth weight was significantly lower (range, 84-195 g) in association with a 1-SD increase in ln-transformed maternal serum concentrations of DDT, PBDE congeners 28 and 183, and paternal serum concentrations of PBDE-183 and PCB-167. Among boys (n = 113), maternal (PCBs 138, 153, 167, 170, 195, and 209 and perfluorooctane sulfonamide) and paternal (PCBs 172 and 195) serum concentrations of several POPs were statistically associated with lower birth weight (range, 98-170 g), whereas paternal concentrations of PBDEs (66, 99) were associated with higher birth weight. Differences in offspring head circumference, length, and ponderal index were also associated with parental exposures. Preconceptional maternal and paternal concentrations of several POPs were associated with statistically significant differences in birth size among offspring.

Prepubertal exposure to cow's milk reduces susceptibility to carcinogen-induced mammary tumorigenesis in rats

DEFF Research Database (Denmark)

Nielsen, Tina Skau; Khan, Galam; Davis, Jennifer

2011-01-01

Cow's milk contains high levels of estrogens, progesterone and insulin-like growth factor 1 (IGF-1), all of which are associated with breast cancer. We investigated whether prepubertal milk exposure affects mammary gland development and carcinogenesis in rats. Sprague-Dawley rats were given either...... whole milk or tap water to drink from postnatal day (PND) 14 to PND 35, and thereafter normal tap water. Mammary tumorigenesis was induced by administering 7,12-dimethylbenz[a]anthracene on PND 50. Milk exposure increased circulating E2 levels on PND 25 by 10-fold (p ... opening, which marks puberty onset, by 2.5 days (p milk before puberty exhibited reduced carcinogen-induced mammary carcinogenesis; that is, their tumor latency was longer (p

Perturbations in immune responses induced by concurrent subchronic exposure to arsenic and endosulfan

International Nuclear Information System (INIS)

Aggarwal, Manoj; Naraharisetti, Suresh Babu; Dandapat, S.; Degen, G.H.; Malik, J.K.

2008-01-01

The metalloid arsenic and the chlorinated insecticide endosulfan are common environmental contaminants. Humans, animals, and birds are exposed to these chemicals through water and food. Although health effects due to either arsenic or endosulfan exposure are documented, the toxicological impact of co-exposure to these environmental pollutants is unpredictable and unknown. The present study was undertaken to assess whether concurrent exposure to arsenic and endosulfan induces significant alterations in immunological functions. Day-old chicks were exposed to 3.7 ppm of arsenic via drinking water and to 30 ppm of endosulfan-mixed feed either individually or concurrently for up to 60 days. All the chicks were vaccinated with Ranikhet disease virus (F-strain; RD-F) on days 1 and 30. During the course of study and at term, parameters of cellular and humoral immunity were determined. None of the treatments altered the absolute body weight or body weight gain, except arsenic significantly reduced weight gain on day 60. Absolute, but not the relative, weights of spleen, thymus and bursa of Fabricius were significantly reduced in all the treatment groups. The metalloid and insecticide combination significantly depressed the ability of peripheral blood and splenic lymphocytes to proliferate in response to antigen RD-F and mitogen Con A. The delayed type hypersensitivity response to 2,4-dinitro-1-chlorobenzene or to PHA-P was also significantly decreased. Nitric oxide production by RD-F or lipopolysaccharide-stimulated peripheral blood and splenic mononuclear cells was significantly suppressed following concurrent exposure to arsenic and endosulfan. Furthermore, the combined exposure also decreased the antibody response to RD-F. The suppression of cellular and humoral immune responses was also evident following administration of individual compounds, and it was not exacerbated following concurrent exposure. To our knowledge, this is the first report describing the suppression

The mechanism of persistent photoconductivity induced by minority carrier trapping effect in ultraviolet photo-detector made of polycrystalline diamond film

International Nuclear Information System (INIS)

Wang Lanxi; Chen Xuekang; Wu Gan; Guo Wantu; Cao Shengzhu; Shang Kaiwen; Han Weihua

2011-01-01

Performances of long persistent photoconductivity, high responsivity and high photoconductive gain were observed in a metal–semiconductor–metal ultraviolet photo-detector fabricated on a microcrystalline diamond film. Charge-based deep level transient spectroscopy measurement confirmed that a shallow level with activation energy of 0.21 eV and capture cross section of 9.9 × 10 −20 cm 2 is presented in the band gap of the diamond film. The shallow level may not act as effective recombination center due to the so small activation energy according to Schockly-Read-Hall statistics. The persistent photoconductivity relaxation fits in with the so called “barrier-limited recombination” model, which may be a minority carrier trapping effect related recombination process. The photo-induced minority carriers (electrons in this paper) may be trapped by the shallow level during light irradiation process and then de-trap slowly via thermal excitation or tunneling effect after removing the light source, which contributes to the persistent photoconductivity. The trapping effect can also reduce the probability of carrier recombination, resulting in the high responsivity and the high gain.

Exposure and effects assessment of persistent organohalogen contaminants in arctic wildlife and fish.

Science.gov (United States)

Letcher, Robert J; Bustnes, Jan Ove; Dietz, Rune; Jenssen, Bjørn M; Jørgensen, Even H; Sonne, Christian; Verreault, Jonathan; Vijayan, Mathilakath M; Gabrielsen, Geir W

2010-07-01

Persistent organic pollutants (POPs) encompass an array of anthropogenic organic and elemental substances and their degradation and metabolic byproducts that have been found in the tissues of exposed animals, especially POPs categorized as organohalogen contaminants (OHCs). OHCs have been of concern in the circumpolar arctic for decades. For example, as a consequence of bioaccumulation and in some cases biomagnification of legacy (e.g., chlorinated PCBs, DDTs and CHLs) and emerging (e.g., brominated flame retardants (BFRs) and in particular polybrominated diphenyl ethers (PBDEs) and perfluorinated compounds (PFCs) including perfluorooctane sulfonate (PFOS) and perfluorooctanic acid (PFOA) found in Arctic biota and humans. Of high concern are the potential biological effects of these contaminants in exposed Arctic wildlife and fish. As concluded in the last review in 2004 for the Arctic Monitoring and Assessment Program (AMAP) on the effects of POPs in Arctic wildlife, prior to 1997, biological effects data were minimal and insufficient at any level of biological organization. The present review summarizes recent studies on biological effects in relation to OHC exposure, and attempts to assess known tissue/body compartment concentration data in the context of possible threshold levels of effects to evaluate the risks. This review concentrates mainly on post-2002, new OHC effects data in Arctic wildlife and fish, and is largely based on recently available effects data for populations of several top trophic level species, including seabirds (e.g., glaucous gull (Larus hyperboreus)), polar bears (Ursus maritimus), polar (Arctic) fox (Vulpes lagopus), and Arctic charr (Salvelinus alpinus), as well as semi-captive studies on sled dogs (Canis familiaris). Regardless, there remains a dearth of data on true contaminant exposure, cause-effect relationships with respect to these contaminant exposures in Arctic wildlife and fish. Indications of exposure effects are largely

Ethanol exposure affects cell movement during gastrulation and induces split axes in zebrafish embryos.

Science.gov (United States)

Zhang, Ying; Shao, Ming; Wang, Lifeng; Liu, Zhongzhen; Gao, Ming; Liu, Chao; Zhang, Hongwei

2010-06-01

To explore the toxic effects of ethanol on axis formation during embryogenesis, zebrafish embryos at different developmental stages were treated with 3% ethanol for 3h. The effects of ethanol exposure appeared to be stage-dependent. The dome stage embryo was most sensible to form posterior split axes upon ethanol exposure. Morphological and histological observations and whole-mount in situ hybridization results showed that ethanol exposure at this stage caused a general gastrulation delay, and induced double notochords, double neural tubes and two sets of somites in the posterior trunk. Mechanistically, no ectopic organizer was found by examining the expression patterns of dorsoventral markers including goosecoid, chordin and eve1 at the onset of gastrulation. However, radial intercalation, epiboly and convergence extension were inhibited by ethanol exposure as revealed by cell labeling, phenotypic observation and the expression patterns of axial or paraxial markers. Further investigation showed that the cell aggregation might be affected by ethanol exposure, as indicated by the much more scattered expression pattern of chordin, eve1 and wnt11 at the early gastrula stage, and the discontinuous gsc positive cells during migration. These results imply that ethanol might affect cell movement before and during gastrulation and as a consequence, induces a split axes phenotype. Copyright 2010 ISDN. Published by Elsevier Ltd. All rights reserved.

Induced tolerance from a sublethal insecticide leads to cross-tolerance to other insecticides.

Science.gov (United States)

Hua, Jessica; Jones, Devin K; Relyea, Rick A

2014-04-01

As global pesticide use increases, the ability to rapidly respond to pesticides by increasing tolerance has important implications for the persistence of nontarget organisms. A recent study of larval amphibians discovered that increased tolerance can be induced by an early exposure to low concentrations of a pesticide. Since natural systems are often exposed to a variety of pesticides that vary in mode of action, we need to know whether the induction of increased tolerance to one pesticide confers increased tolerance to other pesticides. Using larval wood frogs (Lithobates sylvaticus), we investigated whether induction of increased tolerance to the insecticide carbaryl (AChE-inhibitor) can induce increased tolerance to other insecticides that have the same mode of action (chlorpyrifos, malathion) or a different mode of action (Na(+)channel-interfering insecticides; permethrin, cypermethrin). We found that embryonic exposure to sublethal concentrations of carbaryl induced higher tolerance to carbaryl and increased cross-tolerance to malathion and cypermethrin but not to chlorpyrifos or permethrin. In one case, the embryonic exposure to carbaryl induced tolerance in a nonlinear pattern (hormesis). These results demonstrate that that the newly discovered phenomenon of induced tolerance also provides induced cross-tolerance that is not restricted to pesticides with the same mode of action.

Protective effects of selenium on mercury induced immunotoxic effects in mice by way of concurrent drinking water exposure.

Science.gov (United States)

Li, Xuan; Yin, Daqiang; Li, Jiang; Wang, Rui

2014-07-01

Selenium (Se) has been recognized as one key to understanding mercury (Hg) exposure risks. To explore the effects of Se on Hg-induced immunotoxicity, female Balb/c mice were exposed to HgCl2- or MeHgCl-contaminated drinking water (0.001, 0.01, and 0.1 mM as Hg) with coexisting Na2SeO3 at different Se/Hg molar ratios (0:1, 1/3:1, 1:1 and 3:1). The potential immunotoxicity induced by Na2SeO3 exposure alone (by way of drinking water) was also determined within a wide range of concentrations. After 14 days' exposure, the effects of Hg or Se on the immune system of Balb/c mice were investigated by determining the proliferation of T and B lymphocytes and the activity of natural killer cells. Hg exposure alone induced a dose-dependent suppression effect, whereas Se provided promotion effects at low exposure level (0.03 mM). Under Hg and Se coexposure condition, the effects on immunotoxicity depended on the Hg species, Se/Hg ratio, and exposure concentration. At low Hg concentration (0.001 mM), greater Se ingestion exhibited stronger protective effects on Hg-induced suppression effect mainly by way of decreasing Hg concentrations in target organs. At greater Hg concentration (0.01 and 0.1 mM), immunotoxicity induced by Se (>0.03 mM) became evident, and the protective effects appeared more significant at an Se/Hg molar ratio of 1:1. The complex antagonistic effects between Se and Hg suggested that both Se/Hg molar ratio and concentration should be considered when evaluating the potential health risk of Hg-contaminated biota.

Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk.

Science.gov (United States)

Lehmann, Geniece M; Verner, Marc-André; Luukinen, Bryan; Henning, Cara; Assimon, Sue Anne; LaKind, Judy S; McLanahan, Eva D; Phillips, Linda J; Davis, Matthew H; Powers, Christina M; Hines, Erin P; Haddad, Sami; Longnecker, Matthew P; Poulsen, Michael T; Farrer, David G; Marchitti, Satori A; Tan, Yu-Mei; Swartout, Jeffrey C; Sagiv, Sharon K; Welsh, Clement; Campbell, Jerry L; Foster, Warren G; Yang, Raymond S H; Fenton, Suzanne E; Tornero-Velez, Rogelio; Francis, Bettina M; Barnett, John B; El-Masri, Hisham A; Simmons, Jane Ellen

2014-08-01

Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a woman's body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infant's intake of these LPECs may be much greater than his/her mother's average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life. In many cases, current human health risk assessment methods do not account for differences between maternal and infant exposures to LPECs or for lifestage-specific effects of exposure to these chemicals. Because of their persistence and accumulation in body lipids and partitioning into breast milk, LPECs present unique challenges for each component of the human health risk assessment process, including hazard identification, dose-response assessment, and exposure assessment. Specific biological modeling approaches are available to support both dose-response and exposure assessment for lactational exposures to LPECs. Yet, lack of data limits the application of these approaches. The goal of this review is to outline the available approaches and to identify key issues that, if addressed, could improve efforts to apply these approaches to risk assessment of lactational exposure to these chemicals.

Spatiotemporal characterization of ionizing radiation induced DNA damage foci and their relation to chromatin organization

Energy Technology Data Exchange (ETDEWEB)

Costes, Sylvain V; Chiolo, Irene; Pluth, Janice M.; Barcellos-Hoff, Mary Helen; Jakob, Burkhard

2009-09-15

DNA damage sensing proteins have been shown to localize to the sites of DSB within seconds to minutes following ionizing radiation (IR) exposure, resulting in the formation of microscopically visible nuclear domains referred to as radiation-induced foci (RIF). This review characterizes the spatio-temporal properties of RIF at physiological doses, minutes to hours following exposure to ionizing radiation, and it proposes a model describing RIF formation and resolution as a function of radiation quality and nuclear densities. Discussion is limited to RIF formed by three interrelated proteins ATM (Ataxia telangiectasia mutated), 53BP1 (p53 binding protein 1) and ?H2AX (phosphorylated variant histone H2AX). Early post-IR, we propose that RIF mark chromatin reorganization, leading to a local nuclear scaffold rigid enough to keep broken DNA from diffusing away, but open enough to allow the repair machinery. We review data indicating clear kinetic and physical differences between RIF emerging from dense and uncondensed regions of the nucleus. At later time post-IR, we propose that persistent RIF observed days following exposure to ionizing radiation are nuclear ?scars? marking permanent disruption of the chromatin architecture. When DNA damage is resolved, such chromatin modifications should not necessarily lead to growth arrest and it has been shown that persistent RIF can replicate during mitosis. Thus, heritable persistent RIF spanning over tens of Mbp may affect the transcriptome of a large progeny of cells. This opens the door for a non DNA mutation-based mechanism of radiation-induced phenotypes.

Survival of Bactericidal Antibiotic Treatment by a Persister Subpopulation of Listeria monocytogenes

DEFF Research Database (Denmark)

Knudsen, Gitte Maegaard; Ng, Yin; Gram, Lone

2013-01-01

Listeria monocytogenes can cause the serious infection listeriosis, which despite antibiotic treatment has a high mortality. Understanding the response of L. monocytogenes to antibiotic exposure is therefore important to ensure treatment success. Some bacteria survive antibiotic treatment...... by formation of persisters, which are a dormant antibiotic-tolerant subpopulation. The purpose of this study was to determine whether L. monocytogenes can form persisters and how bacterial physiology affects the number of persisters in the population. A stationary-phase culture of L. monocytogenes was adjusted...... that eradication of persisters is possible. Our study adds L. monocytogenes to the list of bacterial species capable of surviving bactericidal antibiotics in a dormant stage, and this persister phenomenon should be borne in mind when developing treatment regimens....

Laboratory diagnosis of persistent human chlamydial infection

Directory of Open Access Journals (Sweden)

Mirja ePuolakkainen

2013-12-01

Full Text Available Diagnostic assays for persistent chlamydial infection are much needed to conduct high-quality, large-scale studies investigating the persistent state in vivo, its disease associations and the response to therapy. Yet in most studies the distinction between acute and persistent infection is based on the interpretation of the data obtained by the assays developed to diagnose acute infections or on complex assays available for research only and/or difficult to establish for clinical use. Novel biomarkers for detection of persistent chlamydial infection are urgently needed. Chlamydial whole genome proteome arrays are now available and they can identify chlamydial antigens that are differentially expressed between acute infection and persistent infection. Utilizing these data will lead to the development of novel diagnostic assays. Carefully selected specimens from well-studied patient populations are clearly needed in the process of translating the proteomic data into assays useful for clinical practice. Before such antigens are identified and validated assays become available, we face a challenge of deciding whether the persistent infection truly induced appearance of the proposed marker or do we just base our diagnosis of persistent infection on the presence of the suggested markers. Consequently, we must bear this in mind when interpreting the available data.

Hematological effects of four ethylene glycol monoalkyl ethers in short-term repeated exposure in rats

Energy Technology Data Exchange (ETDEWEB)

Starek, Andrzej [Jagiellonian University, Department of Biochemical Toxicology, Medical College, Krakow (Poland); Szymczak, Wieslaw [University of Lodz, Institute of Psychology, Lodz (Poland); Zapor, Lidia [Central Institute for Labour Protection National Research Institute, Laboratory of Toxicology, Department of Chemical and Aerosol Hazards, Warsaw (Poland)

2008-02-15

This study was carried out to compare the hematological effects of 2-methoxyethanol (ME), 2-ethoxyethanol (EE), 2-isopropoxyethanol (IPE), and 2-butoxyethanol (BE) in short-term studies in rats. Male rats were subcutaneously treated with ME or EE at a dosage of 0, 1.25, 2.5 and 5.0 mM/kg in saline, 5 days per week, for 4 weeks. Other rats were exposed to IPE or BE at doses of 0, 0.25, 0.5, 0.75 and 1.25 mM/kg in the same manner. Administration of each chemical, except of ME, resulted in a time- and dose-dependent swelling of erythrocytes as evidenced by an increase in mean corpuscular volume (MCV). Subsequently, red blood cells (RBC), packed cell volumes (PCV), hemoglobin concentration (HGB), and mean cell hemoglobin concentration (MCHC) decreased. Furthermore, an increase in mean cell hemoglobin (MCH) and reticulocyte counts was observed. The onset of hemolysis induced by EE, IPE or BE was faster than after ME administration. While in rats exposed to ME hematological changes were strongly pronounced and progressively increased with exposure time beginning from the day 11, those in animals treated with EE were rather persisted at low constant level for all exposure period. In contrast, the rats exposed to IPE and BE demonstrated the dramatic hematological changes more pronounced in case of BE than IPE at the beginning of exposure (on day 4). Despite of exposure duration, these changes were regressed, although the decrease in RBC and MCHC and the increase in MCV and MCH in rats treated with highest doses of both compound (0.5, 0.75, and 1.25 mM/kg) were more persistent, probably due to selective hemolysis of the aged erythrocytes. In addition, significant leukopenia due to reduction of lymphocytes in rats exposed to ME was observed. In summary, this study demonstrated no tolerance to ME- and EE-induced intravascular hemolysis developed under these experimental conditions. On the contrary, tolerance to IPE- and BE-induced hemolysis in rats exposed to these compounds

A reaction-diffusion model for radiation-induced bystander effects.

Science.gov (United States)

Olobatuyi, Oluwole; de Vries, Gerda; Hillen, Thomas

2017-08-01

We develop and analyze a reaction-diffusion model to investigate the dynamics of the lifespan of a bystander signal emitted when cells are exposed to radiation. Experimental studies by Mothersill and Seymour 1997, using malignant epithelial cell lines, found that an emitted bystander signal can still cause bystander effects in cells even 60 h after its emission. Several other experiments have also shown that the signal can persist for months and even years. Also, bystander effects have been hypothesized as one of the factors responsible for the phenomenon of low-dose hyper-radiosensitivity and increased radioresistance (HRS/IRR). Here, we confirm this hypothesis with a mathematical model, which we fit to Joiner's data on HRS/IRR in a T98G glioma cell line. Furthermore, we use phase plane analysis to understand the full dynamics of the signal's lifespan. We find that both single and multiple radiation exposure can lead to bystander signals that either persist temporarily or permanently. We also found that, in an heterogeneous environment, the size of the domain exposed to radiation and the number of radiation exposures can determine whether a signal will persist temporarily or permanently. Finally, we use sensitivity analysis to identify those cell parameters that affect the signal's lifespan and the signal-induced cell death the most.

Abnormal levels of UV-induced unscheduled DNA synthesis in ataxia telangiectasia cells after exposure to ionizing radiation

International Nuclear Information System (INIS)

Jaspers, N.G.J.; Nederlandse Centrale Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek, Rijswijk. Medical Biological Lab.); Bootsma, D.

1982-01-01

In cultured cells from normal individuals and from patients having ataxia telangiectasia (AT) the rate of unscheduled DNA synthesis (UDS) induced by UV light was investigated by autoradiography. The number of grains in 6 different AT cell strains was similar to that observed in normal cells. Exposure of normal cells to doses of X-rays up to 20 krad had no influence on the rate of UV-induced UDS. In contrast, the UV-induced UDS was significantly modified in AT cells by treatment with X-rays. In AT cell strains that were reported to have reduced levels of γ-ray-induced repair DNA synthesis ('excision-deficient' AT cells) the effect of X-rays on UV-induced UDS was inhibitory, whereas UV-induced UDS was stimulated by X-ray exposure in 'excision-proficient' AT cell strains. Different UV and X-ray dose-response relationships were seen in the two categories of AT cell strains. (orig./AJ)

Thrombosis, systemic and cardiac oxidative stress and DNA damage induced by pulmonary exposure to diesel exhaust particles, and the effect of nootkatone thereon.

Science.gov (United States)

Nemmar, Abderrahim; Al-Salam, Suhail; Beegam, Sumaya; Yuvaraju, Priya; Ali, Badreldin H

2018-01-05

Adverse cardiovascular effects of particulate air pollution persist even at lower concentrations than those of the current air quality limit. Therefore, identification of safe and effective measures against particles-induced cardiovascular toxicity is needed. Nootkatone is a sesquiterpenoid in grapefruit with diverse bioactivities including anti-inflammatory and antioxidant effects. However, its protective effect on the cardiovascular injury induced by diesel exhaust particles (DEP) has not been studied before. We assessed the possible protective effect of nootkatone (90 mg/kg) administered by gavage 1h before intratracheal (i.t.) instillation of DEP (30 μg/mouse). Twenty-four h following the i.t. administration of DEP various thrombotic and cardiac parameters were assessed. Nootkatone inhibited the prothrombotic effect induced by DEP in pial arterioles and venules in vivo and platelet aggregation in whole blood in vitro. Also, nootkatone prevented the shortening of activated partial thromboplastin time and prothrombin time induced by DEP. Nootkatone inhibited the increase of plasma concentration of fibrinogen, plasminogen activator inhibitor-1, interleukin-6 and lipid peroxidation induced by DEP. Immunohistochemically, hearts showed an analogous increase in glutathione and nuclear factor erythroid-derived 2-like 2 (Nrf2) expression by cardiac myocytes and endothelial cells following DEP exposure, and these effects were enhanced in mice treated with nootkatone+DEP. Likewise, heme oxygenase-1 (HO-1) was increased in mice treated with nootkatone+DEP compared with those treated with DEP or nootkatone+saline. The DNA damage caused by DEP was prevented by nootkatoone pretreatment. In conclusion, nootkatoone alleviates DEP-induced thrombogenicity and systemic and cardiac oxidative stress and DNA damage, at least partly, through Nrf2 and HO-1 activation.

Prenatal and Postnatal Exposure to Persistent Organic Pollutants and Infant Growth

DEFF Research Database (Denmark)

Iszatt, N.; Stigum, H.; Verner, M. A.

2015-01-01

prenatal and postnatal effects. OBJECTIVES: We investigated prenatal and postnatal exposure to POPs and infant growth (a predictor of obesity). METHODS: We pooled data from seven European birth cohorts with biomarker concentrations of polychlorinated biphenyl 153 (PCB-153) (n = 2,487), and p...... growth, and it contains state-of-the-art exposure modeling. Prenatal p,p'-DDE was associated with increased infant growth, and postnatal PCB-153 with decreased growth at European exposure levels....

Persistent Drug-Induced Parkinsonism in Patients with Normal Dopamine Transporter Imaging.

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Jin Yong Hong

Full Text Available Functional neuroimaging for the dopamine transporter (DAT is used to distinguish drug-induced parkinsonism (DIP from subclinical Parkinson's disease (PD. Although DIP patients who show a normal DAT image are expected to recover completely, some do not. We investigated whether these patients showed changes in striatal DAT activity using semi-quantitative analysis of 18F-FP-CIT PET data. DIP patients with visually normal DAT images were selected from medical records. The subjects were classified as patients who recovered partially (PR or completely within 12 months (CR. The 18F-FP-CIT uptake in each striatal subregion was compared between the CR and the PR groups. In total, 41 and 9 patients of the CR and PR groups were assessed, respectively. The two patient groups were comparable in terms of clinical characteristics including age, sex, and severity of parkinsonism. From semi-quantitative analysis of the PET image, the PR patients showed a relatively lower ligand uptake in the ventral striatum, the anterior putamen and the posterior putamen compared with the CR patients. This result suggests that persistent DIP in patients with visually normal DAT imaging may be associated with subtle decrement of DAT activity.

Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats

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Uta Waterhouse

2016-10-01

Full Text Available Maternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive-enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg at one of three neurodevelopmental time periods [gestation days (GD 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND 60] and included: prepulse inhibition (PPI, latent inhibition (LI and delayed non-matching to sample (DNMTS. Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously were administered, and animals were re-tested in the same tasks (PND 110. Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11 resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI and selective (LI improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI and induced a global enhancement of sensorimotor gating (PPI.

Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells

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Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

2015-02-01

Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR-G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6 μM) for 24 or 48 h. Cell viability was reduced (P < 0.05) after 48 h of exposure to 3 or 6 μM PM. The NOR-G-OH DNA adduct was detected after 24 h of 6 μM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48 h by exposure to both PM concentrations. Phosphorylated H2AX (γH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, γH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response. - Highlights: • PM forms ovarian DNA adducts. • DNA damage marker γH2AX increased by PM exposure. • PM induces ovarian DNA double strand break repair.

In utero exposure to persistent organic pollutants in relation to testicular cancer risk.

