WorldWideScience

Sample records for human exposure pathways

  1. Tracking the pathways of human exposure to perfluorocarboxylates.

    Science.gov (United States)

    Vestergren, Robin; Cousins, Ian T

    2009-08-01

    Recent analyses of perfluorooctanoate (PFOA) in human blood sera show that the background-exposed population in industrialized countries worldwide exhibits a narrow concentration range; arithmetic means of published studies range between 2 and 8 microg/L PFOA, with the exception of a few outlier studies. The globally comparable human serum concentrations of PFOA and characteristic dominance of PFOA with respect to other perfluorocarboxylate (PFCA) homologues indicate that exposure pathways of humans differ from those of wildlife, where perfluorononanoate (PFNA) is often the dominant homologue. The observed correlations between perfluorooctane sulfonate (PFOS) and PFOA in human serum together with a simultaneous downward time trend of these compounds in human blood sera and blood spots from the year 2000 onward indicate a connection between historical perfluorooctanesulfonyl (POSF) production (phased out by the major manufacturer in 2000-2002) and exposure to both PFOS and PFOA. A comparison of estimated daily intakes to humans based on samples from exposure media (collected post 2000) indicates that food intake is the major contemporary exposure pathway for the background population, whereas drinking water exposure is dominant for populations near sources of contaminated drinking water. A one-compartment pharmacokinetic model used to back-calculate daily intakes from serum levels is shown to provide agreement within a factor of 1.5-5.5 of the daily intakes derived from exposure media, which provides further supporting evidence that dietary exposure is a major ongoing exposure pathway of PFOA to the background population.

  2. Sampling strategy for estimating human exposure pathways to consumer chemicals

    Directory of Open Access Journals (Sweden)

    Eleni Papadopoulou

    2016-03-01

    Full Text Available Human exposure to consumer chemicals has become a worldwide concern. In this work, a comprehensive sampling strategy is presented, to our knowledge being the first to study all relevant exposure pathways in a single cohort using multiple methods for assessment of exposure from each exposure pathway. The selected groups of chemicals to be studied are consumer chemicals whose production and use are currently in a state of transition and are; per- and polyfluorinated alkyl substances (PFASs, traditional and “emerging” brominated flame retardants (BFRs and EBFRs, organophosphate esters (OPEs and phthalate esters (PEs. Information about human exposure to these contaminants is needed due to existing data gaps on human exposure intakes from multiple exposure pathways and relationships between internal and external exposure. Indoor environment, food and biological samples were collected from 61 participants and their households in the Oslo area (Norway on two consecutive days, during winter 2013-14. Air, dust, hand wipes, and duplicate diet (food and drink samples were collected as indicators of external exposure, and blood, urine, blood spots, hair, nails and saliva as indicators of internal exposure. A food diary, food frequency questionnaire (FFQ and indoor environment questionnaire were also implemented. Approximately 2000 samples were collected in total and participant views on their experiences of this campaign were collected via questionnaire. While 91% of our participants were positive about future participation in a similar project, some tasks were viewed as problematic. Completing the food diary and collection of duplicate food/drink portions were the tasks most frequent reported as “hard”/”very hard”. Nevertheless, a strong positive correlation between the reported total mass of food/drinks in the food record and the total weight of the food/drinks in the collection bottles was observed, being an indication of accurate performance

  3. Soil is an important pathway of human lead exposure.

    OpenAIRE

    Mielke, H W; Reagan, P L

    1998-01-01

    This review shows the equal or greater importance of leaded gasoline-contaminated dust compared to lead-based paint to the child lead problem, and that soil lead, resulting from leaded gasoline and pulverized lead-based paint, is at least or more important than lead-based paint (intact and not pulverized) as a pathway of human lead exposure. Because lead-based paint is a high-dose source, the biologically relevant dosage is similar to lead in soil. Both lead-based paint and soil lead are asso...

  4. Soil is an important pathway of human lead exposure.

    OpenAIRE

    Mielke, H W; Reagan, P L

    1998-01-01

    This review shows the equal or greater importance of leaded gasoline-contaminated dust compared to lead-based paint to the child lead problem, and that soil lead, resulting from leaded gasoline and pulverized lead-based paint, is at least or more important than lead-based paint (intact and not pulverized) as a pathway of human lead exposure. Because lead-based paint is a high-dose source, the biologically relevant dosage is similar to lead in soil. Both lead-based paint and soil lead are asso...

  5. Environmental pathways and human exposure to manganese in southern Brazil

    Directory of Open Access Journals (Sweden)

    NADIR HERMES

    2013-01-01

    Full Text Available The study of environmental pathways and human exposure to Manganese (Mn in Southern Brazil was performed using two steps. The first step consisted of taking water samples from the surface of the Pardinho River. The average results from this technique showed a significant increase of pollutants, including increased levels of Mn, above the environmentally acceptable standard recommended by the Brazilian National Environment Council. Additionally, 64 soil samples were taken from areas with and without agricultural activity. Many results were above the mean crust and did not indicate significant differences of Mn levels between the sampled areas. For the second step, 12 families were selected and assessed for exposure to Mn in a region with high levels of Mn in the soil. Most of the analyzed foods contained amounts of Mn above the reference values, indicating that food can be an important source of exposure. The Mn content from the hair of most subjects studied was also high compared to reference values from non-exposed populations. Although the contamination appeared to come from a natural origin, the results found in the present study showed that the Mn levels present in the Pardinho River Basin are a relevant public health issue.

  6. Concordant signaling pathways produced by pesticide exposure in mice correspond to pathways identified in human Parkinson's disease.

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    Seema Gollamudi

    Full Text Available Parkinson's disease (PD is a neurodegenerative disease in which the etiology of 90 percent of the patients is unknown. Pesticide exposure is a major risk factor for PD, and paraquat (PQ, pyridaben (PY and maneb (MN are amongst the most widely used pesticides. We studied mRNA expression using transcriptome sequencing (RNA-Seq in the ventral midbrain (VMB and striatum (STR of PQ, PY and paraquat+maneb (MNPQ treated mice, followed by pathway analysis. We found concordance of signaling pathways between the three pesticide models in both the VMB and STR as well as concordance in these two brain areas. The concordant signaling pathways with relevance to PD pathogenesis were e.g. axonal guidance signaling, Wnt/β-catenin signaling, as well as pathways not previously linked to PD, e.g. basal cell carcinoma, human embryonic stem cell pluripotency and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Human PD pathways previously identified by expression analysis, concordant with VMB pathways identified in our study were axonal guidance signaling, Wnt/β-catenin signaling, IL-6 signaling, ephrin receptor signaling, TGF-β signaling, PPAR signaling and G-protein coupled receptor signaling. Human PD pathways concordant with the STR pathways in our study were Wnt/β-catenin signaling, axonal guidance signaling and G-protein coupled receptor signaling. Peroxisome proliferator activated receptor delta (Ppard and G-Protein Coupled Receptors (GPCRs were common genes in VMB and STR identified by network analysis. In conclusion, the pesticides PQ, PY and MNPQ elicit common signaling pathways in the VMB and STR in mice, which are concordant with known signaling pathways identified in human PD, suggesting that these pathways contribute to the pathogenesis of idiopathic PD. The analysis of these networks and pathways may therefore lead to improved understanding of disease pathogenesis, and potential novel therapeutic targets.