Science.gov (United States)

Hardell, Lennart; Bavel, Bert; Lindström, Gunilla; Eriksson, Mikael; Carlberg, Michael

2006-02-01

Testicular cancer is the most common tumour type in young men. In Sweden the annual age-adjusted incidence increased significantly by 2.4% during the time period 1984-1993 and during 1994-2003 by 1.4%. Exposure to endocrine disrupting chemicals during the foetal period has been postulated to be a risk factor. In this investigation we studied the concentrations of chlorinated biphenyls (PCBs), p,p'-dichlorodiphenyl-dichloroethylene (pp'-DDE), hexachlorobenzene (HCB), chlordanes and polybrominated diphenylethers (PBDEs) in 58 cases with testicular cancer and 61 age-matched controls. Furthermore, case and control mothers were also asked to participate and 44 case mothers and 45 control mothers agreed. No significant differences were found between cases and controls. Case mothers had in general higher concentrations of these chemicals. For the sum of PCBs an odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.4-10 was calculated using the median concentration for the controls as cut-off value. For HCB OR = 4.4, CI = 1.7-12 and for PBDE OR = 2.5, 95% CI = 1.02-6.0 were obtained, whereas OR was not significantly increased for pp'-DDE and sum of chlordanes. The cases were born during a period with high concentrations of persistent organic pollutants (POPs) in humans. The decline of the increasing incidence of testicular cancer during recent years may reflect decreasing body burden of certain POPs since the 1980s.

Historical exposure to persistent organic pollutants and risk of incident hypertension

DEFF Research Database (Denmark)

Arrebola, Juan P; Fernández, Mariana F; Martin-Olmedo, Piedad

2015-01-01

The aim of this study was to assess the influence of adipose tissue concentrations of a group of persistent organic pollutants (POPs) on the risk of hypertension in an adult cohort of residents of Granada (Southern Spain) over a 10-year follow-up. No chemical was significantly associated with the...

Cement-Induced Chromate Occupational Allergic Contact Dermatitis.

Science.gov (United States)

Kridin, Khalaf; Bergman, Reuven; Khamaisi, Mogher; Zelber-Sagi, Shira; Weltfriend, Sara

2016-01-01

Hexavalent chromium in cement is a common cause of occupational allergic contact dermatitis (OACD). Analysis of patch test data during 1999 to 2013 was done. Patients with cement-induced chromate OACD filled the Dermatology Life Quality Index, graded 1 to 5. Of 4846 consecutive patients who were patch tested, 146 (3%) were chromate-sensitive. Of 46 (31.5%) who presented with chromate OACD, 27 (59%) had cement-induced chromate OACD. The proportion of chromate-sensitive patients with clinically relevant cement exposure increased from 7.7% in 2002 to 2004 to 28.7% in 2011 to 2013 (P = 0.04). The median age of presentation was younger than for other chromate-sensitive patients (32 vs 42 years). Hand eczema (88.9%) was the most frequent clinical presentation. Of the 27 with cement-induced chromate OACD, 21 (77.8%) had ongoing dermatitis at the time of the review. Although 14/27 (51.9%) changed their occupation to avoid exposure to cement, symptoms persisted in 9/14 (64.3%). Prolonged exposure to cement before development of symptoms was associated with chronicity. All the symptomatic patients experienced at least a moderate effect on their quality of life (grade 3 or higher on the Dermatology Life Quality Index). We recommend the adoption of the European legislation in Israel, to reduce the prevalence of chromate OACD from cement.

Distinguishing potential sources of genotoxic exposure via HPRT mutations

International Nuclear Information System (INIS)

Molholt, B.; Finette, B.A.

2000-01-01

T-cell HPRT (hypoxanthine phosphoribosyltransferase) mutations were used to monitor to environmental mutagens in children who have developed cancer at a persistently high rate in Toms River, New Jersey, USA. A preliminary epidemiological study has found a statistically-significant association between drinking public water (by pregnant mother or infant) and subsequent risk for childhood cancer. Three potential sources of mutagenic exposures in Toms River may have increased the rate of carcinogenic initiation significantly in children: 1. Benzidine-based, other azo-dye and anthraquinone dye wastes released by Ciba-Geigy enterprise; 2. Plastic wastes of Union Carbide enterprise; 3. Radium-224, present in unusually high concentrations in the Cohansey aquifer. Specific patterns of HPRT mutations are utilized to distinguish these various potential sources of carcinogenic exposures in the drinking water of families with childhood cancer and to differentiate chemically or radiologically induced cancers from those which occur spontaneously [ru

Study on the immunological and genetic effects induced by internal exposure to radionuclides

International Nuclear Information System (INIS)

Zhu Shoupeng; Wang Liuyi; Luan Meiling

1995-02-01

The immune system is the important part of defense mechanism in organism. Studies have demonstrated the high radiosensitivity of the immunocytes to internal radionuclide exposure. It is evident that serious functional disturbances and morphological changes of immune organs are induced by internal contamination of radionuclides, including suppression of division and proliferation of immunocytes, induction of irreversible sequelae, leading to injurious effects on both central and peripheral immune organs. In order to study the consequences of the injuries of genetic material caused by internal contamination of radionuclides, researches have developed from the harmful effects on parental generation to those on the offspring. The present paper reports the study on the genetic injuries of somatic and germ cells induced by internal radionuclide exposure. Emphasis is placed on the molecular basis of radio-genetic effect and the relations of the molecular basis of DNA injury to gene mutation and chromosome aberration

Long-term intravenous administration of carboxylated single-walled carbon nanotubes induces persistent accumulation in the lungs and pulmonary fibrosis via the nuclear factor-kappa B pathway

Directory of Open Access Journals (Sweden)

Qin Y

2016-12-01

Full Text Available Yue Qin,1,* Suning Li,2,* Gan Zhao,2,* Xuanhao Fu,1 Xueping Xie,1 Yiyi Huang,1 Xiaojing Cheng,3 Jinbin Wei,1 Huagang Liu,1 Zefeng Lai1 1Pharmaceutical College, Guangxi Medical University, 2Department of Pharmacy, The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, 3Life Sciences Institute, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China *These authors contributed equally to this work Abstract: Numerous studies have demonstrated promising application of single-walled carbon nanotubes (SWNTs in drug delivery, diagnosis, and targeted therapy. However, the adverse health effects resulting from intravenous injection of SWNTs are not completely understood. Studies have shown that levels of “pristine” or carboxylated carbon nanotubes are very high in mouse lungs after intravenous injection. We hypothesized that long-term and repeated intravenous administration of carboxylated SWNTs (c-SWNTs can result in persistent accumulation and induce histopathologic changes in rat lungs. Here, c-SWNTs were administered repeatedly to rats via tail-vein injection for 90 days. Long-term intravenous injection of c-SWNTs caused sustained embolization in lung capillaries and granuloma formation. It also induced a persistent inflammatory response that was regulated by the nuclear factor-kappa B signaling pathway, and which resulted in pulmonary fibrogenesis. c-SWNTs trapped within lung capillaries traversed capillary walls and injured alveolar epithelial cells, thereby stimulating production of pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta and pro-fibrotic growth factors (transforming growth factor-beta 1. Protein levels of type-I and type-III collagens, matrix metalloproteinase-2, and the tissue inhibitor of metalloproteinase-2 were upregulated after intravenous exposure to c-SWNTs as determined by immunohistochemical assays and Western blotting, which suggested collagen deposition

Anti-Inflammatory and Antioxidant Effects of Repeated Exposure to Cruciferous Allyl Nitrile in Sensitizer-Induced Ear Edema in Mice.

Science.gov (United States)

Tanii, Hideji; Sugitani, Kayo; Saijoh, Kiyofumi

2016-02-29

Skin sensitizers induce allergic reactions through the induction of reactive oxygen species. Allyl nitrile from cruciferous vegetables has been reported to induce antioxidants and phase II detoxification enzymes in various tissues. We assessed the effects of repeated exposure to allyl nitrile on sensitizer-induced allergic reactions. Mice were dosed with allyl nitrile (0-200 µmol/kg), and then received a dermal application of 1 of 3 sensitizers on the left ear or 1 of 2 vehicles on the right ear. Quantitative assessment of edema was carried out by measuring the difference in weight between the portions taken from the right and left ears. We tested enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and thiobarbituric acid reactive substances (TBARS) in ears. Repeated exposure to allyl nitrile reduced edemas induced by glutaraldehyde and by 2, 4-dinitrochlorobenzene (DNCB), but not by formaldehyde. The repeated exposure decreased levels of TBARS, a marker of oxidative stress, induced by glutaraldehyde and by DNCB, but not by formaldehyde. Allyl nitrile elevated SOD levels for the 3 sensitizers, and CAT levels for formaldehyde and DNCB. Allyl nitrile also increased GPx levels for formaldehyde and DNCB, but not for glutaraldehyde. The reduced edemas were associated with changes in oxidative stress levels and antioxidant enzymes. Repeated exposure to allyl nitrile reduced allergic reactions induced by glutaraldehyde and by DNCB, but not by formaldehyde. This reduction was associated with changes in ROS levels and antioxidant enzyme activities.

Reduced persistence of the macrolide antibiotics erythromycin, clarithromycin and azithromycin in agricultural soil following several years of exposure in the field

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Topp, Edward, E-mail: ed.topp@agr.gc.ca; Renaud, Justin; Sumarah, Mark; Sabourin, Lyne

2016-08-15

The macrolide antibiotics erythromycin, clarithromycin and azithromycin are very important in human and animal medicine, and can be entrained onto agricultural ground through application of sewage sludge or manures. In the present study, a series of replicated field plots were left untreated or received up to five annual spring applications of a mixture of three drugs to achieve a nominal concentration for each of 10 or 0.1 mg kg{sup −1} soil; the latter an environmentally relevant concentration. Soil samples were incubated in the laboratory, and supplemented with antibiotics to establish the dissipation kinetics of erythromycin and clarithromycin using radioisotope methods, and azithromycin using HPLC-MS/MS. All three drugs were dissipated significantly more rapidly in soils with a history of field exposure to 10 mg kg{sup −1} macrolides, and erythromycin and clarithromycin were also degraded more rapidly in field soil exposed to 0.1 mg kg{sup −1} macrolides. Rapid mineralization of {sup 14}C-labelled erythromycin and clarithromycin are consistent with biodegradation. Analysis of field soils revealed no carryover of parent compound from year to year. Azithromycin transformation products were detected consistent with removal of the desosamine and cladinose moieties. Overall, these results have revealed that following several years of exposure to macrolide antibiotics these are amenable to accelerated degradation. The potential accelerated degradation of these drugs in soils amended with manure and sewage sludge should be investigated as this phenomenon would attenuate environmental exposure and selection pressure for clinically relevant resistance. - Highlights: • The impact of field exposure on persistence of macrolide antibiotics was evaluated. • Soil samples were incubated in the laboratory with macrolides. • Field exposure resulted in more rapid dissipation of all macrolides. • Radiolabelled erythromycin and clarithromycin were rapidly mineralized

Reduced persistence of the macrolide antibiotics erythromycin, clarithromycin and azithromycin in agricultural soil following several years of exposure in the field

International Nuclear Information System (INIS)

Topp, Edward; Renaud, Justin; Sumarah, Mark; Sabourin, Lyne

2016-01-01

The macrolide antibiotics erythromycin, clarithromycin and azithromycin are very important in human and animal medicine, and can be entrained onto agricultural ground through application of sewage sludge or manures. In the present study, a series of replicated field plots were left untreated or received up to five annual spring applications of a mixture of three drugs to achieve a nominal concentration for each of 10 or 0.1 mg kg"−"1 soil; the latter an environmentally relevant concentration. Soil samples were incubated in the laboratory, and supplemented with antibiotics to establish the dissipation kinetics of erythromycin and clarithromycin using radioisotope methods, and azithromycin using HPLC-MS/MS. All three drugs were dissipated significantly more rapidly in soils with a history of field exposure to 10 mg kg"−"1 macrolides, and erythromycin and clarithromycin were also degraded more rapidly in field soil exposed to 0.1 mg kg"−"1 macrolides. Rapid mineralization of "1"4C-labelled erythromycin and clarithromycin are consistent with biodegradation. Analysis of field soils revealed no carryover of parent compound from year to year. Azithromycin transformation products were detected consistent with removal of the desosamine and cladinose moieties. Overall, these results have revealed that following several years of exposure to macrolide antibiotics these are amenable to accelerated degradation. The potential accelerated degradation of these drugs in soils amended with manure and sewage sludge should be investigated as this phenomenon would attenuate environmental exposure and selection pressure for clinically relevant resistance. - Highlights: • The impact of field exposure on persistence of macrolide antibiotics was evaluated. • Soil samples were incubated in the laboratory with macrolides. • Field exposure resulted in more rapid dissipation of all macrolides. • Radiolabelled erythromycin and clarithromycin were rapidly mineralized. • Macrolides

Digital music exposure reliably induces temporary threshold shift in normal-hearing human subjects.

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Le Prell, Colleen G; Dell, Shawna; Hensley, Brittany; Hall, James W; Campbell, Kathleen C M; Antonelli, Patrick J; Green, Glenn E; Miller, James M; Guire, Kenneth

2012-01-01

One of the challenges for evaluating new otoprotective agents for potential benefit in human populations is the availability of an established clinical paradigm with real-world relevance. These studies were explicitly designed to develop a real-world digital music exposure that reliably induces temporary threshold shift (TTS) in normal-hearing human subjects. Thirty-three subjects participated in studies that measured effects of digital music player use on hearing. Subjects selected either rock or pop music, which was then presented at 93 to 95 (n = 10), 98 to 100 (n = 11), or 100 to 102 (n = 12) dBA in-ear exposure level for a period of 4 hr. Audiograms and distortion product otoacoustic emissions (DPOAEs) were measured before and after music exposure. Postmusic tests were initiated 15 min, 1 hr 15 min, 2 hr 15 min, and 3 hr 15 min after the exposure ended. Additional tests were conducted the following day and 1 week later. Changes in thresholds after the lowest-level exposure were difficult to distinguish from test-retest variability; however, TTS was reliably detected after higher levels of sound exposure. Changes in audiometric thresholds had a "notch" configuration, with the largest changes observed at 4 kHz (mean = 6.3 ± 3.9 dB; range = 0-14 dB). Recovery was largely complete within the first 4 hr postexposure, and all subjects showed complete recovery of both thresholds and DPOAE measures when tested 1 week postexposure. These data provide insight into the variability of TTS induced by music-player use in a healthy, normal-hearing, young adult population, with music playlist, level, and duration carefully controlled. These data confirm the likelihood of temporary changes in auditory function after digital music-player use. Such data are essential for the development of a human clinical trial protocol that provides a highly powered design for evaluating novel therapeutics in human clinical trials. Care must be taken to fully inform potential subjects in

Persistent photoconductivity due to trapping of induced charges in Sn/ZnO thin film based UV photodetector

Science.gov (United States)

Yadav, Harish Kumar; Sreenivas, K.; Gupta, Vinay

2010-05-01

Photoconductivity relaxation in rf magnetron sputtered ZnO thin films integrated with ultrathin tin metal overlayer is investigated. Charge carriers induced at the ZnO-metal interface by the tin metal overlayer compensates the surface lying trap centers and leads to the enhanced photoresponse. On termination of ultraviolet radiation, recombination of the photoexcited electrons with the valence band holes leaves the excess carriers deeply trapped at the recombination center and holds the dark conductivity level at a higher value. Equilibrium between the recombination centers and valence band, due to trapped charges, eventually stimulates the persistent photoconductivity in the Sn/ZnO photodetectors.

Persistent photoconductivity due to trapping of induced charges in Sn/ZnO thin film based UV photodetector

International Nuclear Information System (INIS)

Yadav, Harish Kumar; Sreenivas, K.; Gupta, Vinay

2010-01-01

Photoconductivity relaxation in rf magnetron sputtered ZnO thin films integrated with ultrathin tin metal overlayer is investigated. Charge carriers induced at the ZnO-metal interface by the tin metal overlayer compensates the surface lying trap centers and leads to the enhanced photoresponse. On termination of ultraviolet radiation, recombination of the photoexcited electrons with the valence band holes leaves the excess carriers deeply trapped at the recombination center and holds the dark conductivity level at a higher value. Equilibrium between the recombination centers and valence band, due to trapped charges, eventually stimulates the persistent photoconductivity in the Sn/ZnO photodetectors.

Fertilization Induces a Transient Exposure of Phosphatidylserine in Mouse Eggs

Science.gov (United States)

Curia, Claudio A.; Ernesto, Juan I.; Stein, Paula; Busso, Dolores; Schultz, Richard M.; Cuasnicu, Patricia S.; Cohen, Débora J.

2013-01-01

Phosphatidylserine (PS) is normally localized to the inner leaflet of the plasma membrane and the requirement of PS translocation to the outer leaflet in cellular processes other than apoptosis has been demonstrated recently. In this work we investigated the occurrence of PS mobilization in mouse eggs, which express flippase Atp8a1 and scramblases Plscr1 and 3, as determined by RT-PCR; these enzyme are responsible for PS distribution in cell membranes. We find a dramatic increase in binding of flouresceinated-Annexin-V, which specifically binds to PS, following fertilization or parthenogenetic activation induced by SrCl2 treatment. This increase was not observed when eggs were first treated with BAPTA-AM, indicating that an increase in intracellular Ca2+ concentration was required for PS exposure. Fluorescence was observed over the entire egg surface with the exception of the regions overlying the meiotic spindle and sperm entry site. PS exposure was also observed in activated eggs obtained from CaMKIIγ null females, which are unable to exit metaphase II arrest despite displaying Ca2+ spikes. In contrast, PS exposure was not observed in TPEN-activated eggs, which exit metaphase II arrest in the absence of Ca2+ release. PS exposure was also observed when eggs were activated with ethanol but not with a Ca2+ ionophore, suggesting that the Ca2+ source and concentration are relevant for PS exposure. Last, treatment with cytochalasin D, which disrupts microfilaments, or jasplakinolide, which stabilizes microfilaments, prior to egg activation showed that PS externalization is an actin-dependent process. Thus, the Ca2+ rise during egg activation results in a transient exposure of PS in fertilized eggs that is not associated with apoptosis. PMID:23951277

Digital music exposure reliably induces temporary threshold shift (TTS) in normal hearing human subjects

Science.gov (United States)

Le Prell, C. G.; Dell, S.; Hensley, B.; Hall, J. W.; Campbell, K. C. M.; Antonelli, P. J.; Green, G. E.; Miller, J. M.; Guire, K.

2012-01-01

Objectives One of the challenges for evaluating new otoprotective agents for potential benefit in human populations is availability of an established clinical paradigm with real world relevance. These studies were explicitly designed to develop a real-world digital music exposure that reliably induces temporary threshold shift (TTS) in normal hearing human subjects. Design Thirty-three subjects participated in studies that measured effects of digital music player use on hearing. Subjects selected either rock or pop music, which was then presented at 93–95 (n=10), 98–100 (n=11), or 100–102 (n=12) dBA in-ear exposure level for a period of four hours. Audiograms and distortion product otoacoustic emissions (DPOAEs) were measured prior to and after music exposure. Post-music tests were initiated 15 min, 1 hr 15 min, 2 hr 15 min, and 3 hr 15 min after the exposure ended. Additional tests were conducted the following day and one week later. Results Changes in thresholds after the lowest level exposure were difficult to distinguish from test-retest variability; however, TTS was reliably detected after higher levels of sound exposure. Changes in audiometric thresholds had a “notch” configuration, with the largest changes observed at 4 kHz (mean=6.3±3.9dB; range=0–13 dB). Recovery was largely complete within the first 4 hours post-exposure, and all subjects showed complete recovery of both thresholds and DPOAE measures when tested 1-week post-exposure. Conclusions These data provide insight into the variability of TTS induced by music player use in a healthy, normal-hearing, young adult population, with music playlist, level, and duration carefully controlled. These data confirm the likelihood of temporary changes in auditory function following digital music player use. Such data are essential for the development of a human clinical trial protocol that provides a highly powered design for evaluating novel therapeutics in human clinical trials. Care must be

Chronic inorganic mercury exposure induces sex-specific changes in central TNFα expression: Importance in autism?

OpenAIRE

Curtis, J. Thomas; Chen, Yue; Buck, Daniel J.; Davis, Randall L.

2011-01-01

Mercury is neurotoxic and increasing evidence suggests that environmental exposure to mercury may contribute to neuropathologies including Alzheimer's disease and autism spectrum disorders. Mercury is known to disrupt immunocompetence in the periphery, however, little is known about the effects of mercury on neuroimmune signaling. Mercury-induced effects on central immune function are potentially very important given that mercury exposure and neuroinflammation both are implicated in certain n...

Vinclozolin exposure in utero induces postpubertal prostatitis and reduces sperm production via a reversible hormone-regulated mechanism.

Science.gov (United States)

Cowin, Prue A; Gold, Elspeth; Aleksova, Jasna; O'Bryan, Moira K; Foster, Paul M D; Scott, Hamish S; Risbridger, Gail P

2010-02-01

Vinclozolin is an endocrine-disrupting chemical (EDC) that binds with high affinity to the androgen receptor (AR) and blocks the action of gonadal hormones on male reproductive organs. An alternative mechanism of action of Vinclozolin involves transgenerational effects on the male reproductive tract. We previously reported in utero Vinclozolin exposure-induced prostatitis (prostate inflammation) in postpubertal rats concurrent with down-regulation of AR and increased nuclear factor-kappaB activation. We postulated the male reproductive abnormalities induced by in utero Vinclozolin exposure could be reversed by testosterone supplementation, in contrast to the permanent modifications involving DNA methyltransferases (Dnmts) described by others. To test this hypothesis, we administered high-dose testosterone at puberty to Vinclozolin-treated rats and determined the effect on anogenital distance (AGD); testicular germ cell apoptosis, concentration of elongated spermatids, and the onset of prostatitis. Concurrently we examined Dnmt1, -3A, -3B, and -3L mRNA expression. Consistent with previous reports, in utero exposure to Vinclozolin significantly reduced AGD, increased testicular germ cell apoptosis 3-fold, reduced elongated spermatid number by 40%, and induced postpubertal prostatitis in 100% of exposed males. Administration of high-dose testosterone (25 mg/kg) at puberty normalized AGD, reduced germ cell apoptosis, and restored elongated spermatid number. Testosterone restored AR and nuclear factor-kappaB expression in the prostate and abolished Vinclozolin-induced prostatitis. Altered Dnmt expression was evident with in utero Vinclozolin exposure and was not normalized after testosterone treatment. These data demonstrate in utero Vinclozolin-induced male reproductive tract abnormalities are AR mediated and reversible and involve a mechanism independent of Dnmt expression.

Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

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Comish, Paul B; Drumond, Ana Luiza; Kinnell, Hazel L; Anderson, Richard A; Matin, Angabin; Meistrich, Marvin L; Shetty, Gunapala

2014-01-01

Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼ 70% of control and induced atrophic seminiferous tubules in ∼ 30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.

Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

Directory of Open Access Journals (Sweden)

Paul B Comish

Full Text Available Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1 mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2% and to 80% in the male offspring of L1 (control value 33%. These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼ 70% of control and induced atrophic seminiferous tubules in ∼ 30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i DNA damage is a common mechanism leading to induction of testicular cancer, ii increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.

Mechanisms mediating vibration-induced chronic musculoskeletal pain analyzed in the rat.

Science.gov (United States)

Dina, Olayinka A; Joseph, Elizabeth K; Levine, Jon D; Green, Paul G

2010-04-01

While occupational exposure to vibration is a common cause of acute and chronic musculoskeletal pain, eliminating exposure produces limited symptomatic improvement, and reexposure precipitates rapid recurrence or exacerbation. To evaluate mechanisms underlying these pain syndromes, we have developed a model in the rat, in which exposure to vibration (60-80Hz) induces, in skeletal muscle, both acute mechanical hyperalgesia as well as long-term changes characterized by enhanced hyperalgesia to a proinflammatory cytokine or reexposure to vibration. Exposure of a hind limb to vibration-produced mechanical hyperalgesia measured in the gastrocnemius muscle of the exposed hind limb, which persisted for approximately 2 weeks. When nociceptive thresholds had returned to baseline, exposure to a proinflammatory cytokine or reexposure to vibration produced markedly prolonged hyperalgesia. The chronic prolongation of vibration- and cytokine-hyperalgesia was prevented by spinal intrathecal injection of oligodeoxynucleotide (ODN) antisense to protein kinase Cepsilon, a second messenger in nociceptors implicated in the induction and maintenance of chronic pain. Vibration-induced hyperalgesia was inhibited by spinal intrathecal administration of ODN antisense to receptors for the type-1 tumor necrosis factor-alpha (TNFalpha) receptor. Finally, in TNFalpha-pretreated muscle, subsequent vibration-induced hyperalgesia was markedly prolonged. These studies establish a model of vibration-induced acute and chronic musculoskeletal pain, and identify the proinflammatory cytokine TNFalpha and the second messenger protein kinase Cepsilon as targets against which therapies might be directed to prevent and/or treat this common and very debilitating chronic pain syndrome. Copyright 2010 American Pain Society. All rights reserved.

Chronic exposure to Tributyltin induces brain functional damage in juvenile common carp (Cyprinus carpio.

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Zhi-Hua Li

Full Text Available The aim of the present study was to investigate the effect of Tributyltin (TBT on brain function and neurotoxicity of freshwater teleost. The effects of long-term exposure to TBT on antioxidant related indices (MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; GPx, glutathione peroxidase, Na+-K+-ATPase and neurological parameters (AChE, acetylcholinesterase; MAO, monoamine oxidase; NO, nitric oxide in the brain of common carp were evaluated. Fish were exposed to sublethal concentrations of TBT (75 ng/L, 0.75 μg/L and 7.5 μg/L for 15, 30, and 60 days. Based on the results, a low level and short-term TBT-induced stress could not induce the notable responses of the fish brain, but long-term exposure (more than 15 days to TBT could lead to obvious physiological-biochemical responses (based on the measured parameters. The results also strongly indicated that neurotoxicity of TBT to fish. Thus, the measured physiological responses in fish brain could provide useful information to better understand the mechanisms of TBT-induced bio-toxicity.

Chronic Exposure to Tributyltin Induces Brain Functional Damage in Juvenile Common Carp (Cyprinus carpio)

Science.gov (United States)

Li, Zhi-Hua; Li, Ping; Shi, Ze-Chao

2015-01-01

The aim of the present study was to investigate the effect of Tributyltin (TBT) on brain function and neurotoxicity of freshwater teleost. The effects of long-term exposure to TBT on antioxidant related indices (MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; GPx, glutathione peroxidase), Na+-K+-ATPase and neurological parameters (AChE, acetylcholinesterase; MAO, monoamine oxidase; NO, nitric oxide) in the brain of common carp were evaluated. Fish were exposed to sublethal concentrations of TBT (75 ng/L, 0.75 μg/L and 7.5 μg/L) for 15, 30, and 60 days. Based on the results, a low level and short-term TBT-induced stress could not induce the notable responses of the fish brain, but long-term exposure (more than 15 days) to TBT could lead to obvious physiological-biochemical responses (based on the measured parameters). The results also strongly indicated that neurotoxicity of TBT to fish. Thus, the measured physiological responses in fish brain could provide useful information to better understand the mechanisms of TBT-induced bio-toxicity. PMID:25879203

Chronic exposure to Tributyltin induces brain functional damage in juvenile common carp (Cyprinus carpio).

Science.gov (United States)

Li, Zhi-Hua; Li, Ping; Shi, Ze-Chao

2015-01-01

The aim of the present study was to investigate the effect of Tributyltin (TBT) on brain function and neurotoxicity of freshwater teleost. The effects of long-term exposure to TBT on antioxidant related indices (MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; GR, glutathione reductase; GPx, glutathione peroxidase), Na+-K+-ATPase and neurological parameters (AChE, acetylcholinesterase; MAO, monoamine oxidase; NO, nitric oxide) in the brain of common carp were evaluated. Fish were exposed to sublethal concentrations of TBT (75 ng/L, 0.75 μg/L and 7.5 μg/L) for 15, 30, and 60 days. Based on the results, a low level and short-term TBT-induced stress could not induce the notable responses of the fish brain, but long-term exposure (more than 15 days) to TBT could lead to obvious physiological-biochemical responses (based on the measured parameters). The results also strongly indicated that neurotoxicity of TBT to fish. Thus, the measured physiological responses in fish brain could provide useful information to better understand the mechanisms of TBT-induced bio-toxicity.

CYP polymorphisms and pathological conditions related to chronic exposure to organochlorine pesticides

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Anca Oana Docea

Full Text Available The association between genetic variations in the cytochrome P450 (CYP family genes and pathological conditions related to long-term exposure to organochlorine compounds (OCs deserves further elucidation. OCs are persistent organic pollutants with bioaccumulative and lipophilic characteristics. They can act as endocrine disruptors and perturb cellular mechanisms. Prolonged exposure to OCs has been associated with different pathological manifestations. CYP genes are responsible for transcribing enzymes essential in xenobiotic metabolism. Therefore, polymorphisms in these genetic sequences a. alter the metabolic pathways, b. induce false cellular responses, and c. may provoke pathological conditions. The main aim of this review is to define the interaction between parameters a, b and c at a mechanistic/molecular level, with references in clinical cases. Keywords: Organochlorine compounds, Cytochrome P450, Genetic polymorphisms, Pathogenesis, Environmental pollutants

Penicillin G-Induced Chlamydial Stress Response in a Porcine Strain of Chlamydia pecorum

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Cory Ann Leonard

2016-01-01

Full Text Available Chlamydia pecorum causes asymptomatic infection and pathology in ruminants, pigs, and koalas. We characterized the antichlamydial effect of the beta lactam penicillin G on Chlamydia pecorum strain 1710S (porcine abortion isolate. Penicillin-exposed and mock-exposed infected host cells showed equivalent inclusions numbers. Penicillin-exposed inclusions contained aberrant bacterial forms and exhibited reduced infectivity, while mock-exposed inclusions contained normal bacterial forms and exhibited robust infectivity. Infectious bacteria production increased upon discontinuation of penicillin exposure, compared to continued exposure. Chlamydia-induced cell death occurred in mock-exposed controls; cell survival was improved in penicillin-exposed infected groups. Similar results were obtained both in the presence and in the absence of the eukaryotic protein translation inhibitor cycloheximide and at different times of initiation of penicillin exposure. These data demonstrate that penicillin G induces the chlamydial stress response (persistence and is not bactericidal, for this chlamydial species/strain in vitro, regardless of host cell de novo protein synthesis.

Anthropogenic flank attack on polar bears: Interacting consequences of climate warming and pollutant exposure

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Bjørn Munro Jenssen

2015-02-01

Full Text Available Polar bears (Ursus maritimus are subjected to several anthropogenic threats, climate warming and exposure to pollutants being two of these. For polar bears, one of the main effects of climate warming is limited access to prey, due to loss of their sea ice habitat. This will result in prolonged fasting periods and emaciation and condition related negative effects on survival and reproduction success. Prolonged fasting will result in increases of the tissue concentrations of persistent organic pollutants (POPs in polar bears, and thus increase the probability for POP levels to exceed threshold levels for effects on health, and thus on reproductive success and survival. There are clear potentials for interactions between impacts of climate warming and impacts of pollutant exposure on polar bears. It is likely that that fasting-induced increases of POPs will add to mortality rates and decrease reproductive success beyond effects caused by loss of habitat alone. However, there is a lack of studies that have addressed this. Thus, there is a need to focus on population effects of POP exposure in polar bears, and to consider such effects in relation to the effects of climate induced habitat loss.

Severe malformations of eelpout (Zoarces viviparus) fry are induced by maternal estrogenic exposure during early embryogenesis

DEFF Research Database (Denmark)

Morthorst, Jane Ebsen; Korsgaard, Bodil; Bjerregaard, Poul

2016-01-01

Pregnant eelpout were exposed via the water to known endocrine disrupting compounds (EDCs) to clarify if EDCs could be causing the increased eelpout fry malformation frequencies observed in coastal areas receiving high anthropogenic input. The presence of a teratogenic window for estrogen...... induced by EE2 (5.7 and 17.8 ng/L) but not by 4-t-OP and pyrene. A critical period for estrogen-induced fry malformations was identified and closed between 14 and 22 days post fertilization (dpf). Exposure to 17β-estradiol (E2) between 0 and 14 dpf caused severe malformations and severity increased...... the closer exposure start was to fertilization, whereas malformations were absent by exposure starting later than 14 dpf. Data on ovarian fluid volume and larval length supported the suggested teratogenic window. Larval mortality also increased when exposure started right after fertilization....

Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior

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Vetreno, Ryan P.; Broadwater, Margaret A.; Robinson, Donita L.

2016-01-01

Adolescence is a developmental period when physical and cognitive abilities are optimized, when social skills are consolidated, and when sexuality, adolescent behaviors, and frontal cortical functions mature to adult levels. Adolescents also have unique responses to alcohol compared with adults, being less sensitive to ethanol sedative–motor responses that most likely contribute to binge drinking and blackouts. Population studies find that an early age of drinking onset correlates with increased lifetime risks for the development of alcohol dependence, violence, and injuries. Brain synapses, myelination, and neural circuits mature in adolescence to adult levels in parallel with increased reflection on the consequence of actions and reduced impulsivity and thrill seeking. Alcohol binge drinking could alter human development, but variations in genetics, peer groups, family structure, early life experiences, and the emergence of psychopathology in humans confound studies. As adolescence is common to mammalian species, preclinical models of binge drinking provide insight into the direct impact of alcohol on adolescent development. This review relates human findings to basic science studies, particularly the preclinical studies of the Neurobiology of Adolescent Drinking in Adulthood (NADIA) Consortium. These studies focus on persistent adult changes in neurobiology and behavior following adolescent intermittent ethanol (AIE), a model of underage drinking. NADIA studies and others find that AIE results in the following: increases in adult alcohol drinking, disinhibition, and social anxiety; altered adult synapses, cognition, and sleep; reduced adult neurogenesis, cholinergic, and serotonergic neurons; and increased neuroimmune gene expression and epigenetic modifiers of gene expression. Many of these effects are specific to adolescents and not found in parallel adult studies. AIE can cause a persistence of adolescent-like synaptic physiology, behavior, and sensitivity

Immunomodulatory effects of exposure to polychlorinated biphenyls and perfluoroalkyl acids in East Greenland ringed seals (Pusa hispida)

International Nuclear Information System (INIS)

Levin, Milton; Gebhard, Erika; Jasperse, Lindsay; Desforges, Jean-Pierre; Dietz, Rune; Sonne, Christian; Eulaers, Igor; Covaci, Adrian; Bossi, Rossana; De Guise, Sylvain

2016-01-01

To better elucidate the potential immune-related health effects of exposure to environmentally persistent organic pollutants (POP), such as polychlorinated biphenyls (PCBs) and perfluoroalkyl substances (PFASs), in ringed seals (Pusa hispida), a sentinel Arctic species, we assessed 1) associations between mitogen-induced lymphocyte proliferation and in vivo tissue contaminant burdens, and 2) the concentration-response effects of in vitro exposure to PFASs and PCB congeners on mitogen-induced lymphocyte proliferation. Upon in vitro contaminant exposure, the non-coplanar PCB congeners CB 138, 153, and 180, but not the coplanar CB 169, significantly reduced lymphocyte proliferation between 10 and 20 µg g −1 ww. The respective in vitro EC 50 values for these congeners were 13.3, 20.7, 20.8, and 54.6 µg g −1 ww. No modulation of lymphocyte proliferation was observed upon in vitro exposure to two individual PFASs, perfluorooctane sulphonic acid (PFOS) and perfluorooctanoic acid (PFOA), at concentrations up to 1000 ng g-1. In addition, no significant correlations were found between lymphocyte proliferation and any blood or blubber contaminant measured. Taken together, these data suggest this population of ringed seals is not currently at high risk of altered lymphocyte proliferation from exposure to the POPs or PFASs in this study. - Highlights: • Assess relationships between tissue contaminants and changes in immune function. • Risk for contaminant-induced immunotoxicity in East Greenland ringed seal is low. • Weight of evidence suggest non-coplanar PCBs are immunotoxic at high concentrations.

Initial uncertainty in Pavlovian reward prediction persistently elevates incentive salience and extends sign-tracking to normally unattractive cues.

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Robinson, Mike J F; Anselme, Patrick; Fischer, Adam M; Berridge, Kent C

2014-06-01

Uncertainty is a component of many gambling games and may play a role in incentive motivation and cue attraction. Uncertainty can increase the attractiveness for predictors of reward in the Pavlovian procedure of autoshaping, visible as enhanced sign-tracking (or approach and nibbles) by rats of a metal lever whose sudden appearance acts as a conditioned stimulus (CS+) to predict sucrose pellets as an unconditioned stimulus (UCS). Here we examined how reward uncertainty might enhance incentive salience as sign-tracking both in intensity and by broadening the range of attractive CS+s. We also examined whether initially induced uncertainty enhancements of CS+ attraction can endure beyond uncertainty itself, and persist even when Pavlovian prediction becomes 100% certain. Our results show that uncertainty can broaden incentive salience attribution to make CS cues attractive that would otherwise not be (either because they are too distal from reward or too risky to normally attract sign-tracking). In addition, uncertainty enhancement of CS+ incentive salience, once induced by initial exposure, persisted even when Pavlovian CS-UCS correlations later rose toward 100% certainty in prediction. Persistence suggests an enduring incentive motivation enhancement potentially relevant to gambling, which in some ways resembles incentive-sensitization. Higher motivation to uncertain CS+s leads to more potent attraction to these cues when they predict the delivery of uncertain rewards. In humans, those cues might possibly include the sights and sounds associated with gambling, which contribute a major component of the play immersion experienced by problematic gamblers. Copyright © 2014 Elsevier B.V. All rights reserved.

Exposure to time varying magnetic fields associated with magnetic resonance imaging reduces fentanyl-induced analgesia in mice

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Teskey, G.C.; Prato, F.S.; Ossenkopp, K.P.; Kavaliers, M.

1988-01-01

The effects of exposure to clinical magnetic resonance imaging (MRI) on analgesia induced by the mu opiate agonist, fentanyl, was examined in mice. During the dark period, adult male mice were exposed for 23.2 min to the time-varying (0.6 T/sec) magnetic field (TVMF) component of the MRI procedure. Following this exposure, the analgesic potency of fentanyl citrate (0.1 mg/kg) was determined at 5, 10, 15, and 30 min post-injection, using a thermal test stimulus (hot-plate 50 degrees C). Exposure to the magnetic-field gradients attenuated the fentanyl-induced analgesia in a manner comparable to that previously observed with morphine. These results indicate that the time-varying magnetic fields associated with MRI have significant inhibitory effects on the analgesic effects of specific mu-opiate-directed ligands.

Neutralization of TSLP inhibits airway remodeling in a murine model of allergic asthma induced by chronic exposure to house dust mite.

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Zhuang-Gui Chen

Full Text Available Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. However, the initiating factor that links airway inflammation to remodeling is unknown. Thymic stromal lymphopoietin (TSLP, an epithelium-derived cytokine, can strongly activate lung dendritic cells (DCs through the TSLP-TSLPR and OX40L-OX40 signaling pathways to promote Th2 differentiation. To determine whether TSLP is the underlying trigger of airway remodeling in chronic allergen-induced asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM extracts for up to 5 consecutive weeks. We showed that repeated respiratory exposure to HDM caused significant airway eosinophilic inflammation, peribronchial collagen deposition, goblet cell hyperplasia, and airway hyperreactivity (AHR to methacholine. These effects were accompanied with a salient Th2 response that was characterized by the upregulation of Th2-typed cytokines, such as IL-4 and IL-13, as well as the transcription factor GATA-3. Moreover, the levels of TSLP and transforming growth factor beta 1 (TGF-β1 were also increased in the airway. We further demonstrated, using the chronic HDM-induced asthma model, that the inhibition of Th2 responses via neutralization of TSLP with an anti-TSLP mAb reversed airway inflammation, prevented structural alterations, and decreased AHR to methacholine and TGF-β1 level. These results suggest that TSLP plays a pivotal role in the initiation and persistence of airway inflammation and remodeling in the context of chronic allergic asthma.

Effects of interferon on cultured cells persistently infected with viruses

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Crespi, M

1986-01-01

The role of interferon (IFN) in viral persistence at the cellular level was investigated. Two types of persistent infections were chosen. The first type was cell lines which contained hepatitis B virus (HBV) DNA (PLC/PRF/5 and Hep 3B cells) uninfected control hepatoma cells, (Mahlavu, HA22T and Hep G2 cells) or simian virus 40 (SV40) DNA (C2, C6, C11 cells) and control uninfected (CV-1 cells). In the second type of infection Vero cells persistently infected with SSPE or Sendai virus were used. The aim of this work was to determine what effect IFN had in these infections in terms of its antiviral and antiproliferative effects; which of the two major IFN-induced pathways, E enzyme or protein kinase were induced; whether there were any differences in sensitivity to IFN between the DNA and RNA virus persistent infections. The anti-viral effect of IFN was examined by its ability to inhibit Sindbis virus replication using a radioimmunoassay system. The antiproliferative effect of IFN was determined by cell counting and /sup 3/H-thymidine incorporation. The activation of the ribonuclease F, determined by the inhibition of /sup 3/H-leucine incorporation after introduction of 2-5 actin into the cells, was variable, being activated in all cell lines with the exception of the PLC/PRF/5, Hep 3B and Hep G2 cells. Major differences between the two DNA persistent infections and the two RNA persistent infections were found. No correlation was found between the presence of HBV or SV40 persistent infections and the sensitivity of the cell lines to IFN. Both the SSPE and Sendai virus persistent infections were resistant to the antiviral and antiproliferative effect of IFN.

Maternal house dust mite exposure during pregnancy enhances severity of house dust mite-induced asthma in murine offspring.

Science.gov (United States)

Richgels, Phoebe K; Yamani, Amnah; Chougnet, Claire A; Lewkowich, Ian P

2017-11-01

Atopic status of the mother and maternal exposure to environmental factors are associated with increased asthma risk. Moreover, animal models demonstrate that exposure to allergens in strongly sensitized mothers influences offspring asthma development, suggesting that in utero exposures can influence offspring asthma. However, it is unclear whether maternal exposure to common human allergens such as house dust mite (HDM), in the absence of additional adjuvants, influences offspring asthma development. We sought to determine whether maternal HDM exposure influences asthma development in offspring. Pregnant female mice were exposed to PBS or HDM during pregnancy. Using offspring of PBS- or HDM-exposed mothers, the magnitude of HDM or Aspergillus fumigatus (AF) extract-induced airway hyperresponsiveness (AHR), airway inflammation, immunoglobulin production, T H 2-associated cytokine synthesis, and pulmonary dendritic cell activity was assessed. Compared with offspring of PBS-exposed mothers, offspring of HDM-exposed mothers demonstrate increased AHR, airway inflammation, T H 2 cytokine production, and immunoglobulin levels and a modest decrease in the phagocytic capacity of pulmonary macrophage populations following HDM exposure. Increased sensitivity to AF-induced airway disease was not observed. Offspring of HDM-exposed B-cell-deficient mothers also demonstrated increased HDM-induced AHR, suggesting that transfer of maternal immunoglobulins is not required. Our data demonstrate that maternal exposure to HDM during pregnancy increases asthma sensitivity in offspring in an HDM-specific manner, suggesting that vertical transmission of maternal immune responses may be involved. These findings have important implications for regulation of asthma risk, and suggest that exposure to HDM in the developed world may have underappreciated influences on the overall prevalence of allergic asthma. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by

A Clinical Drug Library Screen Identifies Tosufloxacin as Being Highly Active against Staphylococcus aureus Persisters

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Hongxia Niu

2015-07-01

Full Text Available To identify effective compounds that are active against Staphylococcus aureus (S. aureus persisters, we screened a clinical drug library consisting of 1524 compounds and identified six drug candidates that had anti-persister activity: tosufloxacin, clinafloxacin, sarafloxacin, doxycycline, thiostrepton, and chlorosalicylanilide. Among them, tosufloxacin had the highest anti-persister activity, which could completely eradicate S. aureus persisters within 2 days in vitro. Clinafloxacin ranked the second with very few persisters surviving the drug exposure. Interestingly, we found that both tosufloxacin and trovafloxacin that had high activity against persisters contained at the N-1 position the 2,4-difluorophenyl group, which is absent in other less active quinolones and may be associated with the high anti-persister activity. Further studies are needed to evaluate tosufloxacin in animal models and to explain its unique activity against bacterial persisters. Our findings may have implications for improved treatment of persistent bacterial infections.

Foxp3+ regulatory T cells control persistence of viral CNS infection.

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Dajana Reuter

Full Text Available We earlier established a model of a persistent viral CNS infection using two week old immunologically normal (genetically unmodified mice and recombinant measles virus (MV. Using this model infection we investigated the role of regulatory T cells (Tregs as regulators of the immune response in the brain, and assessed whether the persistent CNS infection can be modulated by manipulation of Tregs in the periphery. CD4(+ CD25(+ Foxp3(+ Tregs were expanded or depleted during the persistent phase of the CNS infection, and the consequences for the virus-specific immune response and the extent of persistent infection were analyzed. Virus-specific CD8(+ T cells predominantly recognising the H-2D(b-presented viral hemagglutinin epitope MV-H(22-30 (RIVINREHL were quantified in the brain by pentamer staining. Expansion of Tregs after intraperitoneal (i.p. application of the superagonistic anti-CD28 antibody D665 inducing transient immunosuppression caused increased virus replication and spread in the CNS. In contrast, depletion of Tregs using diphtheria toxin (DT in DEREG (depletion of regulatory T cells-mice induced an increase of virus-specific CD8(+ effector T cells in the brain and caused a reduction of the persistent infection. These data indicate that manipulation of Tregs in the periphery can be utilized to regulate virus persistence in the CNS.

Beam-based measurements of persistent current decay in the Relativistic Heavy Ion Collider

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W. Fischer

2001-04-01

Full Text Available The two rings of the Relativistic Heavy Ion Collider are equipped with superconducting dipole magnets. At injection, induced persistent currents in these magnets lead to a sextupole component. As the persistent currents decay with time, the horizontal and vertical chromaticities change. From magnet measurements of persistent current decays, chromaticity changes in the machine are estimated and compared with chromaticity measurements.

Persistence of Gamma-H2AX Foci in Irradiated Bronchial Cells Correlates with Susceptibility to Radiation Associated Lung Cancer in Mice

Science.gov (United States)

Ochola, Donasian O.; Sharif, Rabab; Bedford, Joel S.; Keefe, Thomas J.; Kato, Takamitsu A.; Fallgren, Christina M.; Demant, Peter; Costes, Sylvain V.; Weil, Michael M.

2018-01-01

The risk of developing radiation-induced lung cancer differs between different strains of mice, but the underlying cause of the strain differences is unknown. Strains of mice also differ in their ability to efficiently repair DNA double strand breaks resulting from radiation exposure. We phenotyped mouse strains from the CcS/Dem recombinant congenic strain set for their efficacy in repairing DNA double strand breaks during protracted radiation exposures. We monitored persistent gamma-H2AX radiation induced foci (RIF) 24 hours after exposure to chronic gamma-rays as a surrogate marker for repair deficiency in bronchial epithelial cells for 17 of the CcS/Dem strains and the BALB/cHeN founder strain. We observed a very strong correlation R2 = 79.18%, P cancer percent incidence measured in the same strains. Interestingly, spontaneous levels of foci in non-irradiated strains also showed good correlation with lung cancer incidence (R2=32.74%, P =0.013). These results suggest that genetic differences in DNA repair capacity largely account for differing susceptibilities to radiation-induced lung cancer among CcS/Dem mouse strains and that high levels of spontaneous DNA damage is also a relatively good marker of cancer predisposition. In a smaller pilot study, we found that the repair capacity measured in peripheral blood leucocytes also correlated well with radiogenic lung cancer susceptibility, raising the possibility that such phenotyping assay could be used to detect radiogenic lung cancer susceptibility in humans.

Herbicide Persistence in Seawater Simulation Experiments.

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Philip Mercurio

Full Text Available Herbicides are detected year-round in marine waters, including those of the World Heritage listed Great Barrier Reef (GBR. The few previous studies that have investigated herbicide persistence in seawater generally reported half-lives in the order of months, and several studies were too short to detect significant degradation. Here we investigated the persistence of eight herbicides commonly detected in the GBR or its catchments in standard OECD simulation flask experiments, but with the aim to mimic natural conditions similar to those found on the GBR (i.e., relatively low herbicide concentrations, typical temperatures, light and microbial communities. Very little degradation was recorded over the standard 60 d period (Experiment 1 so a second experiment was extended to 365 d. Half-lives of PSII herbicides ametryn, atrazine, diuron, hexazinone and tebuthiuron were consistently greater than a year, indicating high persistence. The detection of atrazine and diuron metabolites and longer persistence in mercuric chloride-treated seawater confirmed that biodegradation contributed to the breakdown of herbicides. The shortest half-life recorded was 88 d for growth-regulating herbicide 2,4-D at 31°C in the dark, while the fatty acid-inhibitor metolachlor exhibited a minimum half-life of 281 d. The presence of moderate light and elevated temperatures affected the persistence of most of the herbicides; however, the scale and direction of the differences were not predictable and were likely due to changes in microbial community composition. The persistence estimates here represent some of the first appropriate data for application in risk assessments for herbicide exposure in tropical marine systems. The long persistence of herbicides identified in the present study helps explain detection of herbicides in nearshore waters of the GBR year round. Little degradation of these herbicides would be expected during the wet season with runoff and associated

Herbicide Persistence in Seawater Simulation Experiments

Science.gov (United States)

Mercurio, Philip; Mueller, Jochen F.; Eaglesham, Geoff; Flores, Florita; Negri, Andrew P.

2015-01-01

Herbicides are detected year-round in marine waters, including those of the World Heritage listed Great Barrier Reef (GBR). The few previous studies that have investigated herbicide persistence in seawater generally reported half-lives in the order of months, and several studies were too short to detect significant degradation. Here we investigated the persistence of eight herbicides commonly detected in the GBR or its catchments in standard OECD simulation flask experiments, but with the aim to mimic natural conditions similar to those found on the GBR (i.e., relatively low herbicide concentrations, typical temperatures, light and microbial communities). Very little degradation was recorded over the standard 60 d period (Experiment 1) so a second experiment was extended to 365 d. Half-lives of PSII herbicides ametryn, atrazine, diuron, hexazinone and tebuthiuron were consistently greater than a year, indicating high persistence. The detection of atrazine and diuron metabolites and longer persistence in mercuric chloride-treated seawater confirmed that biodegradation contributed to the breakdown of herbicides. The shortest half-life recorded was 88 d for growth-regulating herbicide 2,4-D at 31°C in the dark, while the fatty acid-inhibitor metolachlor exhibited a minimum half-life of 281 d. The presence of moderate light and elevated temperatures affected the persistence of most of the herbicides; however, the scale and direction of the differences were not predictable and were likely due to changes in microbial community composition. The persistence estimates here represent some of the first appropriate data for application in risk assessments for herbicide exposure in tropical marine systems. The long persistence of herbicides identified in the present study helps explain detection of herbicides in nearshore waters of the GBR year round. Little degradation of these herbicides would be expected during the wet season with runoff and associated flood plumes

Formaldehyde and co-exposure with benzene induce compensation of bone marrow and hematopoietic stem/progenitor cells in BALB/c mice during post-exposure period

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Wei, Chenxi [Key Laboratory of Ecological Safety Monitoring and Evaluation, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan (China); Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China); Chen, Mouying [Key Laboratory of Ecological Safety Monitoring and Evaluation, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan (China); You, Huihui [Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China); Qiu, Feng [Key Laboratory of Ecological Safety Monitoring and Evaluation, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan (China); Wen, Huaxiao; Yuan, Junlin [Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China); Xiang, Shuanglin, E-mail: xshlin@hunnu.edu.cn [Key Laboratory of Ecological Safety Monitoring and Evaluation, School of Life Sciences, Hunan Normal University, Changsha 410081, Hunan (China); Yang, Xu, E-mail: yangxu@mail.ccnu.edu.cn [Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, Hubei (China)

2017-06-01

Formaldehyde (FA) is a human leukemogen. Since there is a latency period between initial FA exposure and the development of leukemia, the subsequent impact of FA on hematopoietic stem or progenitor cells (HSCs/HPCs) in post-exposure stage is crucial for a deep understanding of FA-induced hematotoxicity. BALB/c mice were exposed to 3 mg/m{sup 3} FA for 2 weeks, mimicking occupational exposure, and were monitored for another 7 days post-exposure. Meanwhile, we included benzene (BZ) as a positive control, separately and together with FA because co-exposure occurs frequently. After 7-day recovery, colonies of progenitors for CFU-GM and BFU-E, and nucleated bone marrow cells in FA-exposed mice were comparable to controls, although they were significantly reduced during exposure. Levels of reactive oxygen species (ROS) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in CFU-GM and BFU-E from FA-exposed mice were higher than controls, although the increase in 8-OHdG was not significant. Granulocyte-macrophage colony stimulating factor (GM-CSF) level in the FA group was lower than controls, but the expression level for the receptor was not upregulated. It suggests that HSCs/HPCs in FA-exposed mice respond to a small amount of GM-CSF and proliferate rapidly, which may cause a possible risk of expansion of abnormal stem/progenitor cell clones. FA co-exposure with BZ was more potent for promoting CFU-GM formation and inducing ROS in BFU-E and 8-OHdG in CFU-GM during the post-exposure period. The compensation of myeloid progenitors with elevated ROS and 8-OHdG may lead to a risk of transforming normal HSCs/HPCs to leukemic stem/progenitor cells. Thus, co-exposure may pose a greater leukemia risk. - Highlights: • Nucleated bone marrow cell count recovered after 7 days post-FA and/or BZ exposure. • CFU-GM showed an increase in colonies and 8-OHdG after 7 days post-FA + BZ exposure. • Levels of ROS in CFU-GM and BFU-E were increased by FA or FA + BZ during recovery. • Levels of

Formaldehyde and co-exposure with benzene induce compensation of bone marrow and hematopoietic stem/progenitor cells in BALB/c mice during post-exposure period

International Nuclear Information System (INIS)

Wei, Chenxi; Chen, Mouying; You, Huihui; Qiu, Feng; Wen, Huaxiao; Yuan, Junlin; Xiang, Shuanglin; Yang, Xu

2017-01-01

Formaldehyde (FA) is a human leukemogen. Since there is a latency period between initial FA exposure and the development of leukemia, the subsequent impact of FA on hematopoietic stem or progenitor cells (HSCs/HPCs) in post-exposure stage is crucial for a deep understanding of FA-induced hematotoxicity. BALB/c mice were exposed to 3 mg/m 3 FA for 2 weeks, mimicking occupational exposure, and were monitored for another 7 days post-exposure. Meanwhile, we included benzene (BZ) as a positive control, separately and together with FA because co-exposure occurs frequently. After 7-day recovery, colonies of progenitors for CFU-GM and BFU-E, and nucleated bone marrow cells in FA-exposed mice were comparable to controls, although they were significantly reduced during exposure. Levels of reactive oxygen species (ROS) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in CFU-GM and BFU-E from FA-exposed mice were higher than controls, although the increase in 8-OHdG was not significant. Granulocyte-macrophage colony stimulating factor (GM-CSF) level in the FA group was lower than controls, but the expression level for the receptor was not upregulated. It suggests that HSCs/HPCs in FA-exposed mice respond to a small amount of GM-CSF and proliferate rapidly, which may cause a possible risk of expansion of abnormal stem/progenitor cell clones. FA co-exposure with BZ was more potent for promoting CFU-GM formation and inducing ROS in BFU-E and 8-OHdG in CFU-GM during the post-exposure period. The compensation of myeloid progenitors with elevated ROS and 8-OHdG may lead to a risk of transforming normal HSCs/HPCs to leukemic stem/progenitor cells. Thus, co-exposure may pose a greater leukemia risk. - Highlights: • Nucleated bone marrow cell count recovered after 7 days post-FA and/or BZ exposure. • CFU-GM showed an increase in colonies and 8-OHdG after 7 days post-FA + BZ exposure. • Levels of ROS in CFU-GM and BFU-E were increased by FA or FA + BZ during recovery. • Levels of GM

Oral imazalil exposure induces gut microbiota dysbiosis and colonic inflammation in mice.