  7. Human exposure pathways of heavy metals in a lead-zinc mining area, Jiangsu Province, China.

    Directory of Open Access Journals (Sweden)

    Chang-Sheng Qu

    Full Text Available Heavy metal pollution is becoming a serious issue in developing countries such as China, and the public is increasingly aware of its adverse health impacts in recent years. We assessed the potential health risks in a lead-zinc mining area and attempted to identify the key exposure pathways. We evaluated the spatial distributions of personal exposure using indigenous exposure factors and field monitoring results of water, soil, food, and indoor and outdoor air samples. The risks posed by 10 metals and the contribution of inhalation, ingestion and dermal contact pathways to these risks were estimated. Human hair samples were also analyzed to indicate the exposure level in the human body. Our results show that heavy metal pollution may pose high potential health risks to local residents, especially in the village closest to the mine (V1, mainly due to Pb, Cd and Hg. Correspondingly, the residents in V1 had higher Pb (8.14 mg/kg levels in hair than those in the other two villages. Most of the estimated risks came from soil, the intake of self-produced vegetables and indoor air inhalation. This study highlights the importance of site-specific multipathway health risk assessments in studying heavy-metal exposures in China.

  8. [Indoor dust as a pathway of human exposure to polybrominated diphenyl ethers (PBDEs)].

    Science.gov (United States)

    Góralczyk, Katarzyna; Struciński, Paweł; Hernik, Agnieszka; Czaja, Katarzyna; Korcz, Wojciech; Minorczyk, Maria; Ludwicki, Jan K

    2012-01-01

    The brominated diphenyl ethers (PBDEs) belong to a class of synthetic, additive brominated flame retardants (BFRs). PBDEs are used to reduce the flammability of commercial and household products such as textiles, various plastic polymers, furnishing foam, and electronic equipment. People spend a large percentage of their life-time indoors at home, in offices and cars, etc, providing many opportunities for lengthy exposure to PBDEs from residential settings and commercial products in an indoor environment. In recent time, the foodstuffs, mainly food of animal origin, have been indicated as the main pathway of human exposure to PBDEs. However, many studies have shown that the indoor environment, mainly indoor dust, can be also a significant source of exposure to PBDEs, especially for younger children (toddlers) because of their behavioral patterns, eg. putting fingers, toys, and other items in their mouth. Numerous studies show that the median intakes of PBDEs via dust for adult range from 1.41 to 277 ng x day(-1) is lower than that via food which range from 135 to 333 ng x day-', while the median intake of these compounds via indoor dust for children range from 101 to 404 ng x day(-1) is much higher than via food: 77-190 ng x day(-1). The congener pattern observed in the indoor dust is different to that found in food. The indoor dust is dominated by the congener BDE-209 vs. food where the most dominated congeners are BDE-47 and BDE-99. Human exposure to PBDEs and other brominated flame retardants (BFRs) is widely widespread throughout the world and it depends on a country range of usage, production and legislation concerning these chemicals as well as a citizen's behavior. Generally, human exposure has been found higher in North America than in Europe and Asia. Within European countries the significant highest concentrations in dust have been found in the United Kingdom. It should be noted that many uncertainty factors such as personal habits, dietary preferences

  9. Exposure of Human Lung Cells to Tobacco Smoke Condensate Inhibits the Nucleotide Excision Repair Pathway.

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    Nathaniel Holcomb

    Full Text Available Exposure to tobacco smoke is the number one risk factor for lung cancer. Although the DNA damaging properties of tobacco smoke have been well documented, relatively few studies have examined its effect on DNA repair pathways. This is especially true for the nucleotide excision repair (NER pathway which recognizes and removes many structurally diverse DNA lesions, including those introduced by chemical carcinogens present in tobacco smoke. The aim of the present study was to investigate the effect of tobacco smoke on NER in human lung cells. We studied the effect of cigarette smoke condensate (CSC, a surrogate for tobacco smoke, on the NER pathway in two different human lung cell lines; IMR-90 lung fibroblasts and BEAS-2B bronchial epithelial cells. To measure NER, we employed a slot-blot assay to quantify the introduction and removal of UV light-induced 6-4 photoproducts and cyclobutane pyrimidine dimers. We find a dose-dependent inhibition of 6-4 photoproduct repair in both cell lines treated with CSC. Additionally, the impact of CSC on the abundance of various NER proteins and their respective RNAs was investigated. The abundance of XPC protein, which is required for functional NER, is significantly reduced by treatment with CSC while the abundance of XPA protein, also required for NER, is unaffected. Both XPC and XPA RNA levels are modestly reduced by CSC treatment. Finally, treatment of cells with MG-132 abrogates the reduction in the abundance of XPC protein produced by treatment with CSC, suggesting that CSC enhances proteasome-dependent turnover of the protein that is mediated by ubiquitination. Together, these findings indicate that tobacco smoke can inhibit the same DNA repair pathway that is also essential for the removal of some of the carcinogenic DNA damage introduced by smoke itself, increasing the DNA damage burden of cells exposed to tobacco smoke.

  10. An epidemiological approach to characterise the human exposure pathways in a contaminated estuarine environment.

    Science.gov (United States)

    Machado, Ausenda; Fernandes, Ana Paula; Paixão, Eleonora; Caeiro, Sandra; Matias-Dias, Carlos

    2017-12-01

    This study's aim was to develop and implement an integrative epidemiologic cross-sectional study that allows identifying and characterising exposure pathways of populations living and working on the shores of a contaminated estuarine environment. Population residing in Carrasqueira, located on the Sado estuary with known contaminated areas was compared to another population on a noncontaminated estuary (Vila Nova de Mil Fontes - VNMF), considered a nonexposed population. Simple random samples of individuals were selected in each study population from the National Health Service Lists: 140 individuals were selected in Carrasqueira and 219 in VNMF. Participation rates were higher in the exposed group (62.5%, n=102 in Carrasqueira and 48.3%, n=100 individuals in VNMF). The same structured questionnaire was used in both populations, including questions on occupational activities, leisure activities, consumption of food (including fish and mollusks from the estuary) and use of water for human intake and agriculture. Results showed that a significantly higher proportion of Carrasqueira participants reported doing tasks in their job that promote direct (48.8% vs 1.2% in VNMF, p-valuecontamination from the contaminated estuarine environment. The study design and the selection of both populations were adequate for this type of epidemiologic study of potential routes of human contamination in a mixture of contaminated estuarine environment and can be used in other estuarine areas with similar environmental risk. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Human exposure to per- and polyfluoroalkyl substances (PFASs) via house dust in Korea: Implication to exposure pathway.