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Jin, Cuiyuan; Zeng, Zhaoyang; Fu, Zhengwei; Jin, Yuanxiang

2016-10-01

The fungicide imazalil (IMZ) is used extensively in vegetable and fruit plantations and as a post-harvest treatment to avoid rot. Here, we revealed that ingestion of 25, 50 and 100 mg IMZ kg(-1) body weight for 28 d induced gut microbiota dysbiosis and colonic inflammation in mice. The relative abundance of Bacteroidetes, Firmicutes and Actinobacteria in the cecal contents decreased significantly after exposure to 100 mg kg(-1) IMZ for 28 d. In feces, the relative abundance in Bacteroidetes, Firmicutes and Actinobacteria decreased significantly after being exposed to 100 mg kg(-1) IMZ for 1, 14 and 7 d, respectively. High throughput sequencing of the V3-V4 region of the bacterial 16S rRNA gene revealed a significant reduction in the richness and diversity of microbiota in cecal contents and feces of IMZ-treated mice. Operational taxonomic units (OTUs) analysis identified 49.3% of OTUs changed in cecal contents, while 55.6% of OTUs changed in the feces after IMZ exposure. Overall, at the phylum level, the relative abundance of Firmicutes, Proteobacteria and Actinobacteria increased and that of Bacteroidetes decreased in IMZ-treated groups. At the genus level, the abundance of Lactobacillus and Bifidobacterium decreased while those of Deltaproteobacteria and Desulfovibrio increased in response to IMZ exposure. In addition, it was observed that IMZ exposure could induce colonic inflammation characterized by infiltration of inflammatory cells, elevated levels of lipocalin-2 (lcn-2) in the feces, and increased mRNA levels of Tnf-α, IL-1β, IL-22 and IFN-γ in the colon. Our findings strongly suggest that ingestion of IMZ has some risks to human health. Copyright © 2016 Elsevier Ltd. All rights reserved.

The role of natural and UV-induced skin pigmentation on low-fluence IPL-induced side effects: a randomized controlled trial.

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Thaysen-Petersen, Daniel; Lin, Jennifer Y; Nash, Jf; Beerwerth, Frank; Wulf, Hans C; Philipsen, Peter A; Haedersdal, Merete

2014-02-01

The risk of adverse skin effects following light-based hair removal is greater in pigmented skin based on the theory of selective photothermolysis. Thus sunlight-induced pigment i.e., facultative pigmentation, increases the risk of adverse skin effects, perhaps disproportionately. The aim of this study was to evaluate the influence of constitutive and facultative skin pigmentation on low-fluence intense pulsed light (IPL)-induced adverse skin effects. Twenty-one subjects with Fitzpatrick skin type II-IV were enrolled. Two buttock blocks were randomized to receive 0 or 8 solar simulated ultraviolet radiation (UVR) exposures of consecutively increasing Standard Erythema Doses (2-4 SED). Each block was subdivided into four sites, randomized to receive IPL of 0, 7, 8, or 10 J/cm(2) , once a week for 3 weeks. Biopsies were taken 16-24 hours after the first IPL exposure and subjects were seen 1 and 4 weeks after the last IPL exposure. Outcome measures were: (i) skin reactions, (ii) pain, (iii) mRNA expression of pigment-markers microphthalmia-associated transcription factor (MITF) and pro-opiomelanocortin (POMC), and (iv) clinical appearance of biopsy wounds. Skin pigmentation increased after UVR (baseline median 13.8%, after UVR 28.1%, P = 0.0001) in all skin types. Subjects reported low pain intensities (median 1.5, scale 0-10) and experienced transient erythema immediately after IPL exposure. No persistent erythema, blisters, crusting, textual, or pigment changes were observed. The risk of erythema and pain intensities increased with IPL dose and skin pigmentation (P skin reactions in skin with similar degree of natural and facultative pigmentation (P ≥ 0.104). Expression of cellular pigment-markers was not influenced by IPL exposure, neither in constitutive nor in facultative pigmented skin. Clinical appearance of biopsy wounds was unaffected by IPL exposure. The prevalence and intensity of low-fluence IPL-induced adverse skin effects depended on IPL

Environmental and behavioral changes may influence the exposure of an Arctic apex predator to pathogens and contaminants

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Atwood, Todd C.; Duncan, Colleen G.; Patyk, Kelly A.; Nol, Pauline; Rhyan, Jack; McCollum, Matthew; McKinney, Melissa A.; Ramey, Andy M.; Cerqueira-Cezar, Camila; Kwok, Oliver C H; Dubey, Jitender P; Hennager, S.G.

2017-01-01

Recent decline of sea ice habitat has coincided with increased use of land by polar bears (Ursus maritimus) from the southern Beaufort Sea (SB), which may alter the risks of exposure to pathogens and contaminants. We assayed blood samples from SB polar bears to assess prior exposure to the pathogens Brucella spp., Toxoplasma gondii, Coxiella burnetii, Francisella tularensis, and Neospora caninum, estimate concentrations of persistent organic pollutants (POPs), and evaluate risk factors associated with exposure to pathogens and POPs. We found that seroprevalence of Brucella spp. and T. gondii antibodies likely increased through time, and provide the first evidence of exposure of polar bears to C. burnetii, N. caninum, and F. tularensis. Additionally, the odds of exposure to T. gondii were greater for bears that used land than for bears that remained on the sea ice during summer and fall, while mean concentrations of the POP chlordane (ΣCHL) were lower for land-based bears. Changes in polar bear behavior brought about by climate-induced modifications to the Arctic marine ecosystem may increase exposure risk to certain pathogens and alter contaminant exposure pathways.

Strong Delayed Interactive Effects of Metal Exposure and Warming: Latitude-Dependent Synergisms Persist Across Metamorphosis.

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Debecker, Sara; Dinh, Khuong V; Stoks, Robby

2017-02-21

As contaminants are often more toxic at higher temperatures, predicting their impact under global warming remains a key challenge for ecological risk assessment. Ignoring delayed effects, synergistic interactions between contaminants and warming, and differences in sensitivity across species' ranges could lead to an important underestimation of the risks. We addressed all three mechanisms by studying effects of larval exposure to zinc and warming before, during, and after metamorphosis in Ischnura elegans damselflies from high- and low-latitude populations. By integrating these mechanisms into a single study, we could identify two novel patterns. First, during exposure zinc did not affect survival, whereas it induced mild to moderate postexposure mortality in the larval stage and at metamorphosis, and very strongly reduced adult lifespan. This severe delayed effect across metamorphosis was especially remarkable in high-latitude animals, as they appeared almost insensitive to zinc during the larval stage. Second, the well-known synergism between metals and warming was manifested not only during the larval stage but also after metamorphosis, yet notably only in low-latitude damselflies. These results highlight that a more complete life-cycle approach that incorporates the possibility of delayed interactions between contaminants and warming in a geographical context is crucial for a more realistic risk assessment in a warming world.

Persistence of Coxsackievirus B4 in pancreatic ductal-like cells results in cellular and viral changes.

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Alidjinou, E K; Engelmann, I; Bossu, J; Villenet, C; Figeac, M; Romond, M-B; Sané, F; Hober, D

2017-10-03

Although known as cytolytic viruses, group B coxackieviruses (CVB) are able to establish a persistent infection in vitro and in vivo. Viral persistence has been reported as a key mechanism in the pathogenesis of CVB-associated chronic diseases such as type 1 diabetes (T1D). The impact of CVB4 persistence on human pancreas ductal-like cells was investigated. A persistent CVB4 infection was established in ductal-like cells. PDX-1 expression, resistance to CVB4-induced lysis and CAR expression were evaluated. The profile of cellular microRNAs (miRNAs) was investigated through miRNA-sequencing. Viral phenotypic changes were examined, and genomic modifications were assessed by sequencing of the viral genome. The CVB4 persistence in ductal-like cells was productive, with continuous release of infectious particles. Persistently infected cells displayed a resistance to CVB4-induced lysis upon superinfection and expression of PDX-1 and CAR was decreased. These changes were maintained even after virus clearance. The patterns of cellular miRNA expression in mock-infected and in CVB4-persistently infected ductal-like cells were clearly different. The persistent infection-derived virus (PIDV) was still able to induce cytopathic effect but its plaques were smaller than the parental virus. Several mutations appeared in various PIDV genome regions, but amino acid substitutions did not affect the predicted site of interaction with CAR. Cellular and viral changes occur during persistent infection of human pancreas ductal-like cells with CVB4. The persistence of cellular changes even after virus clearance supports the hypothesis of a long-lasting impact of persistent CVB infection on the cells.

HIV Persistence in Gut-Associated Lymphoid Tissues: Pharmacological Challenges and Opportunities.

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Thompson, Corbin G; Gay, Cynthia L; Kashuba, Angela D M

2017-06-01

An increasing amount of evidence suggests that HIV replication persists in gut-associated lymphoid tissues (GALT), despite treatment with combination antiretroviral therapy (cART). Residual replication in this compartment may propagate infection at other sites in the body and contribute to sustained immune dysregulation and delayed immune recovery. Therefore, it is important to focus efforts on eliminating residual replication at this site. There are several challenges to accomplishing this goal, including low antiretroviral (ARV) exposure at specific tissue locations within GALT, which might be overcome by using the tools of clinical pharmacology. Here, we summarize the evidence for GALT as a site of residual HIV replication, highlight the consequences of persistent infection in tissues, identify current pharmacologic knowledge of drug exposure in GALT, define the challenges that hinder eradication from this site, and propose several avenues for pharmacologic intervention.

Tributyltin exposure induces gut microbiome dysbiosis with increased body weight gain and dyslipidemia in mice.

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Guo, Hao; Yan, Haotian; Cheng, Dong; Wei, Xinglong; Kou, Ruirui; Si, Jiliang

2018-05-03

Gut microbiome dysbiosis plays a profound role in the pathogenesis of obesity and tributyltin (TBT) has been found as an environmental obesogen. However, whether TBT could disturb gut microbiome and the relationship between obesity induced by TBT exposure and alteration in gut microbiota are still unknown. In order to assess the association between them, mice were exposed to TBTCl (50 μg kg -1 ) once every three days from postnatal days (PNDs) 24 to 54. The results demonstrated that TBT exposure resulted in increased body weight gain, lager visceral fat accumulation and dyslipidemia in male mice on PND 84. Correspondingly, 16S rRNA gene sequencing revealed that TBT treatment decreased gut microbial species and perturbed the microbiome composition in mice. Furthermore, Pearson's corelation coefficient analysis showed a significantly negative correlation between the body weight and the alpha diversity of gut microbiome. These results suggested that TBT exposure could induce gut microbiome dysbiosis in mice, which might contribute to the obesity pathogenesis. Copyright © 2018 Elsevier B.V. All rights reserved.

Heavy Chronic Ethanol Exposure From Adolescence to Adulthood Induces Cerebellar Neuronal Loss and Motor Function Damage in Female Rats

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Fernando B. R. da Silva

2018-05-01

Full Text Available Over the last years, heavy ethanol consumption by teenagers/younger adults has increased considerably among females. However, few studies have addressed the long-term impact on brain structures’ morphology and function of chronic exposure to high ethanol doses from adolescence to adulthood in females. In line with this idea, in the current study we investigated whether heavy chronic ethanol exposure during adolescence to adulthood may induce motor impairments and morphological and cellular alterations in the cerebellum of female rats. Adolescent female Wistar rats (35 days old were treated with distilled water or ethanol (6.5 g/kg/day, 22.5% w/v during 55 days by gavage. At 90 days of age, motor function of animals was assessed using open field (OF, pole, beam walking and rotarod tests. Following completion of behavioral tests, morphological and immunohistochemical analyses of the cerebellum were performed. Chronic ethanol exposure impaired significantly motor performance of female rats, inducing spontaneous locomotor activity deficits, bradykinesia, incoordination and motor learning disruption. Moreover, histological analysis revealed that ethanol exposure induced atrophy and neuronal loss in the cerebellum. These findings indicate that heavy ethanol exposure during adolescence is associated with long-lasting cerebellar degeneration and motor impairments in female rats.

Pre-exposure to 50 Hz magnetic fields modifies menadione-induced genotoxic effects in human SH-SY5Y neuroblastoma cells.

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Jukka Luukkonen

Full Text Available BACKGROUND: Extremely low frequency (ELF magnetic fields (MF are generated by power lines and various electric appliances. They have been classified as possibly carcinogenic by the International Agency for Research on Cancer, but a mechanistic explanation for carcinogenic effects is lacking. A previous study in our laboratory showed that pre-exposure to ELF MF altered cancer-relevant cellular responses (cell cycle arrest, apoptosis to menadione-induced DNA damage, but it did not include endpoints measuring actual genetic damage. In the present study, we examined whether pre-exposure to ELF MF affects chemically induced DNA damage level, DNA repair rate, or micronucleus frequency in human SH-SY5Y neuroblastoma cells. METHODOLOGY/PRINCIPAL FINDINGS: Exposure to 50 Hz MF was conducted at 100 µT for 24 hours, followed by chemical exposure for 3 hours. The chemicals used for inducing DNA damage and subsequent micronucleus formation were menadione and methyl methanesulphonate (MMS. Pre-treatment with MF enhanced menadione-induced DNA damage, DNA repair rate, and micronucleus formation in human SH-SY5Y neuroblastoma cells. Although the results with MMS indicated similar effects, the differences were not statistically significant. No effects were observed after MF exposure alone. CONCLUSIONS: The results confirm our previous findings showing that pre-exposure to MFs as low as 100 µT alters cellular responses to menadione, and show that increased genotoxicity results from such interaction. The present findings also indicate that complementary data at several chronological points may be critical for understanding the MF effects on DNA damage, repair, and post-repair integrity of the genome.

Pre-exposure to 50 Hz magnetic fields modifies menadione-induced genotoxic effects in human SH-SY5Y neuroblastoma cells.

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Luukkonen, Jukka; Liimatainen, Anu; Höytö, Anne; Juutilainen, Jukka; Naarala, Jonne

2011-03-23

Extremely low frequency (ELF) magnetic fields (MF) are generated by power lines and various electric appliances. They have been classified as possibly carcinogenic by the International Agency for Research on Cancer, but a mechanistic explanation for carcinogenic effects is lacking. A previous study in our laboratory showed that pre-exposure to ELF MF altered cancer-relevant cellular responses (cell cycle arrest, apoptosis) to menadione-induced DNA damage, but it did not include endpoints measuring actual genetic damage. In the present study, we examined whether pre-exposure to ELF MF affects chemically induced DNA damage level, DNA repair rate, or micronucleus frequency in human SH-SY5Y neuroblastoma cells. Exposure to 50 Hz MF was conducted at 100 µT for 24 hours, followed by chemical exposure for 3 hours. The chemicals used for inducing DNA damage and subsequent micronucleus formation were menadione and methyl methanesulphonate (MMS). Pre-treatment with MF enhanced menadione-induced DNA damage, DNA repair rate, and micronucleus formation in human SH-SY5Y neuroblastoma cells. Although the results with MMS indicated similar effects, the differences were not statistically significant. No effects were observed after MF exposure alone. The results confirm our previous findings showing that pre-exposure to MFs as low as 100 µT alters cellular responses to menadione, and show that increased genotoxicity results from such interaction. The present findings also indicate that complementary data at several chronological points may be critical for understanding the MF effects on DNA damage, repair, and post-repair integrity of the genome.

Exposure to excess insulin (glargine) induces type 2 diabetes mellitus in mice fed on a chow diet.

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Yang, Xuefeng; Mei, Shuang; Gu, Haihua; Guo, Huailan; Zha, Longying; Cai, Junwei; Li, Xuefeng; Liu, Zhenqi; Cao, Wenhong

2014-06-01

We have previously shown that insulin plays an important role in the nutrient-induced insulin resistance. In this study, we tested the hypothesis that chronic exposure to excess long-acting insulin (glargine) can cause typical type 2 diabetes mellitus (T2DM) in normal mice fed on a chow diet. C57BL/6 mice were treated with glargine once a day for 8 weeks, followed by evaluations of food intake, body weight, blood levels of glucose, insulin, lipids, and cytokines, insulin signaling, histology of pancreas, ectopic fat accumulation, oxidative stress level, and cholesterol content in mitochondria in tissues. Cholesterol content in mitochondria and its association with oxidative stress in cultured hepatocytes and β-cells were also examined. Results show that chronic exposure to glargine caused insulin resistance, hyperinsulinemia, and relative insulin deficiency (T2DM). Treatment with excess glargine led to loss of pancreatic islets, ectopic fat accumulation in liver, oxidative stress in liver and pancreas, and increased cholesterol content in mitochondria of liver and pancreas. Prolonged exposure of cultured primary hepatocytes and HIT-TI5 β-cells to insulin induced oxidative stress in a cholesterol synthesis-dependent manner. Together, our results show that chronic exposure to excess insulin can induce typical T2DM in normal mice fed on a chow diet. © 2014 The authors.

Nitrogen narcosis induced by repetitive hyperbaric nitrogen oxygen mixture exposure impairs long-term cognitive function in newborn mice.

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Bin Peng

Full Text Available Human beings are exposed to compressed air or a nitrogen-oxygen mixture, they will produce signs and symptoms of nitrogen narcosis such as amnesia or even loss of memory, which may be disappeared once back to the normobaric environment. This study was designed to investigate the effect of nitrogen narcosis induced by repetitive hyperbaric nitrogen-oxygen mixture exposure on long-term cognitive function in newborn mice and the underlying mechanisms. The electroencephalogram frequency was decreased while the amplitude was increased in a pressure-dependent manner during 0.6, 1.2, 1.8 MPa (million pascal nitrogen-oxygen mixture exposures in adult mice. Nitrogen narcosis in postnatal days 7-9 mice but not in adult mice induced by repetitive hyperbaric exposure prolonged the latency to find the platform and decreased the number of platform-site crossovers during Morris water maze tests, and reduced the time in the center during the open field tests. An increase in the expression of cleaved caspase-3 in the hippocampus and cortex were observed immediately on the first day after hyperbaric exposure, and this lasted for seven days. Additionally, nitrogen narcosis induced loss of the dendritic spines but not of the neurons, which may mainly account for the cognitive dysfunction. Nitrogen narcosis induced long-term cognitive and emotional dysfunction in the postnatal mice but not in the adult mice, which may result from neuronal apoptosis and especially reduction of dendritic spines of neurons.

Could driving safety be compromised by noise exposure at work and noise-induced hearing loss?

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Picard, Michel; Girard, Serge André; Courteau, Marilène; Leroux, Tony; Larocque, Richard; Turcotte, Fernand; Lavoie, Michel; Simard, Marc

2008-10-01

A study was conducted to verify if there is an association between occupational noise exposure, noise-induced hearing loss and driving safety expanding on previous findings by Picard, et al. (2008) that the two factors did increase accident risk in the workplace. This study was made possible when driving records of all Quebec drivers were made available by the Societe de l'assurance automobile du Quebec (SAAQ is the state monopoly responsible for the provision of motor vehicle insurance and the compensation of victims of traffic accidents). These records were linked with personal records maintained by the Quebec National Institute of Public Health as part of its mission to prevent noise induced hearing loss in the workplace. Individualized information on occupational noise exposure and hearing sensitivity was available for 46,030 male workers employed in noisy industries who also held a valid driver's permit. The observation period is of five years duration, starting with the most recent audiometric examination. The associations between occupational noise exposure levels, hearing status, and personal driving record were examined by log-binomial regression on data adjusted for age and duration of exposure. Daily noise exposures and bilateral average hearing threshold levels at 3, 4, and 6 kHz were used as independent variables while the dependent variables were 1) the number of motor vehicle accidents experienced by participants during the study period and 2) participants' records of registered traffic violations of the highway safety code. The findings are reported as prevalence ratios (PRs) with their 95% confidence intervals (CIs). Attributable numbers of events were computed with the relevant PRs, lesser-noise, exposed workers and those with normal hearing levels making the group of reference. Adjusting for age confirmed that experienced workers had fewer traffic accidents. The data show that occupational noise exposure and hearing loss have the same effect on

Persistent tumor-induced osteomalacia confirmed by elevated postoperative levels of serum fibroblast growth factor-23 and 5-year follow-up of bone density changes.

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Zimering, Mark B; Caldarella, Felice A; White, Kenneth E; Econs, Michael J

2005-01-01

To describe a case of persistent tumor-induced osteomalacia, determine whether serum fibroblast growth factor-23 (FGF-23) levels postoperatively indicate incomplete tumor resection, and report lumbar spine and forearm bone mineral density (BMD) changes during 5 years of follow-up. We present clinical, radiologic, histologic, and bone densitometry data as well as serum FGF-23 levels (determined with use of a novel C-terminal enzyme-linked immunosorbent assay) from the study patient and discuss these findings in the context of previous literature. A 52-year-old man, who presented with muscle weakness and multiple fractures, was found to have low values for serum phosphorus, serum 1,25-dihydroxyvitamin D, and maximal tubular reabsorption of phosphate per glomerular filtration rate, a high level of serum alkaline phosphatase, and a normal serum concentration of parathyroid hormone, characteristic of tumor-induced osteomalacia. Magnetic resonance imaging to evaluate an abnormality of the left foot revealed a soft tissue mass, biopsy of which confirmed the presence of a benign, phosphaturic, mesenchymal tumor. The baseline serum FGF-23 level (2,050 RU/mL) was more than 17 times the upper limit of normal for adults (23 to 118 RU/mL) and decreased substantially within 1 day after partial resection of the tumor but remained above normal postoperatively. BMD changes indicated rapid substantial recovery of vertebral BMD but ongoing loss of forearm bone density. The serum FGF-23 level is high in a substantial proportion of patients with tumor-induced osteomalacia. The postoperative above normal levels of serum FGF-23 correlated with known persistence of tumor in our study patient. In a patient with normal renal function, such as our study patient, levels of serum FGF-23 studied with use of the C-terminal enzyme-linked immunosorbent assay reached their nadir within 24 hours postoperatively. This result suggests that this assay can provide clinicians with rapid prognostic

BaP-metals co-exposure induced tissue-specific antioxidant defense in marine mussels Mytilus coruscus.

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Chen, Siyu; Qu, Mengjie; Ding, Jiawei; Zhang, Yifei; Wang, Yi; Di, Yanan

2018-04-18

Both benzo(α)pyrene (BaP) and metals are frequently found in marine ecosystem and can cause detrimental effects in marine organism, especially the filter feeder-marine mussels. Although the biological responses in mussels have been well-studied upon the single metal or BaP exposure, the information about antioxidant defense, especially in different tissues of mussels, are still limited. Considering the variety of contaminants existing in the actual marine environment, single BaP (56 μg/L) and the co-exposure with Cu, Cd and Pb (50 μg/L, 50 μg/L and 3 mg/L respectively) were applied in a 6 days exposure followed by 6 days depuration experiment. The alterations of superoxide dismutase (SOD), catalase (CAT) activities and total antioxidant capacity (TAC) level were assessed in haemolymph, gills and digestive glands of marine mussels, Mytilus coruscus. An unparalleled change in antioxidant biomarkers was observed in all cells/tissues, with the SOD activity showing higher sensitivity to exposure. A tissue-specific response showing unique alteration in gill was investigated, indicating the different function of tissues during stress responses. Depressed antioxidant effects were induced by BaP-metals co-exposure, indicating the interaction may alter the intact properties of BaP. To our knowledge, this is the first research to explore the antioxidant defense induced by combined exposure of BaP-metals regarding to tissue-specific responses in marine mussels. The results and experimental model will provide valuable information and can be utilized in the investigation of stress response mechanisms, especially in relation to tissue functions in marine organism in the future. Copyright © 2018 Elsevier Ltd. All rights reserved.

Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring

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Ruixue Song

2017-01-01

Full Text Available Maternal sevoflurane exposure during pregnancy is associated with increased risk for behavioral deficits in offspring. Several studies indicated that neurogenesis abnormality may be responsible for the sevoflurane-induced neurotoxicity, but the concrete impact of sevoflurane on fetal brain development remains poorly understood. We aimed to investigate whether maternal sevoflurane exposure caused learning and memory impairment in offspring through inducing abnormal development of the fetal prefrontal cortex (PFC. Pregnant mice at gestational day 15.5 received 2.5% sevoflurane for 6 h. Learning function of the offspring was evaluated with the Morris water maze test at postnatal day 30. Brain tissues of fetal mice were subjected to immunofluorescence staining to assess differentiation, proliferation, and cell cycle dynamics of the fetal PFC. We found that maternal sevoflurane anesthesia impaired learning ability in offspring through inhibiting deep-layer immature neuron output and neuronal progenitor replication. With the assessment of cell cycle dynamics, we established that these effects were mediated through cell cycle arrest in neural progenitors. Our research has provided insights into the cell cycle-related mechanisms by which maternal sevoflurane exposure can induce neurodevelopmental abnormalities and learning dysfunction and appeals people to consider the neurotoxicity of anesthetics when considering the benefits and risks of nonobstetric surgical procedures.

Exposure to reactive intermediate-inducing drugs during pregnancy and the incident use of psychotropic medications among children.

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Tran, Yen-Hao; Groen, Henk; Bergman, Jorieke E H; Hak, Eelko; Wilffert, Bob

2017-03-01

Our study aimed to investigate the association between prenatal exposure to reactive intermediate (RI)-inducing drugs and the initiation of psychotropic medications among children. We designed a cohort study using a pharmacy prescription database. Pregnant women were considered exposed when they received a prescription of RI-inducing drugs. These drugs could be either used alone (RI+/FAA-) or combined with drugs exhibiting folic acid antagonism (FAA, RI+/FAA+). The reference group included pregnant women who did not receive any RI-inducing drugs or FAA drugs. We analyzed 4116 exposed and 30 422 reference pregnancies. The hazard ratio (HR) with 95% confidence interval (CI) was 1.27 (95%CI 1.15-1.41) for pregnancies exposed to RI-inducing drugs as a whole. Considering subgroups of RI-inducing drugs, prenatal exposure to both RI+/FAA+ and RI+/FAA- was associated with the children's initiation of psychotropic medications, HRs being 1.35 (95%CI 1.10-1.66) and 1.26 (1.13-1.41), respectively. The HRs were increased with prolonged exposure to RI-inducing drugs, especially in the first and second trimesters. In a detailed examination of the psychotropics, the incidences of receiving antimigraine preparations and psychostimulants were significantly increased for the exposed children, compared with the reference children. The incidences of receiving antipsychotics and hypnotics were also higher for the exposed children; however, the HRs did not reach significance after adjustment. We found a significantly increased incident use of psychotropic medications among children prenatally exposed to RI-inducing drugs, especially during the first and second trimesters. This suggests a detrimental effect during critical periods of brain development. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Polychlorinated biphenyls pattern analysis: Potential nondestructive biomarker in vertebrates for exposure to cytochrome P450-inducing organochlorines

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Brink, N.W. van den; Ruiter-Dijkman, E.M. De; Broekhuizen, S.; Reijnders, P.J.H.; Bosveld, A.T.C.

2000-03-01

Biomarkers are valuable instruments to assess the risks from exposure of organisms to organochlorines. In general, however, these biomarkers are either destructive to the animal of interest or extremely difficult to obtain otherwise. In this paper, the authors present a nondestructive biomarker for exposure to cytochrome P450-inducing organochlorines. This marker is based on a pattern analysis of metabolizable and nonmetabolizable polychlorinated biphenyl (PCB) congeners, which occur in several kinds of tissues (and even blood) that can be obtained without serious effects on the organism involved. The fraction of metabolizable PCB congeners is negatively correlated with exposure to PCBs, which are known to induce specific P450 isoenzymes. This relation can be modeled by a logistic curve, which can be used to define critical levels of exposure. In addition, this method creates an opportunity to analyze biomarker responses in archived tissues stored at standard freezing temperatures ({minus}20 C), at which responses to established biomarkers deteriorate. Furthermore, this method facilitates attribution of the enzyme induction to certain classes of compounds.

Electrostatic stiffening and induced persistence length for coassembled molecular bottlebrushes

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Storm, Ingeborg M.; Stuart, Martien A.C.; Vries, de Renko; Leermakers, Frans A.M.

2018-01-01

A self-consistent field analysis for tunable contributions to the persistence length of isolated semiflexible polymer chains including electrostatically driven coassembled deoxyribonucleic acid (DNA) bottlebrushes is presented. When a chain is charged, i.e., for polyelectrolytes, there is, in

Consequences of adolescent ethanol exposure in male Sprague-Dawley rats on fear conditioning and extinction in adulthood

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Broadwater, Margaret A.

Some evidence suggests that adolescents are more vulnerable than adults to alcohol-induced cognitive deficits and that these deficits may persist into adulthood. Five experiments were conducted to assess long-term consequences of ethanol exposure on tone and context Pavlovian fear conditioning in male Sprague-Dawley rats. Experiment 1 examined age-related differences in sensitivity to ethanol-induced disruptions of fear conditioning to a pre-conditioning ethanol challenge. Experiments 2 examined fear conditioning 22 days after early-mid adolescent (P28-48) or adult (P70-90) exposure to 4 g/kg i.g. ethanol or water given every other day (total of 11 exposures). In Experiment 3, mid-late adolescents (P35-55) were exposed in the same manner to assess whether timing of ethanol exposure within the adolescent period would differentially affect later fear conditioning. Experiment 4 assessed the influence of prior adolescent or adult ethanol exposure on the disrupting effects of a pre-conditioning ethanol challenge. In Experiment 5, neurogenesis (doublecortin---DCX) and cholinergic (choline acetyltransferase---ChAT) markers were measured to assess potential long-term ethanol-induced changes in neural mechanisms important for learning and memory. Results indicated that the long-lasting behavioral effects of ethanol exposure varied depending on exposure age, with early-mid adolescent exposed animals showing attenuated context fear retention (a relatively hippocampal-dependent task), whereas mid-late adolescent and adult exposed animals showed slower context extinction (thought to be reliant on the mPFC). Early-mid adolescent ethanol-exposed animals also had significantly less DCX and ChAT expression than their water-exposed counterparts, possibly contributing to deficits in context fear. Tone fear was not influenced by prior ethanol exposure at any age. In terms of age differences in ethanol sensitivity, adolescents were less sensitive than adults to ethanol-induced

Counterconditioning reduces cue-induced craving and actual cue-elicited consumption.

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Van Gucht, Dinska; Baeyens, Frank; Vansteenwegen, Debora; Hermans, Dirk; Beckers, Tom

2010-10-01

Cue-induced craving is not easily reduced by an extinction or exposure procedure and may constitute an important route toward relapse in addictive behavior after treatment. In the present study, we investigated the effectiveness of counterconditioning as an alternative procedure to reduce cue-induced craving, in a nonclinical population. We found that a cue, initially paired with chocolate consumption, did not cease to elicit craving for chocolate after extinction (repeated presentation of the cue without chocolate consumption), but did so after counterconditioning (repeated pairing of the cue with consumption of a highly disliked liquid, Polysorbate 20). This effect persisted after 1 week. Counterconditioning moreover was more effective than extinction in disrupting reported expectancy to get to eat chocolate, and also appeared to be more effective in reducing actual cue-elicited chocolate consumption. These results suggest that counterconditioning may be more promising than cue exposure for the prevention of relapse in addictive behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

Acute Acrolein Exposure Induces Impairment of Vocal Fold Epithelial Barrier Function.

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Liu, Xinxin; Zheng, Wei; Sivasankar, M Preeti

2016-01-01

Acrolein is a ubiquitous pollutant abundant in cigarette smoke, mobile exhaust, and industrial waste. There is limited literature on the effects of acrolein on vocal fold tissue, although there are clinical reports of voice changes after pollutant exposures. Vocal folds are responsible for voice production. The overall objective of this study was to investigate the effects of acrolein exposure on viable, excised vocal fold epithelial tissue and to characterize the mechanism underlying acrolein toxicity. Vocal fold epithelia were studied because they form the outermost layer of the vocal folds and are a primary recipient of inhaled pollutants. Porcine vocal fold epithelia were exposed to 0, 50, 100, 500, 900 or 1300 μM of acrolein for 3 hours; the metabolic activity, epithelial resistance, epithelial permeability, tight junction protein (occludin and claudin 3) expression, cell membrane integrity and lipid peroxidation were investigated. The data demonstrated that acrolein exposure at 500 μM significantly reduced vocal fold epithelial metabolic activity by 27.2% (p≤0.001). Incubation with 100 μM acrolein caused a marked increase in epithelial permeability by 130.5% (pacrolein-treated samples, the cell membrane integrity was significantly damaged with a 45.6% increase of lipid peroxidation as compared to controls (pacrolein exposure impairs vocal fold epithelial barrier integrity. Lipid peroxidation-induced cell membrane damage may play an important role in reducing the barrier function of the epithelium.

Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure

International Nuclear Information System (INIS)

Zychowski, Katherine E.; Lucas, Selita N.; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J.

2016-01-01

Ozone (O 3 )-related cardiorespiratory effects are a growing public health concern. Ground level O 3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O 3 -induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O 3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O 3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O 2 ) or hypoxia (10.0% O 2 ), followed by a 4-h exposure to either 1 ppm O 3 or filtered air (FA). As an additional experimental intervention fasudil (20 mg/kg) was administered intraperitoneally prior to and after O 3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O 3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O 3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O 3 -induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability. - Highlights: • Environmental exposures can exacerbate chronic obstructive pulmonary disease (COPD). • It is unknown if comorbid

Canadian individual risks of radon-induced lung cancer for different exposure profiles.

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Chen, Jing

2005-01-01

Indoor radon has been determined to be the second leading cause of lung cancer after tobacco smoking. There is an increasing need among radiation practitioners to have numerical values of lung cancer risks for men and women, ever-smokers and never-smokers exposed to radon in homes. This study evaluates individual risks for the Canadian population exposed to radon in homes at different radon concentrations and for different periods of their lives. Based on the risk model developed recently by U.S. Environmental Protection Agency (EPA), individual risks of radon-induced lung cancers are calculated with Canadian age-specific rates for overall and lung cancer mortalities (1996-2000) as well as the Canadian smoking prevalence data in 2002. Convenient tables of lifetime relative risks are constructed for lifetime exposures and short exposures between any two age intervals from 0 to 110, and for various radon concentrations found in homes from 50 to 1000 Bq/m3. The risk of developing lung cancer from residential radon exposure increases with radon concentration and exposure duration. For short exposure periods, such as 10 or 20 years, risks are higher in middle age groups (30-50) compared especially to the later years. Individuals could lower their risks significantly by reducing radon levels earlier in life. The tables could help radiation protection practitioners to better communicate indoor radon risk to members of the public.

Exposure to tobacco-derived materials induces overproduction of secreted proteinases in mast cells

International Nuclear Information System (INIS)

Small-Howard, Andrea; Turner, Helen

2005-01-01

Mast cells reside at interfaces with the environment, including the mucosa of the respiratory and gastrointestinal tracts. This localization exposes mast cells to inhaled, or ingested, environmental challenges. In the airways of smokers, resident immune cells will be in contact with the condensed components of cigarette smoke. Mast cells are of particular interest due to their ability to promote airway remodeling and mucus hypersecretion. Clinical data show increased levels of mast cell-secreted tryptase and increased numbers of degranulated mast cells in the lavage and bronchial tissue of smokers. Since mast cell-secreted proteinases (MCPTs), including tryptases, contribute to pathological airway remodeling, we investigated the relationship between mast cell proteinases and smoke exposure. We exposed a mast cell line to cigarette smoke condensate (CSC). We show that CSC exposure increases MCPT levels in mast cells using an assay for tryptase-type MCPT activity. We hypothesized that this increase in MCPT activity reflects a CSC-induced increase in the cytosolic pool of proteinase molecules, via stimulation of MCPT transcription. Transcript array data suggested that mRNA changes in response to CSC were limited in number and peaked after 3 h of CSC exposure. However, we noted marked transcriptional regulation of several MCPT genes. CSC-induced changes in the mRNA levels for MCPTs were confirmed using quantitative RT-PCR. Taken together, our data suggest that chronic exposure to cigarette smoke up-regulates MCPT levels in mast cells at both the protein and the mRNA level. We suggest that the pathological airway remodeling that has been described in clinical studies of smoke inhalation may be attributable to MCPT overproduction in vivo

Induced sputum nitrite levels correlate with clinical asthma parameters in children aged 7-18 years with mild to moderate persistent asthma

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Devki Nandan

2016-01-01

Full Text Available Purpose: The objective of this study is to measure levels of nitrites in induced sputum in children with asthma and correlate it with clinical asthma parameters. Method: This prospective observational study was done in PGIMER, Dr. Ram Manohar Lohia Hospital, New Delhi, on 91 children aged 7-18 years with mild and moderate persistent asthma. Patients were specifically evaluated for five clinical parameters of asthma (i.e. Days of acute exacerbations, use of salbutamol as rescue medication, emergency visits, nights with cough, days of school absence and induced sputum nitrite levels was done at the time of enrollment and 3 months after treatment with inhaled budesonide. Results: The mean age of subjects was 10.79 ± 2.563yrs. Six (6.59% patients were not able to perform induced sputum, eighty five (93.41% patients were suitable for data analysis. There was significant reduction in sputum nitrite levels from 33.42 ± 22.04nmol/ml at enrollment to 11.72 ± 5.61 nmol/ml (P < 0.0005 after 3 months of inhaled budesonide therapy. Significant positive correlation was found between reduction in sputum nitrite level and control of asthma symptoms: Days of acute exacerbations(r value = 0.548, P value = 0.0001, Days of salbutamol use as rescue medication (r value = 0.431, P value =< 0.0001, Number of emergency visits(r value = 0.414, P value = 0.0001, Nights with cough (r value = 0.259, P value = 0.0169, Days of school absence(r value = 0.411, P value = 0.0001. Sputum nitrite levels were significantly higher in moderate persistent asthmatics as compared to mild at the time of enrollment (P < 0.0005, which shows that induced sputum nitrite levels correlate with asthma severity. Conclusions: This study confirms that nitrites in induced sputum correlate well with clinical asthma parameters and asthma severity in children and is a simple, non invasive, and cheap method which can be used as a parameter for monitoring of asthma.

Evaluation of economic effects and the health and performance of the general cattle population after exposure to cattle persistently infected with bovine viral diarrhea virus in a starter feedlot.

Science.gov (United States)

Hessman, Bill E; Fulton, Robert W; Sjeklocha, David B; Murphy, Timothy A; Ridpath, Julia F; Payton, Mark E

2009-01-01

To evaluate economic effects and health and performance of the general cattle population after exposure to cattle persistently infected (PI) with bovine viral diarrhea virus (BVDV) in a feedlot. 21,743 high-risk calves from the southeastern United States. PI status was determined by use of an antigen-capture ELISA (ACE) and confirmed by use of a second ACE, reverse transcriptase-PCR assay of sera, immunohistochemical analysis, and virus isolation from sera. Groups with various amounts of exposure to BVDV PI cattle were used. After being placed in the feedlot, identified PI cattle were removed from 1 section, but PI cattle remained in another section of the feedlot. Exposure groups for cattle lots arriving without PI animals were determined by spatial association to cattle lots, with PI animals remaining or removed from the lot. 15,348 cattle maintained their exposure group. Performance outcomes improved slightly among the 5 exposure groups as the risk for exposure to BVDV PI cattle decreased. Health outcomes had an association with exposure risk that depended on the exposure group. Comparing cattle lots with direct exposure with those without direct exposure revealed significant improvements in all performance outcomes and in first relapse percentage and mortality percentage in the health outcomes. Economic analysis revealed that fatalities accounted for losses of $5.26/animal and performance losses were $88.26/animal. This study provided evidence that exposure of the general population of feedlot cattle to BVDV PI animals resulted in substantial costs attributable to negative effects on performance and increased fatalities.

The use of docosahexaenoic acid supplementation to ameliorate the hyperactivity of rat pups induced by in utero ethanol exposure

OpenAIRE

Furuya, Hiroyuki; Aikawa, Hiroyuki; Yoshida, Takahiko; Okazaki, Isao

2000-01-01

It has been demonstrated thatin utero ethanol (EtOH) exposure induces hyperactive behavior and learning disturbances in offspring. In order to investigate the effects of docosahexaenoic acid (DHA) on these neurobehavioral dysfunctions of rat pups induced byin utero EtOH exposure, pregnant Wistar rats were divided into four treatment groups depending on the type of oil added to the diet and drinking water as follows; (a) 5% safflower oil with tap water (TW/n-6), (b) 3% safflower oil and 2% DHA...

Adolescent alcohol exposure alters lysine demethylase 1 (LSD1) expression and histone methylation in the amygdala during adulthood.

Science.gov (United States)

Kyzar, Evan J; Zhang, Huaibo; Sakharkar, Amul J; Pandey, Subhash C

2017-09-01

Alcohol exposure in adolescence is an important risk factor for the development of alcoholism in adulthood. Epigenetic processes are implicated in the persistence of adolescent alcohol exposure-related changes, specifically in the amygdala. We investigated the role of histone methylation mechanisms in the persistent effects of adolescent intermittent ethanol (AIE) exposure in adulthood. Adolescent rats were exposed to 2 g/kg ethanol (2 days on/off) or intermittent n-saline (AIS) during postnatal days (PND) 28-41 and used for behavioral and epigenetic studies. We found that AIE exposure caused a long-lasting decrease in mRNA and protein levels of lysine demethylase 1(Lsd1) and mRNA levels of Lsd1 + 8a (a neuron-specific splice variant) in specific amygdaloid structures compared with AIS-exposed rats when measured at adulthood. Interestingly, AIE increased histone H3 lysine 9 dimethylation (H3K9me2) levels in the central nucleus of the amygdala (CeA) and medial nucleus of the amygdala (MeA) in adulthood without producing any change in H3K4me2 protein levels. Acute ethanol challenge (2 g/kg) in adulthood attenuated anxiety-like behaviors and the decrease in Lsd1 + 8a mRNA levels in the amygdala induced by AIE. AIE caused an increase in H3K9me2 occupancy at the brain-derived neurotrophic factor exon IV promoter in the amygdala that returned to baseline after acute ethanol challenge in adulthood. These results indicate that AIE specifically modulates epizymes involved in H3K9 dimethylation in the amygdala in adulthood, which are possibly responsible for AIE-induced chromatin remodeling and adult psychopathology such as anxiety. © Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

[Effects of intermittent hypoxic exposure on the parameter of erythrocyte and serum hypoxia inducible factor-1 alpha and erythropoietin levels].

Science.gov (United States)

Zhang, Cheng-yan; Zhang, Ji-xin; Lü, Xiao-tao; Li, Bao-yu

2009-10-01

To investigate the effects of intermittent hypoxic exposure and normoxic convalescence on the parameter of erythrocyte and serum hypoxia inducible factor-1 alpha (HIF-1alpha) and erythropoietin (EPO) levels. Rat models of intermittent hypoxic exposure were established, combined with the clinical research on volunteers experiencing the intermittent plateau work. Blood samples for red blood cell (RBC) counts, hemoglobin (Hb) and hematocrit (HCT) were collected, serum HIF-1alpha and EPO levels were measured using enzyme linked immunosorbent assay. RBC counts, Hb concentration and HCT were significantly higher than the normoxic group (P hypoxic exposure can enhance serum hypoxia inducible factor-1 alpha and erythropointin levels and the generation of red blood cells, which leads to an increase in hemoglobin concentration and hematocrit. The results have changed with the hypoxic exposure period prolonged. Normoxic convalescence after intermittent hypoxic exposure can make the related indexes reduced, and contribute to the organism recovery.

Experimental photoallergic contact dermatitis (photo-ACD) and persistent light reactivity (PLR) induced by bisphenol-A

International Nuclear Information System (INIS)

Maguire, H.C. Jr.

1986-01-01

Bisphenol-A, a compound widely used in the plastics industry, clinically has been reported to induce photo-ACD and PLR. In mice, the authors find that Bisphenol-A (Bis-A) is a substantial photosensitizer and can serve as a model compound for the study of the cutaneous disorder, PLR. Mice were photosensitized by 2 daily applications of 1% Bis-A followed by irradiation of the skin site with UVB (280-320nm) and UVA (320-400nm). Sometimes, intradermal C.parvum (30 μ g) and/or pretreatment with cyclophosphamide (Cy; 50mg/kg) was used for nonspecific immunopotentiation. Photochallenge of an ear with chemical followed by UVA is usually done on Day 6. The reaction is consistent with that of delayed type hypersensitivity. Positive photochallenge sites react to UVA alone, thereby mimicking the clinical condition of the persistent light reactor

Short-term pre- and post-operative stress prolongs incision-induced pain hypersensitivity without changing basal pain perception.

Science.gov (United States)

Cao, Jing; Wang, Po-Kai; Tiwari, Vinod; Liang, Lingli; Lutz, Brianna Marie; Shieh, Kun-Ruey; Zang, Wei-Dong; Kaufman, Andrew G; Bekker, Alex; Gao, Xiao-Qun; Tao, Yuan-Xiang

2015-12-02

Chronic stress has been reported to increase basal pain sensitivity and/or exacerbate existing persistent pain. However, most surgical patients have normal physiological and psychological health status such as normal pain perception before surgery although they do experience short-term stress during pre- and post-operative periods. Whether or not this short-term stress affects persistent postsurgical pain is unclear. In this study, we showed that pre- or post-surgical exposure to immobilization 6 h daily for three consecutive days did not change basal responses to mechanical, thermal, or cold stimuli or peak levels of incision-induced hypersensitivity to these stimuli; however, immobilization did prolong the duration of incision-induced hypersensitivity in both male and female rats. These phenomena were also observed in post-surgical exposure to forced swimming 25 min daily for 3 consecutive days. Short-term stress induced by immobilization was demonstrated by an elevation in the level of serum corticosterone, an increase in swim immobility, and a decrease in sucrose consumption. Blocking this short-term stress via intrathecal administration of a selective glucocorticoid receptor antagonist, RU38486, or bilateral adrenalectomy significantly attenuated the prolongation of incision-induced hypersensitivity to mechanical, thermal, and cold stimuli. Our results indicate that short-term stress during the pre- or post-operative period delays postoperative pain recovery although it does not affect basal pain perception. Prevention of short-term stress may facilitate patients' recovery from postoperative pain.

Developmental exposure to a complex PAH mixture causes persistent behavioral effects in naive Fundulus heteroclitus (killifish) but not in a population of PAH-adapted killifish.

Science.gov (United States)

Brown, D R; Bailey, J M; Oliveri, A N; Levin, E D; Di Giulio, R T

2016-01-01

Acute exposures to some individual polycyclic aromatic hydrocarbons (PAHs) and complex PAH mixtures are known to cause cardiac malformations and edema in the developing fish embryo. However, the heart is not the only organ impacted by developmental PAH exposure. The developing brain is also affected, resulting in lasting behavioral dysfunction. While acute exposures to some PAHs are teratogenically lethal in fish, little is known about the later life consequences of early life, lower dose subteratogenic PAH exposures. We sought to determine and characterize the long-term behavioral consequences of subteratogenic developmental PAH mixture exposure in both naive killifish and PAH-adapted killifish using sediment pore water derived from the Atlantic Wood Industries Superfund Site. Killifish offspring were embryonically treated with two low-level PAH mixture dilutions of Elizabeth River sediment extract (ERSE) (TPAH 5.04 μg/L and 50.4 μg/L) at 24h post fertilization. Following exposure, killifish were raised to larval, juvenile, and adult life stages and subjected to a series of behavioral tests including: a locomotor activity test (4 days post-hatch), a sensorimotor response tap/habituation test (3 months post hatch), and a novel tank diving and exploration test (3months post hatch). Killifish were also monitored for survival at 1, 2, and 5 months over 5-month rearing period. Developmental PAH exposure caused short-term as well as persistent behavioral impairments in naive killifish. In contrast, the PAH-adapted killifish did not show behavioral alterations following PAH exposure. PAH mixture exposure caused increased mortality in reference killifish over time; yet, the PAH-adapted killifish, while demonstrating long-term rearing mortality, had no significant changes in mortality associated with ERSE exposure. This study demonstrated that early embryonic exposure to PAH-contaminated sediment pore water caused long-term locomotor and behavioral alterations in

Immunomodulatory effects of exposure to polychlorinated biphenyls and perfluoroalkyl acids in East Greenland ringed seals (Pusa hispida)

Energy Technology Data Exchange (ETDEWEB)

Levin, Milton, E-mail: Milton.levin@uconn.edu [Department of Pathobiology and Veterinary Science, University of Connecticut, 61 North Eagleville Road, Storrs, CT 06269-3089 (United States); Gebhard, Erika; Jasperse, Lindsay [Department of Pathobiology and Veterinary Science, University of Connecticut, 61 North Eagleville Road, Storrs, CT 06269-3089 (United States); Desforges, Jean-Pierre; Dietz, Rune; Sonne, Christian; Eulaers, Igor [Department of Bioscience, Arctic Research Centre (ARC), Aarhus University, Frederiksborgvej 399, PO Box 358, DK-4000 Roskilde (Denmark); Covaci, Adrian [Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, BE-2610 Wilrijk (Belgium); Bossi, Rossana [Department of Environmental Science, Aarhus University, Frederiksborgvej 399, PO Box 358, DK-4000 Roskilde (Denmark); De Guise, Sylvain [Department of Pathobiology and Veterinary Science, University of Connecticut, 61 North Eagleville Road, Storrs, CT 06269-3089 (United States)

2016-11-15

To better elucidate the potential immune-related health effects of exposure to environmentally persistent organic pollutants (POP), such as polychlorinated biphenyls (PCBs) and perfluoroalkyl substances (PFASs), in ringed seals (Pusa hispida), a sentinel Arctic species, we assessed 1) associations between mitogen-induced lymphocyte proliferation and in vivo tissue contaminant burdens, and 2) the concentration-response effects of in vitro exposure to PFASs and PCB congeners on mitogen-induced lymphocyte proliferation. Upon in vitro contaminant exposure, the non-coplanar PCB congeners CB 138, 153, and 180, but not the coplanar CB 169, significantly reduced lymphocyte proliferation between 10 and 20 µg g{sup −1} ww. The respective in vitro EC{sub 50} values for these congeners were 13.3, 20.7, 20.8, and 54.6 µg g{sup −1} ww. No modulation of lymphocyte proliferation was observed upon in vitro exposure to two individual PFASs, perfluorooctane sulphonic acid (PFOS) and perfluorooctanoic acid (PFOA), at concentrations up to 1000 ng g-1. In addition, no significant correlations were found between lymphocyte proliferation and any blood or blubber contaminant measured. Taken together, these data suggest this population of ringed seals is not currently at high risk of altered lymphocyte proliferation from exposure to the POPs or PFASs in this study. - Highlights: • Assess relationships between tissue contaminants and changes in immune function. • Risk for contaminant-induced immunotoxicity in East Greenland ringed seal is low. • Weight of evidence suggest non-coplanar PCBs are immunotoxic at high concentrations.