    Science.gov (United States)

    Tian, Zhexi; Kim, Seung-Kyu; Shoeib, Mahiba; Oh, Jeong-Eun; Park, Jong-Eun

    2016-05-15

    A wide range of per- and polyfluoroalkyl substances (PFASs), including fluorotelomer alcohols (FTOHs), perfluorooctane sulfonamidoethanols (FOSEs), perfluoroalkyl carboxylic acids (PFCAs), and perfluoroalkane sulfonic acids (PFSAs), were measured in fifteen house dust and two nonresidential indoor dust of Korea. Total concentrations of PFASs in house dust ranged from 29.9 to 97.6 ng g(-1), with a dominance of perfluorooctane sulfonic acid (PFOS), followed by 8:2 FTOH, N-Ethyl perfluorooctane sulfonamidoethanol (EtFOSE), perfluoroctanoic acid (PFOA). In a typical exposure scenario, the estimated daily intakes (EDIs) of total PFASs via house dust ingestion were 2.83 ng d(-1) for toddlers and 1.13 ng d(-1) for adults, which were within the range of the mean EDIs reported from several countries. For PFOA and PFOS exposure via house dust ingestion, indirect exposure (via precursors) was a minor contributor, accounting for 5% and 12%, respectively. An aggregated exposure (hereafter, overall-EDIs) of PFOA and PFOS occurring via all pathways, estimated using data compiled from the literature, were 53.6 and 14.8 ng d(-1) for toddlers, and 20.5 and 40.6 ng d(-1) for adults, respectively, in a typical scenario. These overall-EDIs corresponded to 82% (PFOA) and 92% (PFOS) of a pharmacokinetic model-based EDIs estimated from adults' serum data. Direct dietary exposure was a major contributor (>89% of overall-EDI) to PFOS in both toddlers and adults, and PFOA in toddlers. As for PFOA exposure of adults, however direct exposure via tap water drinking (37%) and indirect exposure via inhalation (22%) were as important as direct dietary exposure (41%). House dust-ingested exposure (direct+indirect) was responsible for 5% (PFOS in toddlers) and house-dust ingestion was a minor contributor in this study, but should not be ignored for toddlers' PFOS exposure due to its significance in the worst-case scenario.

  12. Low-Frequency Electromagnetic Field Exposure Enhances Extracellular Trap Formation by Human Neutrophils through the NADPH Pathway.

    Science.gov (United States)

    Golbach, Lieke A; Scheer, Marleen H; Cuppen, Jan J M; Savelkoul, Huub; Verburg-van Kemenade, B M Lidy

    2015-01-01

    Low-frequency (LF) electromagnetic fields (EMFs) are abundantly present in modern society, and the potential biological consequences of exposure to these fields are under intense debate. Immune cells are suggested as possible target cells, though a clear mechanism is lacking. Considering their crucial role in innate immune activation, we selected an ex vivo exposure set-up with human neutrophils to investigate a possible correlation between neutrophil extracellular trap (NET) formation and LF EMF exposure. Our study shows that formation of NETs is enhanced by LF EMF exposure. Enhanced NET formation leads to increased antimicrobial properties as well as damage to surrounding cells. We found that LF-EMF-induced NET formation is dependent on the NADPH oxidase pathway and production of reactive oxygen species. Additionally, LF EMF exposure does not influence autophagy and PAD4 activity. Our study provides a mechanism by which exposure to LF EMFs could influence the innate immune system.

  13. MERS-CoV at the Animal-Human interface: inputs on exposure pathways from an Expert-Opinion elicitation

    Directory of Open Access Journals (Sweden)

    Anna Funk

    2016-10-01

    Full Text Available Nearly four years after the first report of the emergence of Middle-East respiratory syndrome Coronavirus (MERS-CoV and nearly 1800 human cases later, the ecology of MERS-CoV, its epidemiology, and risk factors of MERS-CoV transmission between camels are poorly understood. Knowledge about the pathways and mechanisms of transmission from animals to humans is limited; as of yet, transmission risks have not been quantified. Moreover the divergent sanitary situations and exposures to animals among populations in the Arabian Peninsula, where human primary cases appear to dominate, vs. other regions in the Middle East and Africa, with no reported human clinical cases and where the virus has been detected only in dromedaries, represents huge scientific and health challenges. Here, we have used expert opinion elicitation in order to obtain ideas on relative importance of MERS-CoV risk factors and estimates of transmission risks from various types of contact between humans and dromedaries. Fourteen (14 experts with diverse and extensive experience in MERS-CoV relevant fields were enrolled and completed an online questionnaire that examined pathways based on several scenarios e.g. camels-camels, camels-human, bats/other species to camels/humans and the role of diverse biological substances (milk, urine etc. and potential fomites.Experts believed that dromedary camels play the largest role in MERS-CoV infection of other dromedaries; however, they also indicated a significant influence of the season (i.e. calving or weaning periods on transmission risk. All experts thought that MERS-CoV infected dromedaries and asymptomatic humans play the most important role in infection of humans, with bats and other species presenting a possible, but yet undefined, risk. Direct and indirect contact of humans with dromedary camels were identified as the most risky types of contact, when compared to consumption of various camel products, with estimated 'most

  14. Human fecal and pathogen exposure pathways in rural Indian villages and the effect of increased latrine coverage.

    Science.gov (United States)

    Odagiri, Mitsunori; Schriewer, Alexander; Daniels, Miles E; Wuertz, Stefan; Smith, Woutrina A; Clasen, Thomas; Schmidt, Wolf-Peter; Jin, Yujie; Torondel, Belen; Misra, Pravas R; Panigrahi, Pinaki; Jenkins, Marion W

    2016-09-01

    Efforts to eradicate open defecation and improve sanitation access are unlikely to achieve health benefits unless interventions reduce microbial exposures. This study assessed human fecal contamination and pathogen exposures in rural India, and the effect of increased sanitation coverage on contamination and exposure rates. In a cross-sectional study of 60 villages of a cluster-randomized controlled sanitation trial in Odisha, India, human and domestic animal fecal contamination was measured in community tubewells and ponds (n = 301) and via exposure pathways in homes (n = 354), using Bacteroidales microbial source tracking fecal markers validated in India. Community water sources were further tested for diarrheal pathogens (rotavirus, adenovirus and Vibrio cholerae by quantitative PCR; pathogenic Escherichia coli by multiplex PCR; Cryptosporidium and Giardia by immunomagnetic separation and direct fluorescent antibody microscopy). Exposure pathways in intervention and control villages were compared and relationships with child diarrhea examined. Human fecal markers were rarely detected in tubewells (2.4%, 95%CI: 0.3-4.5%) and ponds (5.6%, 95%CI: 0.8-10.3%), compared to homes (35.4%, 95%CI: 30.4-40.4%). In tubewells, V. cholerae was the most frequently detected pathogen (19.8%, 95%CI: 14.4-25.2%), followed by Giardia (14.8%, 95%CI: 10.0-19.7%). In ponds, Giardia was most often detected (74.5%, 95%CI: 65.7-83.3%), followed by pathogenic E. coli (48.1%, 95%CI: 34.8-61.5%) and rotavirus (44.4%, 95%CI: 34.2-54.7%). At village-level, prevalence of fecal pathogen detection in community drinking water sources was associated with elevated prevalence of child diarrhea within 6 weeks of testing (RR 2.13, 95%CI: 1.25-3.63) while within homes, higher levels of human and animal fecal marker detection were associated with increased risks of subsequent child diarrhea (P = 0.044 and 0.013, respectively). There was no evidence that the intervention, which increased

  15. Long-term human exposure to lead from different media and intake pathways

    DEFF Research Database (Denmark)

    Pizzol, Massimo; Thomsen, Marianne; Andersen, Mikael Skou

    2010-01-01

    , and predicting the resulting internal body exposure levels and effects that occur under long-term exposure conditions. In this paper, a modeling approach is used to meet these challenges with reference to Danish exposure conditions. Levels of lead content in various media have been coupled with data for lead......Lead (Pb) is well known as an environmental pollutant: it can accumulate in various media, so actual lead exposure reflects both historical and present contaminations. Two main challenges then emerge: obtaining updated information to gain an overall picture of the sources of exposure......–internalconcentration relationships for the direct linkage between lead in environmental media and resultingconcentrations of lead in blood are then presented....

  16. Photosensitized methyl paraben induces apoptosis via caspase dependent pathway under ambient UVB exposure in human skin cells.

    Science.gov (United States)

    Dubey, Divya; Chopra, Deepti; Singh, Jyoti; Srivastav, Ajeet K; Kumari, Smita; Verma, Ankit; Ray, Ratan Singh

    2017-10-01

    Methyl paraben (MP), is a widely used preservative in pharmaceutical, food and cosmetic products. Its molecular mechanism under ambient ultraviolet radiation is not well understood. We investigated photosensitizing mechanism of MP under ambient UVB (0.6 mW/cm(2)) intensity. MP showed dose dependent decrease in cell viability of human keratinocyte cell line (HaCaT) by MTT and NRU assays. Study showed 40% reduction in antimicrobial activity of UVB irradiated MP through E. coli culture. Photosensitized MP (25 μg/ml) significantly enhanced lipid peroxidation, intracellular ROS generation and disrupted mitochondrial membrane integrity. MP induced loss of lysosomal membrane integrity and endoplasmic reticulum (ER) mediated stress evident from Ca(+2) release. Phototoxicity of MP showed nuclear fragmentation, phosphatidylserine translocation, 30% tail DNA and micronuclei formation. Study showed mitochondria mediated apoptosis via upregulation of Bax, Apaf-1, Cytochrome C and Caspase-3. Upregulation of Caspase-12 (2 folds) specifically showed role of ER in apoptosis. Specific caspase inhibitor, Z-VAD-FMK showed involvement of caspase cascade pathway in apoptosis. Results indicate that photosensitive MP leads to oxidative stress mediated DNA damage and apoptosis through mitochondria and ER. MP causes deleterious effects and its long term exposure to human skin may promote skin diseases. Therefore, MP should be replaced by other photosafe preservatives for humans. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. In vitro Catecholamine Exposure Produces Variable Effects on the B7 Costimulatory Pathway in Human Monocytic Cells

    Science.gov (United States)

    Salicru, A. N.; Crucian, B.; Sams, Clarence; Actor, J. K.; Marshall, G. D., Jr.

    2006-01-01

    Catecholamines have been associated with immunomodulation of the adaptive immune system towards a Th2 response in vitro. We therefore examined the role of in vitro epinephrine (EPI) and norepinephrine (NE) exposure on the B7 costimulatory expression of antigen presenting cells (APC) from human monocytic cell lines and human peripheral blood mononuclear cells (PBMC). THP1 monocytic cells and CD14+ cells from normal human PBMC were stimulated with lipopolysaccharide (LPS) and incubated with physiologic stress levels (10(exp -6) - 10(exp -8)M) of EPI or NE for 24 hours. Cells were subsequently stained with CD80 FITC, CD86 PE, and CD14 PC5 antibodies and analyzed by flow cytometry for changes in fluorescence and mean fluorescence intensity (MFI). Exposure of THP1 to EPI in vitro at concentrations of 10(exp -6), 10(exp -7) and 10(exp -8)M significantly decreased mean CD80 from 42 plus or minus 0.7% to 11 plus or minus 0.44%, 19.1 plus or minus 2.0%, and 30.7 plus or minus 2.1% expression, respectively (p less than 0.01). In addition, CD86 expression increased with EPI at 10(exp -6), 10(exp -7) and 10(exp -8) M from 9.2 plus or minus 0.52% to 41 plus or minus 3.8%, 26.4 plus or minus 1.9%, and 15.74 plus or minus 1.8% expression, respectively (p less than 0.01). Similar results for mean CD80 and CD86 percent expression were observed for CD14+ cells from PBMC with a sample size of N = 6 and for NE when substituted for EPI. The data show that in vitro exposure to catecholamines significantly decreases %CD86 expression and significantly increases %CD86 expression in THP1 cells and human CD14+ APC. Previous studies have suggested an association between increased CD86 expression and TH2 activity. Thus, these data suggest that immunomodulation by catecholamines results in part by the variable effects of the B7 costimulatory pathway in APC.