Effects of perinatal exposure to environmentally persistent organic pollutants and heavy metals on neurobehavioral development in Japanese children: IV. Thyroid hormones and neonatal neurobehavioral status

Energy Technology Data Exchange (ETDEWEB)

Suzuki, K.; Nakai, K.; Oka, T.; Kurokawa, N.; Satoh, H. [Dept. of Environmental Health Sciences, Tohoku Univ. Graduate School of Medicine, Sendai (Japan); Hosokawa, T. [Dept. of Human Development, Tohoku Univ., Sendai (Japan); Okamura, K. [Dept. of Obstetrics, Tohoku Univ. Graduate School of Medicine, Sendai (Japan); Sakai, T. [Miyagi Childrens Hospital, Sendai (Japan)

2004-09-15

From several epidemiological studies, it has been reported that there are some associations between perinatal exposures to PCBs, dioxins and heavy metals, and neurobehavioral defects such as postnatal growth delay and poorer cognitive function. We have started a prospective cohort study to examine the effects of perinatal exposures to environmentally persistent organic pollutants on neurobehavioral development in Japanese children. Thyroid hormones (THs) are essential for normal brain development. A lack of THs in pregnancy can result in congenital hypothyroidism, which causes moderate to severe intellectual defects. It has been reported that perinatal exposure to PCBs adversely affects on children's intellectual functions. The chemical structures of some PCBs resembles thyroxine (T4), and therefore, it is suspected that the action mechanism of PCBs is disruption of TH function. Some PCBs and their metabolites are thought to bind with transthyretine (TTR), which is necessary for the transfer of T4 into the brain, and this may cause a shortage of T4 in the developing brain. To examine the effects of perinatal exposure to PCBs on children's development, it is essential to evaluate the functions of THs at a fundamental level. In this report, we examined the correlations of THs in maternal peripheral blood and cord blood, and the association between THs and neonatal neurobehavioral status.

Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia

Science.gov (United States)

Planel, Emmanuel; Bretteville, Alexis; Liu, Li; Virag, Laszlo; Du, Angela L.; Yu, Wai Haung; Dickson, Dennis W.; Whittington, Robert A.; Duff, Karen E.

2009-01-01

Alzheimer’s disease and other tauopathies are characterized by the presence of intracellular neurofibrillary tangles composed of hyperphosphorylated, insoluble tau. General anesthesia has been shown to be associated with increased risk of Alzheimer’s disease, and we have previously demonstrated that anesthesia induces hypothermia, which leads to overt tau hyperphosphorylation in the brain of mice regardless of the anesthetic used. To investigate whether anesthesia enhances the long-term risk of developing pathological forms of tau, we exposed a mouse model with tauopathy to anesthesia and monitored the outcome at two time points—during anesthesia, or 1 wk after exposure. We found that exposure to isoflurane at clinically relevant doses led to increased levels of phospho-tau, increased insoluble, aggregated forms of tau, and detachment of tau from microtubules. Furthermore, levels of phospho-tau distributed in the neuropil, as well as in cell bodies increased. Interestingly, the level of insoluble tau was increased 1 wk following anesthesia, suggesting that anesthesia precipitates changes in the brain that provoke the later development of tauopathy. Overall, our results suggest that anesthesia-induced hypothermia could lead to an acceleration of tau pathology in vivo that could have significant clinical implications for patients with early stage, or overt neurofibrillary tangle pathology.—Planel, E., Bretteville, A., Liu, L., Virag, L., Du, A. L., Yu, W. Y., Dickson, D. W., Whittington, R. A., Duff, K. E. Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. PMID:19279139

Scrambled and fried: Cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress

International Nuclear Information System (INIS)

Sobinoff, A.P.; Beckett, E.L.; Jarnicki, A.G.; Sutherland, J.M.; McCluskey, A.; Hansbro, P.M.; McLaughlin, E.A.

2013-01-01

Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes; an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction. - Highlights: • Cigarette smoke exposure targets developing follicle oocytes. • The antral follicle oocyte is a primary site of ovarian cigarette smoke metabolism. • Cyp2e1 is a major enzyme involved in ameliorating smoke-induced ovotoxicity. • Cigarette smoke causes oocyte

Scrambled and fried: Cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress

Energy Technology Data Exchange (ETDEWEB)

Sobinoff, A.P. [Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308 (Australia); Priority Research Centre for Chemical Biology, University of Newcastle, Callaghan, NSW 2308 (Australia); Beckett, E.L.; Jarnicki, A.G. [Centre for Asthma and Respiratory Disease, The University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2308 (Australia); Sutherland, J.M. [Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308 (Australia); Priority Research Centre for Chemical Biology, University of Newcastle, Callaghan, NSW 2308 (Australia); McCluskey, A. [Priority Research Centre for Chemical Biology, University of Newcastle, Callaghan, NSW 2308 (Australia); Hansbro, P.M. [Centre for Asthma and Respiratory Disease, The University of Newcastle and Hunter Medical Research Institute, Callaghan, NSW 2308 (Australia); McLaughlin, E.A., E-mail: eileen.mclaughlin@newcastle.edu.au [Reproductive Science Group, School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308 (Australia); Priority Research Centre for Chemical Biology, University of Newcastle, Callaghan, NSW 2308 (Australia)

2013-09-01

Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes; an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction. - Highlights: • Cigarette smoke exposure targets developing follicle oocytes. • The antral follicle oocyte is a primary site of ovarian cigarette smoke metabolism. • Cyp2e1 is a major enzyme involved in ameliorating smoke-induced ovotoxicity. • Cigarette smoke causes oocyte

Exploring Tinnitus-Induced Disablement by Persistent Frustration in Aging Individuals: A Grounded Theory Study.

Science.gov (United States)

Dauman, Nicolas; Erlandsson, Soly I; Albarracin, Dolorès; Dauman, René

2017-01-01

Background: Qualitative research can help to improve the management of patients, meet their expectations and assist physicians in alleviating their suffering. The perception of moment-to-moment variability in tinnitus annoyance is an emerging field of exploration. This study sought to enlighten variability in tinnitus-induced disablement using a qualitative approach. Methods: Twelve participants (six females, six males, aged 51-79) were recruited via the French Tinnitus Association Journal for participation in recorded semi-structured interviews. Each participant had three interviews lasting 1 h, the sessions being separated one from the other by 2 weeks. Following recommendations of Charmaz (2014), the second and third interviews were aimed at gathering rich data, by enhancing the participants' reflexivity in the circumstances of distress caused by tinnitus. After transcription, the data ( n = 36 interviews) were analyzed using the approach to Grounded Theory proposed by Strauss and Corbin (1998). Results: Tinnitus as persistent frustration emerged as being the core category uniting all the other categories of the study. Hence, the core category accounted for the broader scope in participants' experience of chronic tinnitus. It is suggested that tinnitus-induced disablement varied according to the degree of frustration felt by the participants in not being able to achieve their goals. The implications of this were analyzed using the following categories: "Losing body ownership," "Lacking perspectives," and "Persevering through difficulties." Based on these findings, we draw a substantive theory of tinnitus tolerance that promotes an active, disciplined and individualized approach to tinnitus-induced disablement. The model distinguishes pathways from sustained suffering to reduced annoyance (i.e., emerging tolerance). It accounts for difficulties that the participants experienced with a perceived unchanged annoyance over time. Furthermore, this model identifies a

METHOD EVALUATION TO MEASURE PERSISTENT BIOACCUMULATIVE TOXIC POLLUTANTS IN COW MILK

Science.gov (United States)

It is important to understand the persistent and bioaccumulative toxic (PBT) levels in milk, as milk fat may be one of the highest dietary sources of PBT exposure. Analysis of milk also allows the opportunity to investigate geographic variability, as milk is produced and distrib...

Chronic inorganic mercury induced peripheral neuropathy

Energy Technology Data Exchange (ETDEWEB)

Chu, C.-C.; Huang, C.-C.; Ryu, S.-J. [Chang Gung Memorial Hospital and Chang Gung University, Dept. of Neurology, Tapei (Taiwan, Province of China); Wu, T.-N. [Executive Yuan, Dept. of Health, Surveillance and Quarantine Service, Taipei (Taiwan, Province of China)

1998-12-01

We report the clinical features, electrophysiological studies, and morphometric analysis of sural nerve pathology in a patient with polyneuropathy due to inorganic mercury intoxication. He developed slowly progressive generalized paralysis of all limbs after 3 months ingestion of herb drugs which contained mercuric sulfate. Electrophysiologic studies revealed axonal polyneuropathy involving both motor and sensory fibers. Sural nerve biopsy demonstrated axonal degeneration with demyelination and a predominant loss of large myelinated fibers. His muscle strength showed only mild improvement after 2 years` follow-up. We concluded that inorganic mercury exposure may induce severe axonal sensorimotor polyneuropathy in humans and that neurological deficits may persist in severe cases. (au) 21 refs.

Chronic inorganic arsenic exposure in vitro induces a cancer cell phenotype in human peripheral lung epithelial cells

Energy Technology Data Exchange (ETDEWEB)

Person, Rachel J.; Olive Ngalame, Ntube N.; Makia, Ngome L.; Bell, Matthew W.; Waalkes, Michael P.; Tokar, Erik J., E-mail: tokare@niehs.nih.gov

2015-07-01

Inorganic arsenic is a human lung carcinogen. We studied the ability of chronic inorganic arsenic (2 μM; as sodium arsenite) exposure to induce a cancer phenotype in the immortalized, non-tumorigenic human lung peripheral epithelial cell line, HPL-1D. After 38 weeks of continuous arsenic exposure, secreted matrix metalloproteinase-2 (MMP2) activity increased to over 200% of control, levels linked to arsenic-induced cancer phenotypes in other cell lines. The invasive capacity of these chronic arsenic-treated lung epithelial (CATLE) cells increased to 320% of control and colony formation increased to 280% of control. CATLE cells showed enhanced proliferation in serum-free media indicative of autonomous growth. Compared to control cells, CATLE cells showed reduced protein expression of the tumor suppressor gene PTEN (decreased to 26% of control) and the putative tumor suppressor gene SLC38A3 (14% of control). Morphological evidence of epithelial-to-mesenchymal transition (EMT) occurred in CATLE cells together with appropriate changes in expression of the EMT markers vimentin (VIM; increased to 300% of control) and e-cadherin (CDH1; decreased to 16% of control). EMT is common in carcinogenic transformation of epithelial cells. CATLE cells showed increased KRAS (291%), ERK1/2 (274%), phosphorylated ERK (p-ERK; 152%), and phosphorylated AKT1 (p-AKT1; 170%) protein expression. Increased transcript expression of metallothioneins, MT1A and MT2A and the stress response genes HMOX1 (690%) and HIF1A (247%) occurred in CATLE cells possibly in adaptation to chronic arsenic exposure. Thus, arsenic induced multiple cancer cell characteristics in human peripheral lung epithelial cells. This model may be useful to assess mechanisms of arsenic-induced lung cancer. - Highlights: • Chronic arsenic exposure transforms a human peripheral lung epithelia cell line. • Cells acquire characteristics in common with human lung adenocarcinoma cells. • These transformed cells provide a

Exposure to radiofrequency radiation induces oxidative stress in duckweed Lemna minor L

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Tkalec, Mirta [Department of Botany, Division of Biology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, HR-10000 Zagreb (Croatia)], E-mail: mtkalec@zg.biol.pmf.hr; Malaric, Kresimir [Faculty of Electrical Engineering and Computing, University of Zagreb, Unska 3, HR-10000 Zagreb (Croatia); Pevalek-Kozlina, Branka [Department of Botany, Division of Biology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, HR-10000 Zagreb (Croatia)

2007-12-15

23 V m{sup -1}. At both frequencies no differences in isoenzyme patterns of antioxidative enzymes or HSP70 level were found between control and exposed plants. Our results showed that non-thermal exposure to investigated radiofrequency fields induced oxidative stress in duckweed as well as unspecific stress responses, especially of antioxidative enzymes. However, the observed effects markedly depended on the field frequencies applied as well as on other exposure parameters (strength, modulation and exposure time). Enhanced lipid peroxidation and H{sub 2}O{sub 2} content accompanied by diminished antioxidative enzymes activity caused by exposure to investigated EMFs, especially at 900 MHz, indicate that oxidative stress could partly be due to changed activities of antioxidative enzymes.

Exposure to radiofrequency radiation induces oxidative stress in duckweed Lemna minor L

International Nuclear Information System (INIS)

Tkalec, Mirta; Malaric, Kresimir; Pevalek-Kozlina, Branka

2007-01-01

patterns of antioxidative enzymes or HSP70 level were found between control and exposed plants. Our results showed that non-thermal exposure to investigated radiofrequency fields induced oxidative stress in duckweed as well as unspecific stress responses, especially of antioxidative enzymes. However, the observed effects markedly depended on the field frequencies applied as well as on other exposure parameters (strength, modulation and exposure time). Enhanced lipid peroxidation and H 2 O 2 content accompanied by diminished antioxidative enzymes activity caused by exposure to investigated EMFs, especially at 900 MHz, indicate that oxidative stress could partly be due to changed activities of antioxidative enzymes

Histopathological nerve and skeletal muscle changes in rats subjected to persistent insulin-induced hypoglycemia

DEFF Research Database (Denmark)

Jensen, Vivi Flou Hjorth; Mølck, Anne-Marie; Heydenreich, Annette

2016-01-01

femoris muscle tissue, as little is known about the response to persistent hypoglycemia in these tissues. Histopathologic changes in insulin-infused animals included axonal degeneration and myofibre degeneration. To our knowledge, this is the first study to show that persistent IIH provokes peripheral...

Perinatal BPA Exposure Induces Hyperglycemia, Oxidative Stress and Decreased Adiponectin Production in Later Life of Male Rat Offspring

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Shunzhe Song

2014-04-01

Full Text Available The main object of the present study was to explore the effect of perinatal bisphenol A (BPA exposure on glucose metabolism in early and later life of male rat offspring, and to establish the potential mechanism of BPA-induced dysglycemia. Pregnant rats were treated with either vehicle or BPA by drinking water at concentrations of 1 and 10 µg/mL BPA from gestation day 6 through the end of lactation. We measured the levels of fasting serum glucose, insulin, adiponectin and parameters of oxidative stress on postnatal day (PND 50 and PND100 in male offspring, and adiponectin mRNA and protein expression in adipose tissue were also examined. Our results showed that perinatal exposure to 1 or 10 µg/mL BPA induced hyperglycemia with insulin resistance on PND100, but only 10 µg/mL BPA exposure had similar effects as early as PND50. In addition, increased oxidative stress and decreased adiponectin production were also observed in BPA exposed male offspring. Our findings indicated that perinatal exposure to BPA resulted in abnormal glucose metabolism in later life of male offspring, with an earlier and more exacerbated effect at higher doses. Down-regulated expression of adiponectin gene and increased oxidative stress induced by BPA may be associated with insulin resistance.

Hyperacute peripheral neuropathy is a predictor of oxaliplatin-induced persistent peripheral neuropathy.

Science.gov (United States)

Tanishima, Hiroyuki; Tominaga, Toshiji; Kimura, Masamichi; Maeda, Tsunehiro; Shirai, Yasutsugu; Horiuchi, Tetsuya

2017-05-01

Chronic peripheral neuropathy is a major adverse response to oxaliplatin-containing chemotherapy regimens, but there are no established risk factors pertaining to it. We investigated the efficacy of hyperacute peripheral neuropathy (HAPN) as a predictor of oxaliplatin-induced persistent peripheral neuropathy (PPN). Forty-seven cases of stage III colorectal cancer who received adjuvant chemotherapy with oxaliplatin after curative surgery between January 2010 and August 2014 were retrospectively reviewed. HAPN was defined as acute peripheral neuropathy (APN) occurring on day 1 (≤24 h after oxaliplatin infusion) of the first cycle. PPN was defined as neuropathy lasting >1 year after oxaliplatin discontinuation. The average total dose of oxaliplatin was 625.8 mg/m 2 , and the average relative dose intensity was 66.7%. Twenty-two of the 47 patients (46.8%) had PPN and 13 (27.7%) had HAPN. Male sex, treatment for neuropathy, HAPN, and APN were significantly more frequent in patients with PPN (p = 0.013, 0.02, <0.001, and 0.023, respectively). There was no significant difference in the total oxaliplatin dose between patients with and without PPN (p = 0.061). Multivariate analyses revealed total dose of oxaliplatin and HAPN as independent predictors of PPN [p = 0.015; odds ratio (OR) = 1.005, 95% confidence interval (CI), 1.001-1.009 and p = 0.001; OR = 75.307, 5.3-1070.123, respectively]. The total dose of oxaliplatin was relatively lower in patients with HAPN than that in those without HAPN in the PPN-positive group (not significant, p = 0.068). HAPN was found to be a predictor of oxaliplatin-induced PPN.

Resistance to asbestos-induced apoptosis with continuous exposure to crocidolite on a human T cell

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Maeda, Megumi [Department of Biofunctional Chemistry, Graduate School of Natural Science and Technology, Okayama University, 1-1-1 Tsushima-Naka, Okayama 700-8530 (Japan); Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192 (Japan); Yamamoto, Shoko [Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192 (Japan); Chen, Ying [Division of Pneumoconiosis, School of Public Health, China Medical University, 92 North 2nd, Heping District, Shenyang 110001 (China); Kumagai-Takei, Naoko [Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192 (Japan); Hayashi, Hiroaki [Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192 (Japan); Department of Dermatology, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192 (Japan); Matsuzaki, Hidenori; Lee, Suni; Hatayama, Tamayo; Miyahara, Naomi; Katoh, Minako [Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192 (Japan); Hiratsuka, Juni-ichi [Department of Radiation Oncology, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192 (Japan); Nishimura, Yasumitsu [Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192 (Japan); Otsuki, Takemi, E-mail: takemi@med.kawasaki-m.ac.jp [Department of Hygiene, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192 (Japan)

2012-07-01

We have been investigating the immunological effects of asbestos. The establishment of a low-dose and continuously exposed human T cell line, HTLV-1 immortalized MT-2, to chrysotile (CB) revealed reduction of CXCR3 chemokine receptor and production of IFN-{gamma} that caused a decline of tumor immunity. These effects were coupled with upregulation of IL-10, TGF-{beta}, and BCL-2 in asbestos-exposed patients. To observe the immunological effects of crocidolite (CR) on human T cells, a trial to establish a low-dose and continuously exposed model was conducted and compared with a previously reported CB-exposed model (MT-2CB). Transient exposure of MT-2 original cells to CB or CR induced a similar level of apoptosis and growth inhibition. The establishment of a continuously exposed subline to CR (MT-2CR) revealed resistance against CR-induced apoptosis and upregulation of the BCL-2/BAX ratio similar to that recorded for MT-2CB. Both sublines showed reduced production of IFN-{gamma}, TNF-{alpha}, and IL-6 with increased IL-10. cDNA microarray with network/pathway analyses focusing on transcription factors revealed that many similar factors related to cell proliferation were involved following continuous exposure to asbestos in both MT-2CB and MT-2CR. These results indicate that both CB and CR fibers affect human T cells with similar degrees even though the carcinogenic activity of these substances differs due to their chemical and physical forms. Trials to identify early detection markers for asbestos exposure or the occurrence of asbestos-inducing malignancies using these findings may lead to the development of clinical tools for asbestos-related diseases and chemoprevention that modifies the reduced tumor immunity. - Highlights: Black-Right-Pointing-Pointer Comparison of effects of chrysotile and crocidolite on human T cell was done. Black-Right-Pointing-Pointer Both fibers caused apoptosis of T cells by transient exposure. Black-Right-Pointing-Pointer T cells

p,p′-DDE Induces Apoptosis of Rat Sertoli Cells via a FasL-Dependent Pathway

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Yuqin Shi

2009-01-01

Full Text Available One,1-dichloro-2,2 bis(p-chlorophenyl ethylene (p,p′-DDE, the major metabolite of 2,2-bis(4-Chlorophenyl-1,1,1-trichloroethane (DDT, is a known persistent organic pollutant and male reproductive toxicant. It has antiandrogenic effect. However, the mechanism by which p,p′-DDE exposure causes male reproductive toxicity remains unknown. In the present study, rat Sertoli cells were used to investigate the molecular mechanism involved in p,p′-DDE-induced toxicity in male reproductive system. The results indicated that p,p′-DDE exposure at over 30 μM showed the induction of apoptotic cell death. p,p′-DDE could induce increases in FasL mRNA and protein, which could be blocked by an antioxidant agent, N-acetyl-l-cysteine (NAC. In addition, caspase-3 and -8 were activated by p,p′-DDE treatment in these cells. The activation of NF-κB was enhanced with the increase of p,p′-DDE dose. Taken together, these results suggested that exposure to p,p′-DDE might induce apoptosis of rat Sertoli cells through a FasL-dependent pathway.

Epicutaneous exposure to nickel induces nickel allergy in mice via a MyD88-dependent and interleukin-1-dependent pathway

DEFF Research Database (Denmark)

Vennegaard, Marie T; Dyring-Andersen, Beatrice; Skov, Lone

2014-01-01

-lasting epicutaneous exposure to nickel. OBJECTIVE: To develop a mouse model reflecting nickel allergy in humans induced by epicutaneous exposure to nickel, and to investigate the mechanisms involved in such allergic responses. METHODS: Mice were exposed to NiCl2 on the dorsal side of the ears. Inflammation...... was evaluated by the swelling and cell infiltration of the ears. T cell responses were determined as numbers of CD4(+) and CD8(+) T cells in the draining lymph nodes. Localization of nickel was examined by dimethylglyoxime staining. RESULTS: Epicutaneous exposure to nickel results in prolonged localization...... of nickel in the epidermis, and induces nickel allergy in mice. The allergic response to nickel following epicutaneous exposure is MyD88-dependent and interleukin (IL)-1 receptor-dependent, but independent of toll-like receptor (TLR)-4. CONCLUSION: This new model for nickel allergy that reflects...

Mitochondrial damage: An important mechanism of ambient PM2.5 exposure-induced acute heart injury in rats

International Nuclear Information System (INIS)

Li, Ruijin; Kou, Xiaojing; Geng, Hong; Xie, Jingfang; Tian, Jingjing; Cai, Zongwei; Dong, Chuan

2015-01-01

Highlights: • PM 2.5 induces heart mitochondrial morphological damage of rats. • Mitochondrial fission/fusion gene expression is important regulation mechanism. • Proinflammatoy cytokine level changes are accompanied with mitochondrial damage. • Alterations in oxidative stress and calcium homeostasis are focused on. - Abstract: Epidemiological studies suggested that ambient fine particulate matter (PM 2.5 ) exposure was associated with cardiovascular disease. However, the underlying mechanism, especially the mitochondrial damage mechanism, of PM 2.5 -induced heart acute injury is still unclear. In this study, the alterations of mitochondrial morphology and mitochondrial fission/fusion gene expression, oxidative stress, calcium homeostasis and inflammation in hearts of rats exposed to PM 2.5 with different dosages (0.375, 1.5, 6.0 and 24.0 mg/kg body weight) were investigated. The results indicated that the PM 2.5 exposure induced pathological changes and ultra-structural damage in hearts such as mitochondrial swell and cristae disorder. Furthermore, PM 2.5 exposure significantly increased specific mitochondrial fission/fusion gene (Fis1, Mfn1, Mfn2, Drp1 and OPA1) expression in rat hearts. These changes were accompanied by decreases of activities of superoxide dismutase (SOD), Na + K + -ATPase and Ca 2+ -ATPase and increases of levels of malondialdehyde (MDA), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) as well as levels of pro-inflammatory mediators including TNF-α, IL-6 and IL-1β in rat hearts. The results implicate that mitochondrial damage, oxidative stress, cellular homeostasis imbalance and inflammation are potentially important mechanisms for the PM 2.5 -induced heart injury, and may have relations with cardiovascular disease

DNA vaccination protects mice against Zika virus-induced damage to the testes

Science.gov (United States)

Griffin, Bryan D.; Muthumani, Kar; Warner, Bryce M.; Majer, Anna; Hagan, Mable; Audet, Jonathan; Stein, Derek R.; Ranadheera, Charlene; Racine, Trina; De La Vega, Marc-Antoine; Piret, Jocelyne; Kucas, Stephanie; Tran, Kaylie N.; Frost, Kathy L.; De Graff, Christine; Soule, Geoff; Scharikow, Leanne; Scott, Jennifer; McTavish, Gordon; Smid, Valerie; Park, Young K.; Maslow, Joel N.; Sardesai, Niranjan Y.; Kim, J. Joseph; Yao, Xiao-jian; Bello, Alexander; Lindsay, Robbin; Boivin, Guy; Booth, Stephanie A.; Kobasa, Darwyn; Embury-Hyatt, Carissa; Safronetz, David; Weiner, David B.; Kobinger, Gary P.

2017-01-01

Zika virus (ZIKV) is an emerging pathogen causally associated with serious sequelae in fetuses, inducing fetal microcephaly and other neurodevelopment defects. ZIKV is primarily transmitted by mosquitoes, but can persist in human semen and sperm, and sexual transmission has been documented. Moreover, exposure of type-I interferon knockout mice to ZIKV results in severe damage to the testes, epididymis and sperm. Candidate ZIKV vaccines have shown protective efficacy in preclinical studies carried out in animal models, and several vaccines have entered clinical trials. Here, we report that administration of a synthetic DNA vaccine encoding ZIKV pre-membrane and envelope (prME) completely protects mice against ZIKV-associated damage to the testes and sperm and prevents viral persistence in the testes following challenge with a contemporary strain of ZIKV. These data suggest that DNA vaccination merits further investigation as a potential means to reduce ZIKV persistence in the male reproductive tract. PMID:28589934

Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms.