  18. Highly pathogenic avian influenza (H5N1: pathways of exposure at the animal-human interface, a systematic review.

    Directory of Open Access Journals (Sweden)

    Maria D Van Kerkhove

    Full Text Available BACKGROUND: The threat posed by highly pathogenic avian influenza A H5N1 viruses to humans remains significant, given the continued occurrence of sporadic human cases (499 human cases in 15 countries with a high case fatality rate (approximately 60%, the endemicity in poultry populations in several countries, and the potential for reassortment with the newly emerging 2009 H1N1 pandemic strain. Therefore, we review risk factors for H5N1 infection in humans. METHODS AND FINDINGS: Several epidemiologic studies have evaluated the risk factors associated with increased risk of H5N1 infection among humans who were exposed to H5N1 viruses. Our review shows that most H5N1 cases are attributed to exposure to sick poultry. Most cases are sporadic, while occasional limited human-to-human transmission occurs. The most commonly identified factors associated with H5N1 virus infection included exposure through contact with infected blood or bodily fluids of infected poultry via food preparation practices; touching and caring for infected poultry; [corrected] exposure to H5N1 via swimming or bathing in potentially virus laden ponds; and exposure to H5N1 at live bird markets. CONCLUSIONS: Research has demonstrated that despite frequent and widespread contact with poultry, transmission of the H5N1 virus from poultry to humans is rare. Available research has identified several risk factors that may be associated with infection including close direct contact with poultry and transmission via the environment. However, several important data gaps remain that limit our understanding of the epidemiology of H5N1 in humans. Although infection in humans with H5N1 remains rare, human cases continue to be reported and H5N1 is now considered endemic among poultry in parts of Asia and in Egypt, providing opportunities for additional human infections and for the acquisition of virus mutations that may lead to more efficient spread among humans and other mammalian species

  19. Assessment of human exposures

    Energy Technology Data Exchange (ETDEWEB)

    Lebret, E. [RIVM-National Inst. of Public Health and Environmental Protection (Netherlands)

    1995-12-31

    This article describes some of the features of the assessment of human exposure to environmental pollutants in epidemiological studies. Since exposure assessment in air pollution epidemiology studies typically involve professionals from various backgrounds, interpretation of a concepts like `exposure` may vary. A brief descriptions is therefore given by way of introduction

  20. The application of equilibrium models to incidence situations using the example of the exposure pathway human milk

    Energy Technology Data Exchange (ETDEWEB)

    Steiner, Martin; Karcher, Klaus; Nosske, Dietmar [Bundesamt fuer Strahlenschutz, Oberschleissheim (Germany)

    2012-06-15

    The radiation exposure after a short-term release of radioactive substances is often calculated assuming equilibrium conditions. An example is that of the German Incident Calculation Bases for nuclear power plants with pressurized water reactors. Here, the contamination of human milk is calculated using transfer factors. Applying this equilibrium model to incident situations raises the question whether baby's radiation exposure is adequately assessed. This contribution shows that compliance with the relevant dose limits of paragraph 49 of the German Radiation Protection Ordinance is ensured for design basis accidents on the assumption that the hypothetical breastfeeding period starts at the beginning of the activity release. Comparative analyses were performed against the biokinetic models applied by ICRP for radiation protection purposes, taking the reference nuclides {sup 137}Cs, {sup 90}Sr, {sup 131}I, {sup 241}Am and long-lived plutonium isotopes as examples. (orig.)

  1. Merging Models and Biomonitoring Data to Characterize Sources andPathways of Human Exposure to Organophosphorous Pesticides in the SalinasValley of California

    Energy Technology Data Exchange (ETDEWEB)

    McKone, Thomas E.; Castorina, Rosemary; Kuwabara, Yu; Harnly,Martha E.; Eskenazi, Brenda; Bradman, Asa

    2006-06-01

    By drawing on human biomonitoring data and limited environmental samples together with outputs from the CalTOX multimedia, multipathway source-to-dose model, we characterize cumulative intake of organophosphorous (OP) pesticides in an agricultural region of California. We assemble regional OP pesticide use, environmental sampling, and biological tissue monitoring data for a large and geographically dispersed population cohort of 592 pregnant Latina women in California (the CHAMACOS cohort). We then use CalTOX with regional pesticide usage data to estimate the magnitude and uncertainty of exposure and intake from local sources. We combine model estimates of intake from local sources with food intake based on national residue data to estimate for the CHAMACOS cohort cumulative median OP intake, which corresponds to expected levels of urinary dialkylphosphate (DAP) metabolite excretion for this cohort. From these results we develop premises about relative contributions from different sources and pathways of exposure. We evaluate these premises by comparing the magnitude and variation of DAPs in the CHAMACOS cohort with the whole U.S. population using data from the National Health and Nutrition Evaluation Survey (NHANES). This comparison supports the premise that in both populations diet is the common and dominant exposure pathway. Both the model results and biomarker comparison supports the observation that the CHAMACOS population has a statistically significant higher intake of OP pesticides that appears as an almost constant additional dose among all participants. We attribute the magnitude and small variance of this intake to non-dietary exposure in residences from local sources.

  2. Size-dependent characterisation of historical gold mine wastes to examine human pathways of exposure to arsenic and other potentially toxic elements.

    Science.gov (United States)

    Martin, Rachael; Dowling, Kim; Pearce, Dora C; Florentine, Singarayer; Bennett, John W; Stopic, Attila

    2016-10-01

    Abandoned historical gold mining wastes often exist as geographically extensive, unremediated, and poorly contained deposits that contain elevated levels of As and other potentially toxic elements (PTEs). One of the key variables governing human exposure to PTEs in mine waste is particle size. By applying a size-resolved approach to mine waste characterisation, this study reports on the proportions of mine waste relevant to human exposure and mobility, as well as their corresponding PTE concentrations, in four distinct historical mine wastes from the gold province in Central Victoria, Australia. To the best of our knowledge, such a detailed investigation and comparison of historical mining wastes has not been conducted in this mining-affected region. Mass distribution analysis revealed notable proportions of waste material in the readily ingestible size fraction (≤250 µm; 36.1-75.6 %) and the dust size fraction (≤100 µm; 5.9-45.6 %), suggesting a high potential for human exposure and dust mobilisation. Common to all mine waste types were statistically significant inverse trends between particle size and levels of As and Zn. Enrichment of As in the finest investigated size fraction (≤53 µm) is of particular concern as these particles are highly susceptible to long-distance atmospheric transport. Human populations that reside in the prevailing wind direction from a mine waste deposit may be at risk of As exposure via inhalation and/or ingestion pathways. Enrichment of PTEs in the finer size fractions indicates that human health risk assessments based on bulk contaminant concentrations may underestimate potential exposure intensities.

  3. Malignant transformation of human gastric epithelium cells via reactive oxygen species production and Wnt/β-catenin pathway activation following 40-week exposure to ochratoxin A.

    Science.gov (United States)

    Jia, Xin; Cui, Jinfeng; Meng, Xinxing; Xing, Lingxiao; Shen, Haitao; Wang, Juan; Liu, Jing; Wang, Yuan; Lian, Weiguang; Zhang, Xianghong

    2016-03-01

    Ochratoxin A (OTA), one of the most abundant food-contaminating mycotoxins, is a possible carcinogenic to humans. We previously demonstrated that OTA treatment induced oxidative damage in human gastric epithelium cells (GES-1) in vitro. In this study, we found that long-term OTA treatment could result in increased proliferation, migration, and invasion abilities of GES-1 cells and induce anchorage-independent growth of cells in soft agar. Inoculation of OTA-treated GES-1 cells resulted in the formation of tumor xenografts in Balb/c nude mice in vivo, confirming that long-term OTA treatment can induce the malignant transformation of GES-1 cells. In addition, we found that long-term OTA treatment induced oxidative stress and activated the Wnt/β-catenin pathway, including the nuclear transition of β-catenin and the upregulation of the downstream molecules of the pathway. Finally, pretreatment with the antioxidant N-acetyl-L-cysteine (NAC) inhibited ROS formation and activation of the Wnt pathway in OTA-transformed GES-1 cells, which decreased the tumor formation abilities of these cells after inoculation in nude mice. These findings suggest that long-term OTA exposure induces the malignant transformation of GES-1 cells via intracellular ROS production and activation of the Wnt/β-catenin signaling pathway.

  4. Human exposure to aluminium.

    Science.gov (United States)

    Exley, Christopher

    2013-10-01

    Human activities have circumvented the efficient geochemical cycling of aluminium within the lithosphere and therewith opened a door, which was previously only ajar, onto the biotic cycle to instigate and promote the accumulation of aluminium in biota and especially humans. Neither these relatively recent activities nor the entry of aluminium into the living cycle are showing any signs of abating and it is thus now imperative that we understand as fully as possible how humans are exposed to aluminium and the future consequences of a burgeoning exposure and body burden. The aluminium age is upon us and there is now an urgent need to understand how to live safely and effectively with aluminium.

  5. Low-frequency electromagnetic field exposure enhances extracellular trap formation by human neutrophils through the NADPH pathway

    NARCIS (Netherlands)

    Golbach, L.A.; Scheer, M.H.; Cuppen, J.J.M.; Savelkoul, H.F.J.; Verburg-van Kemenade, B.M.L.

    2015-01-01

    Low-frequency (LF) electromagnetic fields (EMFs) are abundantly present in modern society, and the potential biological consequences of exposure to these fields are under intense debate. Immune cells are suggested as possible target cells, though a clear mechanism is lacking. Considering their cruci

  6. Exposure to p,p′-DDE Induces Morphological Changes and Activation of the PKCα-p38-C/EBPβ Pathway in Human Promyelocytic HL-60 Cells

    Science.gov (United States)

    Torres-Avilés, Nallely A.; Albores-García, Damaris; Luna, Ana L.; Moreno-Galván, Monica; Salgado-Bustamante, Mariana; Portales-Pérez, Diana Patricia

    2016-01-01

    Dichlorodiphenyldichloroethylene (p,p′-DDE), the most persistent metabolite of dichlorodiphenyltrichloroethane (DDT), is still present in the human population. Both are present in the bone marrow of patients with bone marrow disorders, but thus far there are no studies that assess the capability of p,p′-DDE to affect myeloid cells. The aim of this study was to determine the effect of p,p′-DDE on promyelocytic cell differentiation and intracellular pathways related to this event. p,p′-DDE induced morphological changes compatible with promyelocytic differentiation in a concentration-dependent manner. The p,p′-DDE effect on [Ca2+]i, C/EBPβ protein levels, PKCα and p38 activation, and the role of oxidative stress or PLA2 was assayed. Exposure to 1.9 μg/mL of p,p′-DDE increased [Ca2+]i, PKCα, p38, and C/EBPβ protein levels; the increase of nuclear C/EBPβ protein was dependent on p38. PKCα phosphorylation was dependent on PLA2 and p,p′-DDE-induced oxidative stress. p38 phosphorylation induced by p,p′-DDE was dependent on PLA2, PKC activation, and oxidative stress. These effects of p,p′-DDE at concentrations found in human bone marrow may induce alterations in immature myeloid cells and could affect their cellular homeostasis. In order to establish the risk from exposure to p,p′-DDE on the development of bone marrow disorders in humans, these effects deserve further study. PMID:27833915

  7. Exposure to p,p′-DDE Induces Morphological Changes and Activation of the PKCα-p38-C/EBPβ Pathway in Human Promyelocytic HL-60 Cells

    Directory of Open Access Journals (Sweden)

    Nallely A. Torres-Avilés

    2016-01-01

    Full Text Available Dichlorodiphenyldichloroethylene (p,p′-DDE, the most persistent metabolite of dichlorodiphenyltrichloroethane (DDT, is still present in the human population. Both are present in the bone marrow of patients with bone marrow disorders, but thus far there are no studies that assess the capability of p,p′-DDE to affect myeloid cells. The aim of this study was to determine the effect of p,p′-DDE on promyelocytic cell differentiation and intracellular pathways related to this event. p,p′-DDE induced morphological changes compatible with promyelocytic differentiation in a concentration-dependent manner. The p,p′-DDE effect on Ca2+i, C/EBPβ protein levels, PKCα and p38 activation, and the role of oxidative stress or PLA2 was assayed. Exposure to 1.9 μg/mL of p,p′-DDE increased Ca2+i, PKCα, p38, and C/EBPβ protein levels; the increase of nuclear C/EBPβ protein was dependent on p38. PKCα phosphorylation was dependent on PLA2 and p,p′-DDE-induced oxidative stress. p38 phosphorylation induced by p,p′-DDE was dependent on PLA2, PKC activation, and oxidative stress. These effects of p,p′-DDE at concentrations found in human bone marrow may induce alterations in immature myeloid cells and could affect their cellular homeostasis. In order to establish the risk from exposure to p,p′-DDE on the development of bone marrow disorders in humans, these effects deserve further study.

  8. Human Exposure Database System (HEDS)

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Human Exposure Database System (HEDS) provides public access to data sets, documents, and metadata from EPA on human exposure. It is primarily intended for...

  9. Domestic duck eggs: an important pathway of human exposure to PBDEs around e-waste and scrap metal processing areas in Eastern China.

    Science.gov (United States)

    Labunska, Iryna; Harrad, Stuart; Santillo, David; Johnston, Paul; Yun, Lai

    2013-08-20

    Although consumption of local foods is recognized as an important pathway of human exposure to PBDEs in areas of China involved in rudimentary recycling of electronic waste (e-waste), dietary intake studies to date have not considered the contribution from consumption of duck eggs, despite being a common dietary component. Fresh duck eggs (n = 11) were collected from each of five farms located within 500 m of e-waste recycling workshops in the Wenling and Luqiao districts of Taizhou City, Eastern China, in November 2011, along with eggs from a control site located 90 km to the northeast. Average ΣPBDE yolk concentrations in eggs from the Taizhou farms ranged from 52.7 to 1778 ng/g lipid weight (8 ng/g lipid weight at the control site), at the high end of values previously reported for PBDEs in chicken eggs from the same locations and with BDE-209 predominant in over 60% of samples. Estimated typical adult daily ΣPBDE intakes due to consumption of duck eggs were in the range of 159-5124 ng/person per day. For the pentabrominated BDE-99 congener, estimated intakes from duck eggs alone were substantially above the no adverse effect level (NAEL) for impaired human spermatogenesis proposed by Netherlands researchers.