Science.gov (United States)

Stenmark, Kurt R; Fagan, Karen A; Frid, Maria G

2006-09-29

Chronic hypoxic exposure induces changes in the structure of pulmonary arteries, as well as in the biochemical and functional phenotypes of each of the vascular cell types, from the hilum of the lung to the most peripheral vessels in the alveolar wall. The magnitude and the specific profile of the changes depend on the species, sex, and the developmental stage at which the exposure to hypoxia occurred. Further, hypoxia-induced changes are site specific, such that the remodeling process in the large vessels differs from that in the smallest vessels. The cellular and molecular mechanisms vary and depend on the cellular composition of vessels at particular sites along the longitudinal axis of the pulmonary vasculature, as well as on local environmental factors. Each of the resident vascular cell types (ie, endothelial, smooth muscle, adventitial fibroblast) undergo site- and time-dependent alterations in proliferation, matrix protein production, expression of growth factors, cytokines, and receptors, and each resident cell type plays a specific role in the overall remodeling response. In addition, hypoxic exposure induces an inflammatory response within the vessel wall, and the recruited circulating progenitor cells contribute significantly to the structural remodeling and persistent vasoconstriction of the pulmonary circulation. The possibility exists that the lung or lung vessels also contain resident progenitor cells that participate in the remodeling process. Thus the hypoxia-induced remodeling of the pulmonary circulation is a highly complex process where numerous interactive events must be taken into account as we search for newer, more effective therapeutic interventions. This review provides perspectives on each of the aforementioned areas.

Intraocular 6-hydroxydopamine prevents the persistent estrus induced by continuous light.

Science.gov (United States)

Shimizu, K; Hokano, M

1985-01-15

Following the intraocular injection of 6-hydroxydopamine, which can destroy the retinal dopaminergic neurons, female rats showed a normal estrous cycle in LD 12:12 but not a persistent estrus in continuous light.

Immune Evasion Strategies and Persistence of Helicobacter pylori.

Science.gov (United States)

Mejías-Luque, Raquel; Gerhard, Markus

Helicobacter pylori infection is commonly acquired during childhood, can persist lifelong if not treated, and can cause different gastric pathologies, including chronic gastritis, peptic ulcer disease, and eventually gastric cancer. H. pylori has developed a number of strategies in order to cope with the hostile conditions found in the human stomach as well as successful mechanisms to evade the strong innate and adaptive immune responses elicited upon infection. Thus, by manipulating innate immune receptors and related signaling pathways, inducing tolerogenic dendritic cells and inhibiting effector T cell responses, H. pylori ensures low recognition by the host immune system as well as its persistence in the gastric epithelium. Bacterial virulence factors such as cytotoxin-associated gene A, vacuolating cytotoxin A, or gamma-glutamyltranspeptidase have been extensively studied in the context of bacterial immune escape and persistence. Further, the bacterium possesses other factors that contribute to immune evasion. In this chapter, we discuss in detail the main evasion and persistence strategies evolved by the bacterium as well as the specific bacterial virulence factors involved.

Ophthalmological assessment of cannabis-induced persisting perception disorder: is there a direct retinal effect?

Science.gov (United States)

Zobor, Ditta; Strasser, Torsten; Zobor, Gergely; Schober, Franziska; Messias, Andre; Strauss, Olaf; Batra, Anil; Zrenner, Eberhart

2015-04-01

Cannabis is a psychotomimetic agent that induces impairment of sensory perception. We present detailed clinical and electrophysiological data of patients with hallucinogen persisting perception disorder (HPPD) after marijuana consumption. A HPPD patient and four heavy cannabis smokers with no visual disturbances (controls) underwent complete ophthalmological examination including psychophysical tests (visual acuity, color vision, visual field, and dark adaptation) and detailed electrophysiological examinations, including extended Ganzfeld ERG, multifocal ERG, and electrooculography (EOG). Furthermore, electrically evoked phosphene thresholds (EPTs) were measured to further evaluate retinal function. Ophthalmological and most electrophysiological examinations were within normal limits for the HPPD patient and for all control subjects. Interestingly, EOG results of the HPPD patient showed a slightly reduced fast oscillation ratio, diminished standing potentials of the slow oscillations, and a light peak within normal range resulting in higher Arden ratios. The EPTs of the patient were reduced, in particular for pulses with long durations (50 ms) causing visual sensations even at lowest possible currents of the neurostimulator. The control subjects did not reveal such alterations. Our findings suggest a direct effect of cannabinoids on the retina and retinal pigment epithelium function, which may be involved in disturbances of the visual function experienced after drug consumption. The observations presented here may contribute to the elucidation of the detailed mechanism. Furthermore, EOG and EPT measurements may be useful tools to demonstrate long-term retinal alterations in cannabis-induced HPPD in patients.

Zika Virus Persistently Infects and Is Basolaterally Released from Primary Human Brain Microvascular Endothelial Cells

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Megan C. Mladinich

2017-07-01

Full Text Available Zika virus (ZIKV is a mosquito-borne Flavivirus that has emerged as the cause of encephalitis and fetal microencephaly in the Americas. ZIKV uniquely persists in human bodily fluids for up to 6 months, is sexually transmitted, and traverses the placenta and the blood-brain barrier (BBB to damage neurons. Cells that support persistent ZIKV replication and mechanisms by which ZIKV establishes persistence remain enigmatic but central to ZIKV entry into protected neuronal compartments. The endothelial cell (EC lining of capillaries normally constrains transplacental transmission and forms the BBB, which selectively restricts access of blood constituents to neurons. We found that ZIKV (strain PRVABC59 persistently infects and continuously replicates in primary human brain microvascular ECs (hBMECs, without cytopathology, for >9 days and following hBMEC passage. ZIKV did not permeabilize hBMECs but was released basolaterally from polarized hBMECs, suggesting a direct mechanism for ZIKV to cross the BBB. ZIKV-infected hBMECs were rapidly resistant to alpha interferon (IFN-α and transiently induced, but failed to secrete, IFN-β and IFN-λ. Global transcriptome analysis determined that ZIKV constitutively induced IFN regulatory factor 7 (IRF7, IRF9, and IFN-stimulated genes (ISGs 1 to 9 days postinfection, despite persistently replicating in hBMECs. ZIKV constitutively induced ISG15, HERC5, and USP18, which are linked to hepatitis C virus (HCV persistence and IFN regulation, chemokine CCL5, which is associated with immunopathogenesis, as well as cell survival factors. Our results reveal that hBMECs act as a reservoir of persistent ZIKV replication, suggest routes for ZIKV to cross hBMECs into neuronal compartments, and define novel mechanisms of ZIKV persistence that can be targeted to restrict ZIKV spread.

UVC-induced stress granules in mammalian cells.

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Mohamed Taha Moutaoufik

Full Text Available Stress granules (SGs are well characterized cytoplasmic RNA bodies that form under various stress conditions. We have observed that exposure of mammalian cells in culture to low doses of UVC induces the formation of discrete cytoplasmic RNA granules that were detected by immunofluorescence staining using antibodies to RNA-binding proteins. UVC-induced cytoplasmic granules are not Processing Bodies (P-bodies and are bone fide SGs as they contain TIA-1, TIA-1/R, Caprin1, FMRP, G3BP1, PABP1, well known markers, and mRNA. Concomitant with the accumulation of the granules in the cytoplasm, cells enter a quiescent state, as they are arrested in G1 phase of the cell cycle in order to repair DNA damages induced by UVC irradiation. This blockage persists as long as the granules are present. A tight correlation between their decay and re-entry into S-phase was observed. However the kinetics of their formation, their low number per cell, their absence of fusion into larger granules, their persistence over 48 hours and their slow decay, all differ from classical SGs induced by arsenite or heat treatment. The induction of these SGs does not correlate with major translation inhibition nor with phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α. We propose that a restricted subset of mRNAs coding for proteins implicated in cell cycling are removed from the translational apparatus and are sequestered in a repressed form in SGs.

Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening

Energy Technology Data Exchange (ETDEWEB)

Wilson, Jodie [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom); Berntsen, Hanne Friis; Zimmer, Karin Elisabeth [Norwegian University of Life Sciences, Oslo (Norway); Frizzell, Caroline [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom); Verhaegen, Steven; Ropstad, Erik [Norwegian University of Life Sciences, Oslo (Norway); Connolly, Lisa, E-mail: l.connolly@qub.ac.uk [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom)

2016-03-01

Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POPs were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds, chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2 h and 48 h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC + Br mixture in comparison to the effects of the individual mixtures. No significant effects were detected in the Br + Cl, PFC + Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment. - Highlights: • High content analysis (HCA) is a novel approach for determining toxicity of

Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening

International Nuclear Information System (INIS)

Wilson, Jodie; Berntsen, Hanne Friis; Zimmer, Karin Elisabeth; Frizzell, Caroline; Verhaegen, Steven; Ropstad, Erik; Connolly, Lisa

2016-01-01

Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POPs were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds, chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2 h and 48 h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC + Br mixture in comparison to the effects of the individual mixtures. No significant effects were detected in the Br + Cl, PFC + Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment. - Highlights: • High content analysis (HCA) is a novel approach for determining toxicity of

Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure

Energy Technology Data Exchange (ETDEWEB)

Zychowski, Katherine E.; Lucas, Selita N.; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J., E-mail: mcampen@salud.unm.edu

2016-08-15

Ozone (O{sub 3})-related cardiorespiratory effects are a growing public health concern. Ground level O{sub 3} can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O{sub 3}-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O{sub 3} pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O{sub 3} exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O{sub 2}) or hypoxia (10.0% O{sub 2}), followed by a 4-h exposure to either 1 ppm O{sub 3} or filtered air (FA). As an additional experimental intervention fasudil (20 mg/kg) was administered intraperitoneally prior to and after O{sub 3} exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O{sub 3} exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O{sub 3} exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O{sub 3}-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability. - Highlights: • Environmental exposures can exacerbate chronic obstructive

Perinatal exposure to environmental tobacco smoke is associated with changes in DNA methylation that precede the adult onset of lung disease in a mouse model.

Science.gov (United States)

Cole, Elizabeth; Brown, Traci A; Pinkerton, Kent E; Postma, Britten; Malany, Keegan; Yang, Mihi; Kim, Yang Jee; Hamilton, Raymond F; Holian, Andrij; Cho, Yoon Hee

2017-08-01

Prenatal and early-life environmental tobacco smoke (ETS) exposure can induce epigenetic alterations associated with inflammation and respiratory disease. The objective of this study was to address the long-term epigenetic consequences of perinatal ETS exposure on latent respiratory disease risk, which are still largely unknown. C57BL/6 mice were exposed to prenatal and early-life ETS; offspring lung pathology, global DNA, and gene-specific methylation were measured at two adult ages. Significant alterations in global DNA methylation and promoter methylation of IFN-γ and Thy-1 were found in ETS-exposed offspring at 10-12 and 20 weeks of age. These sustained epigenetic alterations preceded the onset of significant pulmonary pathologies observed at 20 weeks of age. This study suggests that perinatal ETS exposure induces persistent epigenetic alterations in global DNA, as well as IFN-γ and Thy-1 promoter methylation that precede the adult onset of fibrotic lung pathology. These epigenetic findings could represent potential biomarkers of latent respiratory disease risk.

Epicutaneous exposure to nickel induces nickel allergy in mice via a MyD88-dependent and interleukin-1-dependent pathway.

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Vennegaard, Marie T; Dyring-Andersen, Beatrice; Skov, Lone; Nielsen, Morten M; Schmidt, Jonas D; Bzorek, Michael; Poulsen, Steen S; Thomsen, Allan R; Woetmann, Anders; Thyssen, Jacob P; Johansen, Jeanne D; Odum, Niels; Menné, Torkil; Geisler, Carsten; Bonefeld, Charlotte M

2014-10-01

Several attempts to establish a model in mice that reflects nickel allergy in humans have been made. Most models use intradermal injection of nickel in combination with adjuvant to induce nickel allergy. However, such models poorly reflect induction of nickel allergy following long-lasting epicutaneous exposure to nickel. To develop a mouse model reflecting nickel allergy in humans induced by epicutaneous exposure to nickel, and to investigate the mechanisms involved in such allergic responses. Mice were exposed to NiCl2 on the dorsal side of the ears. Inflammation was evaluated by the swelling and cell infiltration of the ears. T cell responses were determined as numbers of CD4+ and CD8+ T cells in the draining lymph nodes. Localization of nickel was examined by dimethylglyoxime staining. Epicutaneous exposure to nickel results in prolonged localization of nickel in the epidermis, and induces nickel allergy in mice. The allergic response to nickel following epicutaneous exposure is MyD88-dependent and interleukin (IL)-1 receptor-dependent, but independent of toll-like receptor (TLR)-4. This new model for nickel allergy that reflects epicutaneous exposure to nickel in humans shows that nickel allergy is dependent on MyD88 and IL-1 receptor signalling, but independent of TLR4. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sensitivity analysis for direct and indirect effects in the presence of exposure-induced mediator-outcome confounders

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Chiba, Yasutaka

2014-01-01

Questions of mediation are often of interest in reasoning about mechanisms, and methods have been developed to address these questions. However, these methods make strong assumptions about the absence of confounding. Even if exposure is randomized, there may be mediator-outcome confounding variables. Inference about direct and indirect effects is particularly challenging if these mediator-outcome confounders are affected by the exposure because in this case these effects are not identified irrespective of whether data is available on these exposure-induced mediator-outcome confounders. In this paper, we provide a sensitivity analysis technique for natural direct and indirect effects that is applicable even if there are mediator-outcome confounders affected by the exposure. We give techniques for both the difference and risk ratio scales and compare the technique to other possible approaches. PMID:25580387

Chronic exposure to low concentrations of lead induces metabolic disorder and dysbiosis of the gut microbiota in mice.

Science.gov (United States)

Xia, Jizhou; Jin, Cuiyuan; Pan, Zihong; Sun, Liwei; Fu, Zhengwei; Jin, Yuanxiang

2018-08-01

Lead (Pb) is one of the most prevalent toxic, nonessential heavy metals that can contaminate food and water. In this study, effects of chronic exposure to low concentrations of Pb on metabolism and gut microbiota were evaluated in mice. It was observed that exposure of mice to 0.1mg/L Pb, supplied via drinking water, for 15weeks increased hepatic TG and TCH levels. The levels of some key genes related to lipid metabolism in the liver increased significantly in Pb-treated mice. For the gut microbiota, at the phylum level, the relative abundance of Firmicutes and Bacteroidetes changed obviously in the feces and the cecal contents of mice exposed to 0.1mg/L Pb for 15weeks. In addition, 16s rRNA gene sequencing further discovered that Pb exposure affected the structure and richness of the gut microbiota. Moreover, a 1 H NMR metabolic analysis unambiguously identified 31 metabolites, and 15 metabolites were noticeably altered in 0.1mg/L Pb-treated mice. Taken together, the data indicate that chronic Pb exposure induces dysbiosis of the gut microbiota and metabolic disorder in mice. Chronic Pb exposure induces metabolic disorder, dysbiosis of the gut microbiota and hepatic lipid metabolism disorder in mice. Copyright © 2018 Elsevier B.V. All rights reserved.

A ZnO nanowire-based photo-inverter with pulse-induced fast recovery.

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Raza, Syed Raza Ali; Lee, Young Tack; Hosseini Shokouh, Seyed Hossein; Ha, Ryong; Choi, Heon-Jin; Im, Seongil

2013-11-21

We demonstrate a fast response photo-inverter comprised of one transparent gated ZnO nanowire field-effect transistor (FET) and one opaque FET respectively as the driver and load. Under ultraviolet (UV) light the transfer curve of the transparent gate FET shifts to the negative side and so does the voltage transfer curve (VTC) of the inverter. After termination of UV exposure the recovery of photo-induced current takes a long time in general. This persistent photoconductivity (PPC) is due to hole trapping on the surface of ZnO NWs. Here, we used a positive voltage short pulse after UV exposure, for the first time resolving the PPC issue in nanowire-based photo-detectors by accumulating electrons at the ZnO/dielectric interface. We found that a pulse duration as small as 200 ns was sufficient to reach a full recovery to the dark state from the UV induced state, realizing a fast UV detector with a voltage output.

Hepatitis B virus core antigen determines viral persistence in a C57BL/6 mouse model.

Science.gov (United States)

Lin, Yi-Jiun; Huang, Li-Rung; Yang, Hung-Chih; Tzeng, Horng-Tay; Hsu, Ping-Ning; Wu, Hui-Lin; Chen, Pei-Jer; Chen, Ding-Shinn

2010-05-18

We recently developed a mouse model of hepatitis B virus (HBV) persistence, in which a single i.v. hydrodynamic injection of HBV DNA to C57BL/6 mice allows HBV replication and induces a partial immune response, so that about 20-30% of the mice carry HBV for more than 6 months. The model was used to identify the viral antigen crucial for HBV persistence. We knocked out individual HBV genes by introducing a premature termination codon to the HBV core, HBeAg, HBx, and polymerase ORFs. The specific-gene-deficient HBV mutants were hydrodynamically injected into mice and the HBV profiles of the mice were monitored. About 90% of the mice that received the HBcAg-mutated HBV plasmid exhibited high levels of hepatitis B surface antigenemia and maintained HBsAg expression for more than 6 months after injection. To map the region of HBcAg essential for viral clearance, we constructed a set of serial HBcAg deletion mutants for hydrodynamic injection. We localized the essential region of HBcAg to the carboxyl terminus, specifically to the 10 terminal amino acids (HBcAg176-185). The majority of mice receiving this HBV mutant DNA did not elicit a proper HBcAg-specific IFN-gamma response and expressed HBV virions for 6 months. These results indicate that the immune response triggered in mice by HBcAg during exposure to HBV is important in determining HBV persistence.

Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure.

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Cristiane Miranda da Silva

Full Text Available Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA, an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1% or vehicle (distillated water during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure. Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant.

Timing and Duration of Traffic-related Air Pollution Exposure and the Risk for Childhood Wheeze and Asthma.

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Brunst, Kelly J; Ryan, Patrick H; Brokamp, Cole; Bernstein, David; Reponen, Tiina; Lockey, James; Khurana Hershey, Gurjit K; Levin, Linda; Grinshpun, Sergey A; LeMasters, Grace

2015-08-15

The timing and duration of traffic-related air pollution (TRAP) exposure may be important for childhood wheezing and asthma development. We examined the relationship between TRAP exposure and longitudinal wheezing phenotypes and asthma at age 7 years. Children completed clinical examinations annually from age 1 year through age 4 years and age 7 years. Parental-reported wheezing was assessed at each age, and longitudinal wheezing phenotypes (early-transient, late-onset, persistent) and asthma were defined at age 7 years. Participants' time-weighted exposure to TRAP, from birth through age 7 years, was estimated using a land-use regression model. The relationship between TRAP exposure and wheezing phenotypes and asthma was examined. High TRAP exposure at birth was significantly associated with both transient and persistent wheezing phenotypes (adjusted odds ratio [aOR] = 1.64; 95% confidence interval [CI], 1.04-2.57 and aOR = 2.31; 95% CI, 1.28-4.15, respectively); exposure from birth to age 1 year and age 1 to 2 years was also associated with persistent wheeze. Only children with high average TRAP exposure from birth through age 7 years were at significantly increased risk for asthma (aOR = 1.71; 95% CI, 1.01-2.88). Early-life exposure to TRAP is associated with increased risk for persistent wheezing, but only long-term exposure to high levels of TRAP throughout childhood was associated with asthma development.

Impact of persistent cytomegalovirus infection on human neuroblastoma cell gene expression

International Nuclear Information System (INIS)

Hoever, Gerold; Vogel, Jens-Uwe; Lukashenko, Polina; Hofmann, Wolf-Karsten; Komor, Martina; Doerr, Hans Wilhelm; Cinatl, Jindrich

2005-01-01

In a model of human neuroblastoma (NB) cell lines persistently infected with human cytomegalovirus (HCMV) we previously showed that persistent HCMV infection is associated with an increased malignant phenotype, enhanced drug resistance, and invasive properties. To gain insights into the mechanisms of increased malignancy we analyzed the global changes in cellular gene expression induced by persistent HCMV infection of human neuroblastoma cells by use of high-density oligonucleotide microarrays (HG-U133A, Affymetrix) and RT-PCR. Comparing the gene expression of different NB cell lines with persistently infected cell sub-lines revealed 11 host cell genes regulated in a similar manner throughout all infected samples. Nine of these 11 genes may contribute to the previously observed changes in malignant phenotype of persistently HCMV infected NB cells by influencing invasive growth, apoptosis, angiogenesis, and proliferation. Thus, this work provides the basis for further functional studies

Induction and persistence of chromosome aberrations in human lymphocytes exposed to neutrons in vitro or in vivo: Implications of findings in 'retrospective' biological dosimetry

International Nuclear Information System (INIS)

Littlefield, L.G.; McFee, A.F.; Sayer, A.M.; O'Neill, J.P.; Kleinerman, R.A.; Maor, M.H.

2000-01-01

The induction and persistence were evaluated of chromosome aberrations in lymphocytes exposed in vitro to highly efficient 1 MeV monoenergetic neutrons and in patients who received fast neutrons as therapy for tumours. For the in vitro studies, lymphocytes were exposed to various doses of neutrons and cultured for one or 20 cell cycles. Aberrations were quantified in painted chromosome pairs 1, 2 or 4. These 1 MeV neutrons were highly efficient in inducing aberrations, and dicentrics as well as one-way and two-way translocations increased as a linear function of dose. About 30% of the aberrant metaphases displayed complex aberrations. After multiple in vitro cell divisions, virtually all asymmetrical aberrations had been eliminated from the cell population, and the frequency of one-way translocations was reduced dramatically. In contrast, most two-way translocations apparently survived through multiple cell divisions and still displayed excellent correlation with dose after 20 cell cycles. Classical methods were used to evaluate persistence of aberrations in patients who received fractionated neutron therapy to tumours located in many different sites. Neutron induced dicentrics and rings disappeared from the peripheral circulation within the first three years after exposure, while translocations persisted for more than 17 y. However, considerable variability in numbers of aberrations were observed between patients who had received similar 'average bone marrow doses'. Results of these studies are discussed in relation to the possible use of translocations as retrospective dosemeters in persons exposed to radiation many years ago. (author)

Reproductive hormone levels in men exposed to persistent organohalogen pollutants: a study of inuit and three European cohorts

DEFF Research Database (Denmark)

Giwercman, Aleksander; Rignell-Hydbom, Anna; Toft, Gunnar

2006-01-01

OBJECTIVE: Persistent organohalogen pollutant (POP) exposure may have a negative impact on reproductive function. The objective of this study was to assess the impact of POP exposure on the male hypothalamo-pituitary-gonadal axis. PARTICIPANTS: Participants included 184 Swedish fishermen and spou...

Diesel Exhaust Exposure, Wheezing and Sneezing

Science.gov (United States)

2012-01-01

The rising incidence of allergic disorders in developed countries is unexplained. Exposure to traffic related air pollutants may be an important cause of wheezing and asthma in childhood. Experimental evidence from human studies suggests that diesel exhaust particles, constituents of fine particulate matter less than 2.5 microns (PM2.5), may act to enhance IgE mediated aeroallergen sensitization and Th2 directed cytokine responses. To date, epidemiologic investigations indicate that children living in close proximity to heavily travelled roads are more likely to be atopic and wheeze. The Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort study was initiated to test the hypothesis that early high exposure to traffic related air pollutants is associated with early aeroallergen sensitization and allergic respiratory phenotypes. Using an exposure cohort design, more than 700 infants born to atopic parents were recruited at age 1 living either less than 400 meters (high traffic pollutant exposure) or greater than 1,500 meters (low exposure) from a major road. Children were medically evaluated and underwent skin prick testing with aeroallergen at screening, and re-evaluated sequentially at ages 1, 2, 3, 4, and 7. In this study, both proximity and land use regression (LUR) models of traffic air pollutant exposure have been assessed. Proximity to stop and go traffic with large concentrations of bus and truck traffic predicted persistent wheezing during infancy. The LUR model estimated elemental carbon attributable to traffic (ECAT) as a proxy for diesel exhaust particulate exposure. High ECAT was significantly associated with wheezing at age 1 as well as persistent wheezing at age 3. High mold exposure predicted a well defined asthma phenotype at age 7. PMID:22754710

Chronic corticosterone exposure reduces hippocampal glycogen level and induces depression-like behavior in mice.

Science.gov (United States)

Zhang, Hui-yu; Zhao, Yu-nan; Wang, Zhong-li; Huang, Yu-fang

2015-01-01

Long-term exposure to stress or high glucocorticoid levels leads to depression-like behavior in rodents; however, the cause remains unknown. Increasing evidence shows that astrocytes, the most abundant cells in the central nervous system (CNS), are important to the nervous system. Astrocytes nourish and protect the neurons, and serve as glycogen repositories for the brain. The metabolic process of glycogen, which is closely linked to neuronal activity, can supply sufficient energy substrates for neurons. The research team probed into the effects of chronic corticosterone (CORT) exposure on the glycogen level of astrocytes in the hippocampal tissues of male C57BL/6N mice in this study. The results showed that chronic CORT injection reduced hippocampal neurofilament light protein (NF-L) and synaptophysin (SYP) levels, induced depression-like behavior in male mice, reduced hippocampal glycogen level and glycogen synthase activity, and increased glycogen phosphorylase activity. The results suggested that the reduction of the hippocampal glycogen level may be the mechanism by which chronic CORT treatment damages hippocampal neurons and induces depression-like behavior in male mice.