  10. Design and implementation of an epidemiological study for the characterization of potential pathway human exposure in a contaminated estuary environment

    OpenAIRE

    Dias, Carlos Matias; Machado, Ausenda; Paixão, Eleonora; Mateus, Inês; Joaquin, Toro; Caeiro, Sandra

    2011-01-01

    Introduction Sado River estuary is located in the west coast of Portugal. Previous environmental studies identified industrial contamination, non-point anthropogenic sources and contamination coming from the river, all promoting accumulation of polluted sediments with known impacts on the ecological system. Surrounding human populations have intense economic fishery activities. Together with agriculture, estuary fishing products are available to local residents. Food usage previously chara...

  11. Levels and congener specific profiles of PBDEs in human breast milk from China: implication on exposure sources and pathways.

    Science.gov (United States)

    Sudaryanto, Agus; Kajiwara, Natsuko; Tsydenova, Oyuna V; Isobe, Tomohiko; Yu, Hongxia; Takahashi, Shin; Tanabe, Shinsuke

    2008-11-01

    Fourteen PBDE congeners from mono- to deca-BDE were determined in breast milk of primiparous mothers from two locations in East China, i.e. Nanjing (n=9), an urban area, and Zhoushan (n=10), a semi rural coastal area. PBDEs were detected in all the human breast milk samples of the present study, indicating that general population in these two locations are widely exposed to these pollutants. Relatively higher concentrations of PBDEs were found in the milk of mothers from Nanjing than Zhoushan, suggesting the existence of significant sources of PBDEs in urban areas. PBDE levels in the present study were similar to those in European countries, but one or two orders of magnitude lower than in North America. Except for BDE-3, all congeners from di- to deca-BDE were detected in the samples of the present study. BDE-209, a congener considered to have less bioavailability, was detected in about 50% of the samples at concentrations higher than that of other congeners. Other higher brominated congeners, such as BDE-153, -197 and -207, were also prominent in the present study, which is different from the pattern generally observed in previous studies on human milk as well as biota samples. These results may indicate that the inhabitants of Nanjing and Zhoushan are exposed to location specific sources of PBDEs.

  12. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

    Science.gov (United States)

    Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

    2016-06-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations.

  13. Breastfeeding as an Exposure Pathway for Perfluorinated Alkylates

    DEFF Research Database (Denmark)

    Mogensen, Ulla B; Grandjean, Philippe; Nielsen, Flemming

    2015-01-01

    Perfluorinated alkylate substances (PFASs) are widely used and have resulted in human exposures worldwide. PFASs occur in breast milk, and the duration of breastfeeding is associated with serum-PFAS concentrations in children. To determine the time-dependent impact of this exposure pathway, we...... examined the serum concentrations of five major PFASs in a Faroese birth cohort at birth, and at ages 11, 18, and 60 months. Information about the children's breastfeeding history was obtained from the mothers. The trajectory of serum-PFAS concentrations during months with and without breastfeeding...... increases during partial breast-feeding. In contrast to this main pattern, perfluorohexanesulfonate was not affected by breast-feeding. After cessation of breastfeeding, all serum concentrations decreased. This finding supports the evidence of breastfeeding being an important exposure pathway to some PFASs...

  14. Activation of stress-related signalling pathway in human cells upon SiO2 nanoparticles exposure as an early indicator of cytotoxicity

    LENUS (Irish Health Repository)

    Mohamed, Bashir M

    2011-07-29

    Abstract Background Nanomaterials such as SiO2 nanoparticles (SiO2NP) are finding increasing applications in the biomedical and biotechnological fields such as disease diagnostics, imaging, drug delivery, food, cosmetics and biosensors development. Thus, a mechanistic and systematic evaluation of the potential biological and toxic effects of SiO2NP becomes crucial in order to assess their complete safe applicability limits. Results In this study, human monocytic leukemia cell line THP-1 and human alveolar epithelial cell line A549 were exposed to a range of amorphous SiO2NP of various sizes and concentrations (0.01, 0.1 and 0.5 mg\\/ml). Key biological indicators of cellular functions including cell population density, cellular morphology, membrane permeability, lysosomal mass\\/pH and activation of transcription factor-2 (ATF-2) were evaluated utilizing quantitative high content screening (HCS) approach and biochemical techniques. Despite the use of extremely high nanoparticle concentrations, our findings showed a low degree of cytotoxicity within the panel of SiO2NP investigated. However, at these concentrations, we observed the onset of stress-related cellular response induced by SiO2NP. Interestingly, cells exposed to alumina-coated SiO2NP showed low level, and in some cases complete absence, of stress response and this was consistent up to the highest dose of 0.5 mg\\/ml. Conclusions The present study demonstrates and highlights the importance of subtle biological changes downstream of primary membrane and endocytosis-associated phenomena resulting from high dose SiO2NP exposure. Increased activation of transcription factors, such as ATF-2, was quantitatively assessed as a function of i) human cell line specific stress-response, ii) SiO2NP size and iii) concentration. Despite the low level of cytotoxicity detected for the amorphous SiO2NP investigated, these findings prompt an in-depth focus for future SiO2NP-cell\\/tissue investigations based on the combined

  15. Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay

    NARCIS (Netherlands)

    Schulpen, Sjors H. W.; Pennings, Jeroen L. A.; Piersma, Aldert H.

    2015-01-01

    Differentiating pluripotent stem cells in vitro have proven useful for the study of developmental toxicity. Here, we studied the effects of anticonvulsant drug exposure in a human embryonic stem cell (hESC)-based neurodevelopmental toxicity test (hESTn). During neural differentiation the cells were

  16. Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay

    NARCIS (Netherlands)

    Schulpen, Sjors H. W.; Pennings, Jeroen L. A.; Piersma, Aldert H.

    Differentiating pluripotent stem cells in vitro have proven useful for the study of developmental toxicity. Here, we studied the effects of anticonvulsant drug exposure in a human embryonic stem cell (hESC)-based neurodevelopmental toxicity test (hESTn). During neural differentiation the cells were

  17. Polycyclic aromatic hydrocarbons in edible grain: a pilot study of agricultural crops as a human exposure pathway for environmental contaminants using wheat as a model crop.