Inhibition of HAS2 induction enhances the radiosensitivity of cancer cells via persistent DNA damage

International Nuclear Information System (INIS)

Shen, Yan Nan; Shin, Hyun-Jin; Joo, Hyun-Yoo; Park, Eun-Ran; Kim, Su-Hyeon; Hwang, Sang-Gu; Park, Sang Jun; Kim, Chun-Ho; Lee, Kee-Ho

2014-01-01

Highlights: •HAS2 may be a promising target for the radiosensitization of human cancer. •HAS2 is elevated (up to ∼10-fold) in irradiated radioresistant and -sensitive cancer cells. •HAS2 knockdown sensitizes cancer cells to radiation. •HAS2 knockdown potentiates irradiation-induced DNA damage and apoptotic death. •Thus, the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. -- Abstract: Hyaluronan synthase 2 (HAS2), a synthetic enzyme for hyaluronan, regulates various aspects of cancer progression, including migration, invasion and angiogenesis. However, the possible association of HAS2 with the response of cancer cells to anticancer radiotherapy, has not yet been elucidated. Here, we show that HAS2 knockdown potentiates irradiation-induced DNA damage and apoptosis in cancer cells. Upon exposure to radiation, all of the tested human cancer cell lines exhibited marked (up to 10-fold) up-regulation of HAS2 within 24 h. Inhibition of HAS2 induction significantly reduced the survival of irradiated radioresistant and -sensitive cells. Interestingly, HAS2 depletion rendered the cells to sustain irradiation-induced DNA damage, thereby leading to an increase of apoptotic death. These findings indicate that HAS2 knockdown sensitizes cancer cells to radiation via persistent DNA damage, further suggesting that the irradiation-induced up-regulation of HAS2 contributes to the radioresistance of cancer cells. Thus, HAS2 could potentially be targeted for therapeutic interventions aimed at radiosensitizing cancer cells

Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk

Science.gov (United States)

BACKGROUND: A breastfeeding infant’s intake of persistent organic pollutants (POPs) may be much greater than his/her mother’s average daily POP exposure. In many cases, current human health risk assessment methods do not account for differences between maternal and infant POP exp...

Turbulence-induced persistence in laser beam wandering.

Science.gov (United States)

Zunino, Luciano; Gulich, Damián; Funes, Gustavo; Pérez, Darío G

2015-07-01

We have experimentally confirmed the presence of long-memory correlations in the wandering of a thin Gaussian laser beam over a screen after propagating through a turbulent medium. A laboratory-controlled experiment was conducted in which coordinate fluctuations of the laser beam were recorded at a sufficiently high sampling rate for a wide range of turbulent conditions. Horizontal and vertical displacements of the laser beam centroid were subsequently analyzed by implementing detrended fluctuation analysis. This is a very well-known and widely used methodology to unveil memory effects from time series. Results obtained from this experimental analysis allow us to confirm that both coordinates behave as highly persistent signals for strong turbulent intensities. This finding is relevant for a better comprehension and modeling of the turbulence effects in free-space optical communication systems and other applications related to propagation of optical signals in the atmosphere.

Hazards of radiation exposure

International Nuclear Information System (INIS)

Solomon, S.B.

1982-01-01

Radiation induced carcinogenesis and mutagenesis form the main risks to health from exposure to low levels of radiation. There is scant data on somatic and genetic risks at environmental and occupational levels of radiation exposure. The available data on radiation induced carcinogenesis and mutagenesis are for high doses and high dose rates of radiation. Risk assessments for low level radiation are obtained using these data, assuming a linear dose-response relationship. During uranium mining the chief source of radiation hazard is inhalation of radon daughters. The correlation between radon daughter exposure and the increased incidence of lung cancer has been well documented. For radiation exposures at and below occupational limits, the associated risk of radiation induced cancers and genetic abnormalities is small and should not lead to a detectable increase over naturally occurring rates

Deficits in water maze performance and oxidative stress in the hippocampus and striatum induced by extremely low frequency magnetic field exposure.

Directory of Open Access Journals (Sweden)

Yonghua Cui

Full Text Available The exposures to extremely low frequency magnetic field (ELF-MF in our environment have dramatically increased. Epidemiological studies suggest that there is a possible association between ELF-MF exposure and increased risks of cardiovascular disease, cancers and neurodegenerative disorders. Animal studies show that ELF-MF exposure may interfere with the activity of brain cells, generate behavioral and cognitive disturbances, and produce deficits in attention, perception and spatial learning. Although, many research efforts have been focused on the interaction between ELF-MF exposure and the central nervous system, the mechanism of interaction is still unknown. In this study, we examined the effects of ELF-MF exposure on learning in mice using two water maze tasks and on some parameters indicative of oxidative stress in the hippocampus and striatum. We found that ELF-MF exposure (1 mT, 50 Hz induced serious oxidative stress in the hippocampus and striatum and impaired hippocampal-dependent spatial learning and striatum-dependent habit learning. This study provides evidence for the association between the impairment of learning and the oxidative stress in hippocampus and striatum induced by ELF-MF exposure.

Long-term nicotine exposure dampens LPS-induced nerve-mediated airway hyperreactivity in murine airways.

Science.gov (United States)

Xu, Yuan; Cardell, Lars-Olaf

2017-09-01

Nicotine is a major component of cigarette smoke. It causes addiction and is used clinically to aid smoke cessation. The aim of the present study is to investigate the effect of nicotine on lipopolysaccharide (LPS)-induced airway hyperreactivity (AHR) and to explore the potential involvement of neuronal mechanisms behind nicotine's effects in murine models in vivo and in vitro. BALB/c mice were exposed to nicotine in vivo via subcutaneous Alzet osmotic minipumps containing nicotine tartate salt solution (24 mg·kg -1 ·day -1 ) for 28 days. LPS (0.1 mg/ml, 20 µl) was administered intranasally for 3 consecutive days during the end of this period. Lung functions were measured with flexiVent. For the in vitro experiments, mice tracheae were organcultured with either nicotine (10 μM) or vehicle (DMSO, 0.1%) for 4 days. Contractile responses of the tracheal segments were measured in myographs following electric field stimulation (EFS; increasing frequencies of 0.2 to 12.8 Hz) before and after incubation with 10 µg/ml LPS for 1 h. Results showed that LPS induced AHR to methacholine in vivo and increased contractile responses to EFS in vitro. Interestingly, long-term nicotine exposure markedly dampened this LPS-induced AHR both in vitro and in vivo. Tetrodotoxin (TTX) inhibited LPS-induced AHR but did not further inhibit nicotine-suppressed AHR in vivo. In conclusion, long-term nicotine exposure dampened LPS-induced AHR. The effect of nicotine was mimicked by TTX, suggesting the involvement of neuronal mechanisms. This information might be used for evaluating the long-term effects of nicotine and further exploring of how tobacco products interact with bacterial airway infections. Copyright © 2017 the American Physiological Society.

Photo-induced toxicity in early life stage fiddler crab (Uca longisignalis) following exposure to Deepwater Horizon oil.

Science.gov (United States)

Damare, Leigh M; Bridges, Kristin N; Alloy, Matthew M; Curran, Thomas E; Soulen, Brianne K; Forth, Heather P; Lay, Claire R; Morris, Jeffrey M; Stoeckel, James A; Roberts, Aaron P

2018-05-01

The 2010 explosion of the Deepwater Horizon (DWH) oil rig led to the release of millions of barrels of oil in the Gulf of Mexico. Oil in aquatic ecosystems exerts toxicity through multiple mechanisms, including photo-induced toxicity following co-exposure with UV radiation. The timing and location of the spill coincided with both fiddler crab reproduction and peak yearly UV intensities, putting early life stage fiddler crabs at risk of injury due to photo-induced toxicity. The present study assessed sensitivity of fiddler crab larvae to photo-induced toxicity during co-exposure to a range of environmentally relevant dilutions of high-energy water accommodated fractions of DWH oil, and either dark recovery period (duration: 17-h) in between. Survival was significantly decreased in treatments the presence of >10% UV and relatively low concentrations of oil. Results of the present study indicate fiddler crab larvae are sensitive to photo-induced toxicity in the presence of DWH oil. These results are of concern, as fiddler crabs play an important role as ecosystem engineers, modulating sediment biogeochemical processes via burrowing action. Furthermore, they occupy an important place in the food web in the Gulf of Mexico.

Gene networks and toxicity pathways induced by acute cadmium exposure in adult largemouth bass (Micropterus salmoides).

Science.gov (United States)

Mehinto, Alvine C; Prucha, Melinda S; Colli-Dula, Reyna C; Kroll, Kevin J; Lavelle, Candice M; Barber, David S; Vulpe, Christopher D; Denslow, Nancy D

2014-07-01

Cadmium is a heavy metal that can accumulate to toxic levels in the environment leading to detrimental effects in animals and humans including kidney, liver and lung injuries. Using a transcriptomics approach, genes and cellular pathways affected by a low dose of cadmium were investigated. Adult largemouth bass were intraperitoneally injected with 20μg/kg of cadmium chloride (mean exposure level - 2.6μg of cadmium per fish) and microarray analyses were conducted in the liver and testis 48h after injection. Transcriptomic profiles identified in response to cadmium exposure were tissue-specific with the most differential expression changes found in the liver tissues, which also contained much higher levels of cadmium than the testis. Acute exposure to a low dose of cadmium induced oxidative stress response and oxidative damage pathways in the liver. The mRNA levels of antioxidants such as catalase increased and numerous transcripts related to DNA damage and DNA repair were significantly altered. Hepatic mRNA levels of metallothionein, a molecular marker of metal exposure, did not increase significantly after 48h exposure. Carbohydrate metabolic pathways were also disrupted with hepatic transcripts such as UDP-glucose, pyrophosphorylase 2, and sorbitol dehydrogenase highly induced. Both tissues exhibited a disruption of steroid signaling pathways. In the testis, estrogen receptor beta and transcripts linked to cholesterol metabolism were suppressed. On the contrary, genes involved in cholesterol metabolism were highly increased in the liver including genes encoding for the rate limiting steroidogenic acute regulatory protein and the catalytic enzyme 7-dehydrocholesterol reductase. Integration of the transcriptomic data using functional enrichment analyses revealed a number of enriched gene networks associated with previously reported adverse outcomes of cadmium exposure such as liver toxicity and impaired reproduction. Copyright © 2014 Elsevier B.V. All rights

Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome

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Laura R. Hoyt

2017-08-01

Full Text Available Alcohol use disorders are common both in the United States and globally, and are associated with a variety of co-morbid, inflammation-linked diseases. The pathogenesis of many of these ailments are driven by the activation of the NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the pro-inflammatory cytokines IL-1β and IL-18. We hypothesized that protracted exposure of leukocytes to ethanol would amplify inflammasome activation, which would help to implicate mechanisms involved in diseases associated with both alcoholism and aberrant NLRP3 inflammasome activation. Here we show that long-term ethanol exposure of human peripheral blood mononuclear cells and a mouse macrophage cell line (J774 amplifies IL-1β secretion following stimulation with NLRP3 agonists, but not with AIM2 or NLRP1b agonists. The augmented NRLP3 activation was mediated by increases in iNOS expression and NO production, in conjunction with increases in mitochondrial membrane depolarization, oxygen consumption rate, and ROS generation in J774 cells chronically exposed to ethanol (CE cells, effects that could be inhibited by the iNOS inhibitor SEITU, the NO scavenger carboxy-PTIO, and the mitochondrial ROS scavenger MitoQ. Chronic ethanol exposure did not alter K+ efflux or Zn2+ homeostasis in CE cells, although it did result in a lower intracellular concentration of NAD+. Prolonged administration of acetaldehyde, the product of alcohol dehydrogenase (ADH mediated metabolism of ethanol, mimicked chronic ethanol exposure, whereas ADH inhibition prevented ethanol-induced IL-1β hypersecretion. Together, these results indicate that increases in iNOS and mitochondrial ROS production are critical for chronic ethanol-induced IL-1β hypersecretion, and that protracted exposure to the products of ethanol metabolism are probable mediators of NLRP3 inflammasome hyperactivation. Keywords: Inflammasome, IL

Induction by mercury compounds of brain metallothionein in rats: Hg{sup 0} exposure induces long-lived brain metallothionein

Energy Technology Data Exchange (ETDEWEB)

Yasutake, Akira; Nakano, Atsuhiro [Biochemistry Section, National Institute for Minamata Disease, Kumamoto (Japan); Hirayama, Kimiko [Kumamoto University, College of Medical Science (Japan)

1998-03-01

Metallothionein (MT) is one of the stress proteins which can easily be induced by various kind of heavy metals. However, MT in the brain is difficult to induce because of blood-brain barrier impermeability to most heavy metals. In this paper, we have attempted to induce brain MT in rats by exposure to methylmercury (MeHg) or metallic mercury vapor, both of which are known to penetrate the blood-brain barrier and cause neurological damage. Rats treated with MeHg (40 {mu}mol/kg per day x 5 days, p.o.) showed brain Hg levels as high as 18 {mu}g/g with slight neurological signs 10 days after final administration, but brain MT levels remained unchanged. However, rats exposed to Hg vapor for 7 days showed 7-8 {mu}g Hg/g brain tissue 24 h after cessation of exposure. At that time brain MT levels were about twice the control levels. Although brain Hg levels fell gradually with a half-life of 26 days, MT levels induced by Hg exposure remained unchanged for >2 weeks. Gel fractionation revealed that most Hg was in the brain cytosol fraction and thus bound to MT. Hybridization analysis showed that, despite a significant increase in MT-I and -II mRNA in brain, MT-III mRNA was less affected. Although significant Hg accumulation and MT induction were observed also in kidney and liver of Hg vapor-exposed rats, these decreased more quickly than in brain. The long-lived MT in brain might at least partly be accounted for by longer half-life of Hg accumulated there. The present results showed that exposure to Hg vapor might be a suitable procedure to provide an in vivo model with enhanced brain MT. (orig.) With 4 figs., 1 tab., 27 refs.

A mathematical model for leukemogenesis of radiation-induced acute myeloid leukemia in C3H/He mice

International Nuclear Information System (INIS)

Kai, M.; Ban, N.

2002-01-01

We developed a mathematical model in leukemogenesis of acute myeloid leukemia(AML) in C3H/He mice irradiated. Our previous study indicated that the leukemogenesis of AML was associated with a deletion of chromosome 2 directly induced by acute radiation. We hypothesized that radiation-induced AML needs both inactivation of one allele of a causative gene directly induced by acute radiation and another mutational event at the other allele. We analyzed data using a two-stage stochastic model for carcinogenesis. Model fitting was based on the maximum likelihood method. Our model analysis suggested that a single exposure might induce the long-lasting delayed cell death of radiation-induced initiated cells, and that the incidence of AML may be determined through both radiation-induced initiation and persistent increase of delayed cell death of the initiated cell induced by radiation

Respiratory syncytial virus infections enhance cigarette smoke induced COPD in mice.

Directory of Open Access Journals (Sweden)

Robert F Foronjy

Full Text Available Respiratory syncytial viral (RSV infections are a frequent cause of chronic obstructive pulmonary disease (COPD exacerbations, which are a major factor in disease progression and mortality. RSV is able to evade antiviral defenses to persist in the lungs of COPD patients. Though RSV infection has been identified in COPD, its contribution to cigarette smoke-induced airway inflammation and lung tissue destruction has not been established. Here we examine the long-term effects of cigarette smoke exposure, in combination with monthly RSV infections, on pulmonary inflammation, protease production and remodeling in mice. RSV exposures enhanced the influx of macrophages, neutrophils and lymphocytes to the airways of cigarette smoke exposed C57BL/6J mice. This infiltration of cells was most pronounced around the vasculature and bronchial airways. By itself, RSV caused significant airspace enlargement and fibrosis in mice and these effects were accentuated with concomitant smoke exposure. Combined stimulation with both smoke and RSV synergistically induced cytokine (IL-1α, IL-17, IFN-γ, KC, IL-13, CXCL9, RANTES, MIF and GM-CSF and protease (MMP-2, -8, -12, -13, -16 and cathepsins E, S, W and Z expression. In addition, RSV exposure caused marked apoptosis within the airways of infected mice, which was augmented by cigarette smoke exposure. RSV and smoke exposure also reduced protein phosphatase 2A (PP2A and protein tyrosine phosphates (PTP1B expression and activity. This is significant as these phosphatases counter smoke-induced inflammation and protease expression. Together, these findings show for the first time that recurrent RSV infection markedly enhances inflammation, apoptosis and tissue destruction in smoke-exposed mice. Indeed, these results indicate that preventing RSV transmission and infection has the potential to significantly impact on COPD severity and progression.

Ultrastructural effects on gill, muscle, and gonadal tissues induced in zebrafish (Danio rerio) by a waterborne uranium exposure

International Nuclear Information System (INIS)

Barillet, Sabrina; Larno, Valerie; Floriani, Magali; Devaux, Alain; Adam-Guillermin, Christelle

2010-01-01

Experiments on adult zebrafish (Danio rerio) were conducted to assess histopathological effects induced on gill, muscle, and gonadal tissues after waterborne uranium exposure. Although histopathology is often employed as a tool for the detection and assessment of xenobiotic-mediated effects in aquatic organisms, few studies have been dedicated to the investigation of histopathological consequences of uranium exposure in fish. Results showed that gill tissue architecture was markedly disrupted. Major symptoms were alterations of the secondary lamellae epithelium (from extensive oedema to desquamation), hyperplasia of chloride cells, and breakdown of the pillar cell system. Muscle histology was also affected. Degeneration and disorganization of myofibrillar sarcomeric pattern as well as abnormal localization of mitochondria within muscle and altered endomysial sheaths were observed. Morphological alterations of spermatozoa within the gonadal tissue were also noticed. This study demonstrated that uranium exposure induced a variety of histological impairments in fish, supporting environmental concerns when uranium contaminates aquatic systems.

Ultrastructural effects on gill, muscle, and gonadal tissues induced in zebrafish (Danio rerio) by a waterborne uranium exposure

Energy Technology Data Exchange (ETDEWEB)

Barillet, Sabrina, E-mail: sabrina.barillet@free.fr [Laboratory of Radioecology and Ecotoxicology, IRSN (Institute for Radiological Protection and Nuclear Safety), DEI/SECRE/LRE, Cadarache, Bat 186, BP 3, 13115 St-Paul-Lez-Durance cedex (France); Larno, Valerie, E-mail: valerie.larno@irsn.fr [Laboratory of Radioecology and Ecotoxicology, IRSN (Institute for Radiological Protection and Nuclear Safety), DEI/SECRE/LRE, Cadarache, Bat 186, BP 3, 13115 St-Paul-Lez-Durance cedex (France); Floriani, Magali, E-mail: magali.floriani@irsn.fr [Laboratory of Radioecology and Ecotoxicology, IRSN (Institute for Radiological Protection and Nuclear Safety), DEI/SECRE/LRE, Cadarache, Bat 186, BP 3, 13115 St-Paul-Lez-Durance cedex (France); Devaux, Alain, E-mail: alain.devaux@entpe.fr [INRA, EFPA Department, 54280, Champenoux and Environmental Science Laboratory, ENTPE, 69518 Vaulx en Velin cedex (France); Adam-Guillermin, Christelle, E-mail: christelle.adam-guillermin@irsn.fr [Laboratory of Radioecology and Ecotoxicology, IRSN (Institute for Radiological Protection and Nuclear Safety), DEI/SECRE/LRE, Cadarache, Bat 186, BP 3, 13115 St-Paul-Lez-Durance cedex (France)

2010-11-01

Experiments on adult zebrafish (Danio rerio) were conducted to assess histopathological effects induced on gill, muscle, and gonadal tissues after waterborne uranium exposure. Although histopathology is often employed as a tool for the detection and assessment of xenobiotic-mediated effects in aquatic organisms, few studies have been dedicated to the investigation of histopathological consequences of uranium exposure in fish. Results showed that gill tissue architecture was markedly disrupted. Major symptoms were alterations of the secondary lamellae epithelium (from extensive oedema to desquamation), hyperplasia of chloride cells, and breakdown of the pillar cell system. Muscle histology was also affected. Degeneration and disorganization of myofibrillar sarcomeric pattern as well as abnormal localization of mitochondria within muscle and altered endomysial sheaths were observed. Morphological alterations of spermatozoa within the gonadal tissue were also noticed. This study demonstrated that uranium exposure induced a variety of histological impairments in fish, supporting environmental concerns when uranium contaminates aquatic systems.

Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

Energy Technology Data Exchange (ETDEWEB)

Zago, A. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Leão, R.M.; Carneiro-de-Oliveira, P.E. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Programa Interinstitucional de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de São Carlos/Universidade Estadual de São Paulo, Araraquara, SP (Brazil); Marin, M.T.; Cruz, F.C. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Planeta, C.S. [Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista, Araraquara, SP (Brazil); Programa Interinstitucional de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de São Carlos/Universidade Estadual de São Paulo, Araraquara, SP (Brazil)

2011-11-18

Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although crosssensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P) 28-37) and adult (P60-67) rats received nicotine (0.4 mg/kg, sc) or saline (0.9% NaCl, sc) and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc) or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats.

Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

International Nuclear Information System (INIS)

Zago, A.; Leão, R.M.; Carneiro-de-Oliveira, P.E.; Marin, M.T.; Cruz, F.C.; Planeta, C.S.

2011-01-01

Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although crosssensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P) 28-37) and adult (P60-67) rats received nicotine (0.4 mg/kg, sc) or saline (0.9% NaCl, sc) and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc) or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats

Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

Directory of Open Access Journals (Sweden)

A. Zago

2012-01-01

Full Text Available Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although cross-sensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P 28-37 and adult (P60-67 rats received nicotine (0.4 mg/kg, sc or saline (0.9% NaCl, sc and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats.

Severe, multimodal stress exposure induces PTSD-like characteristics in a mouse model of single prolonged stress.

Science.gov (United States)

Perrine, Shane A; Eagle, Andrew L; George, Sophie A; Mulo, Kostika; Kohler, Robert J; Gerard, Justin; Harutyunyan, Arman; Hool, Steven M; Susick, Laura L; Schneider, Brandy L; Ghoddoussi, Farhad; Galloway, Matthew P; Liberzon, Israel; Conti, Alana C

2016-04-15

Appropriate animal models of posttraumatic stress disorder (PTSD) are needed because human studies remain limited in their ability to probe the underlying neurobiology of PTSD. Although the single prolonged stress (SPS) model is an established rat model of PTSD, the development of a similarly-validated mouse model emphasizes the benefits and cross-species utility of rodent PTSD models and offers unique methodological advantages to that of the rat. Therefore, the aims of this study were to develop and describe a SPS model for mice and to provide data that support current mechanisms relevant to PTSD. The mouse single prolonged stress (mSPS) paradigm, involves exposing C57Bl/6 mice to a series of severe, multimodal stressors, including 2h restraint, 10 min group forced swim, exposure to soiled rat bedding scent, and exposure to ether until unconsciousness. Following a 7-day undisturbed period, mice were tested for cue-induced fear behavior, effects of paroxetine on cue-induced fear behavior, extinction retention of a previously extinguished fear memory, dexamethasone suppression of corticosterone (CORT) response, dorsal hippocampal glucocorticoid receptor protein and mRNA expression, and prefrontal cortex glutamate levels. Exposure to mSPS enhanced cue-induced fear, which was attenuated by oral paroxetine treatment. mSPS also disrupted extinction retention, enhanced suppression of stress-induced CORT response, increased mRNA expression of dorsal hippocampal glucocorticoid receptors and decreased prefrontal cortex glutamate levels. These data suggest that the mSPS model is a translationally-relevant model for future PTSD research with strong face, construct, and predictive validity. In summary, mSPS models characteristics relevant to PTSD and this severe, multimodal stress modifies fear learning in mice that coincides with changes in the hypothalamo-pituitary-adrenal (HPA) axis, brain glucocorticoid systems, and glutamatergic signaling in the prefrontal cortex

Exploring Tinnitus-Induced Disablement by Persistent Frustration in Aging Individuals: A Grounded Theory Study

Science.gov (United States)

Dauman, Nicolas; Erlandsson, Soly I.; Albarracin, Dolorès; Dauman, René

2017-01-01

Background: Qualitative research can help to improve the management of patients, meet their expectations and assist physicians in alleviating their suffering. The perception of moment-to-moment variability in tinnitus annoyance is an emerging field of exploration. This study sought to enlighten variability in tinnitus-induced disablement using a qualitative approach. Methods: Twelve participants (six females, six males, aged 51–79) were recruited via the French Tinnitus Association Journal for participation in recorded semi-structured interviews. Each participant had three interviews lasting 1 h, the sessions being separated one from the other by 2 weeks. Following recommendations of Charmaz (2014), the second and third interviews were aimed at gathering rich data, by enhancing the participants' reflexivity in the circumstances of distress caused by tinnitus. After transcription, the data (n = 36 interviews) were analyzed using the approach to Grounded Theory proposed by Strauss and Corbin (1998). Results: Tinnitus as persistent frustration emerged as being the core category uniting all the other categories of the study. Hence, the core category accounted for the broader scope in participants' experience of chronic tinnitus. It is suggested that tinnitus-induced disablement varied according to the degree of frustration felt by the participants in not being able to achieve their goals. The implications of this were analyzed using the following categories: “Losing body ownership,” “Lacking perspectives,” and “Persevering through difficulties.” Based on these findings, we draw a substantive theory of tinnitus tolerance that promotes an active, disciplined and individualized approach to tinnitus-induced disablement. The model distinguishes pathways from sustained suffering to reduced annoyance (i.e., emerging tolerance). It accounts for difficulties that the participants experienced with a perceived unchanged annoyance over time. Furthermore, this model

Exploring Tinnitus-Induced Disablement by Persistent Frustration in Aging Individuals: A Grounded Theory Study

Directory of Open Access Journals (Sweden)

Nicolas Dauman

2017-08-01

Full Text Available Background: Qualitative research can help to improve the management of patients, meet their expectations and assist physicians in alleviating their suffering. The perception of moment-to-moment variability in tinnitus annoyance is an emerging field of exploration. This study sought to enlighten variability in tinnitus-induced disablement using a qualitative approach.Methods: Twelve participants (six females, six males, aged 51–79 were recruited via the French Tinnitus Association Journal for participation in recorded semi-structured interviews. Each participant had three interviews lasting 1 h, the sessions being separated one from the other by 2 weeks. Following recommendations of Charmaz (2014, the second and third interviews were aimed at gathering rich data, by enhancing the participants' reflexivity in the circumstances of distress caused by tinnitus. After transcription, the data (n = 36 interviews were analyzed using the approach to Grounded Theory proposed by Strauss and Corbin (1998.Results: Tinnitus as persistent frustration emerged as being the core category uniting all the other categories of the study. Hence, the core category accounted for the broader scope in participants' experience of chronic tinnitus. It is suggested that tinnitus-induced disablement varied according to the degree of frustration felt by the participants in not being able to achieve their goals. The implications of this were analyzed using the following categories: “Losing body ownership,” “Lacking perspectives,” and “Persevering through difficulties.” Based on these findings, we draw a substantive theory of tinnitus tolerance that promotes an active, disciplined and individualized approach to tinnitus-induced disablement. The model distinguishes pathways from sustained suffering to reduced annoyance (i.e., emerging tolerance. It accounts for difficulties that the participants experienced with a perceived unchanged annoyance over time. Furthermore

Oxidative DNA damage of peripheral blood polymorphonuclear leukocytes, selectively induced by chronic arsenic exposure, is associated with extent of arsenic-related skin lesions