    Science.gov (United States)

    Kobayashi, Reiko; Okamoto, Robert A; Maddalena, Randy L; Kado, Norman Y

    2008-06-01

    The concentrations of polycyclic aromatic hydrocarbons (PAHs) were investigated in a pilot study of field wheat grain as a model indicator for environmental contamination. The edible grain would serve as a portal for human exposure. Wheat grain was initially studied since it is one of the major food crops consumed internationally by many including infants and children. Wheat grain samples from five different geographical growing locations in California that span approximately 450 km were collected during the same growing season. The same variety of grain was harvested and analyzed for PAHs that ranged from 2- to 6-rings. PAHs were detected in all grain samples and were mainly 2- to 4-ring PAHs with naphthalene the most abundant among them. There were geographical differences in the levels of PAHs in the grain. The sources of the PAHs were not known in this pilot study, but the principal component analysis indicates that the major source is similar in all locations except for naphthalene. Grain naphthalene concentrations may reflect local naphthalene emissions. Diesel-fueled harvesting operations did not appear to contribute to the observed PAH concentrations in the grain. An estimate of naphthalene intake from eating grain compared to inhalation intake demonstrated the potential importance of field contamination of grain as a possible portal of human exposure. The relationship between PAH concentrations in grain and air should be quantitatively investigated to better quantitate exposure and to identify effective measures to lower the risk from PAH exposure through eating grain.

  18. Contribution of the Exposure Pathways After a Severe Accident

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joeun; Hwang, Wontae; Han, Moonhee [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Jae, Moosung [Hanyang University, Seoul (Korea, Republic of)

    2016-10-15

    A radiological dose assessment calculates the amount of radiation energy absorbed by a potentially exposed individual as a result of a specific exposure. Public can be exposure from several exposure pathways. External doses occur when the body is exposed to radioactive material outside the body. When making the emergency preparedness for severe accident from NPPs, therefore, we need to have comprehension about those exposure pathways. Thus, in this study, an evaluation of external and internal dose from radioactive materials during severe accident was performed to find out exposure pathway from which the dose has the highest value for several radionuclides. The basic study to make out the relation between exposure pathways and dose from them was performed. In the emergency phase, the most affecting nuclide type on public was noble gas, especially {sup 133}Xe, and the dominant exposure pathway was could shine. Also, in the long term-phase, the most affecting nuclide type on public was fission product, especially {sup 90}Sr, and the dominant exposure pathway was water ingestion. The information of the dose composition from exposure pathway obtained in this study might be basic data for making emergency preparedness plan for severe accident. In the future, assessment of the source term is expected to enhance the reliability of dose assessment during severe accident.

  19. A flexible matrix-based human exposure assessment framework suitable for LCA and CAA

    DEFF Research Database (Denmark)

    Jolliet, Olivier; Ernstoff, Alexi; Huang, Lei

    2016-01-01

    of near-and far-field pathways and helps to understand the contribution of individual pathways to overall human exposure in various product application contexts. When combined with toxicity information this approach is a resourceful way to inform LCA and CAA and minimize human exposure to toxic chemicals......Humans can be exposed to chemicals via near-field exposure pathways (e.g. through consumer product use) and far-field exposure pathways (e.g. through environmental emissions along product life cycles). Pathways are often complex where chemicals can transfer directly from products to humans during...... use or exchange between near-and far-field compartments until sub -fractions reach humans via inhalation, ingestion or dermal uptake. Currently, however, multimedia exposure models mainly focus on far-field exposure pathways. Metrics and modeling approaches used in far-field, emission-based models...

  20. Human Exposure Modeling - Databases to Support Exposure Modeling

    Science.gov (United States)

    Human exposure modeling relates pollutant concentrations in the larger environmental media to pollutant concentrations in the immediate exposure media. The models described here are available on other EPA websites.

  1. Pathways of inhalation exposure to manganese in children ...

    Science.gov (United States)

    Manganese (Mn) is both essential element and neurotoxicant. Exposure to Mn can occur from various sources and routes. Structural equation modeling was used to examine routes of exposure to Mn among children residing near a ferromanganese refinery in Marietta, Ohio. An inhalation pathway model to ambient air Mn was hypothesized. Data for model evaluation were obtained from participants in the Communities Actively Researching Exposure Study (CARES). These data were collected in 2009 and included levels of Mn in residential soil and dust, levels of Mn in children's hair, information on the amount of time the child spent outside, heat and air conditioning in the home and level of parent education. Hair Mn concentration was the primary endogenous variable used to assess the theoretical inhalation exposure pathways. The model indicated that household dust Mn was a significant contributor to child hair Mn (0.37). Annual ambient air Mn concentration (0.26), time children spent outside (0.24) and soil Mn (0.24) significantly contributed to the amount of Mn in household dust. These results provide a potential framework for understanding the inhalation exposure pathway for children exposed to ambient air Mn who live in proximity to an industrial emission source. The purpose of this study was to use a structural equations modeling approach combined with exposure estimates derived from air-dispersion modeling to assess potential inhalation exposure pathways for children to a

  2. Pathways of inhalation exposure to manganese in children ...

    Science.gov (United States)

    Manganese (Mn) is both essential element and neurotoxicant. Exposure to Mn can occur from various sources and routes. Structural equation modeling was used to examine routes of exposure to Mn among children residing near a ferromanganese refinery in Marietta, Ohio. An inhalation pathway model to ambient air Mn was hypothesized. Data for model evaluation were obtained from participants in the Communities Actively Researching Exposure Study (CARES). These data were collected in 2009 and included levels of Mn in residential soil and dust, levels of Mn in children's hair, information on the amount of time the child spent outside, heat and air conditioning in the home and level of parent education. Hair Mn concentration was the primary endogenous variable used to assess the theoretical inhalation exposure pathways. The model indicated that household dust Mn was a significant contributor to child hair Mn (0.37). Annual ambient air Mn concentration (0.26), time children spent outside (0.24) and soil Mn (0.24) significantly contributed to the amount of Mn in household dust. These results provide a potential framework for understanding the inhalation exposure pathway for children exposed to ambient air Mn who live in proximity to an industrial emission source. The purpose of this study was to use a structural equations modeling approach combined with exposure estimates derived from air-dispersion modeling to assess potential inhalation exposure pathways for children to a

  3. Genome Wide Evaluation of Normal Human Tissue in Response to Controlled, In vivo Low-Dose Low LET Ionizing Radiation Exposure: Pathways and Mechanisms Final Report, September 2013

    Energy Technology Data Exchange (ETDEWEB)

    Rocke, David M. [University of California Davis

    2013-09-09

    During course of this project, we have worked in several areas relevant to low-dose ionizing radiation. Using gene expression to measure biological response, we have examined the response of human skin exposed in-vivo to radation, human skin exposed ex-vivo to radiation, and a human-skin model exposed to radiation. We have learned a great deal about the biological response of human skin to low-dose ionizing radiation.

  4. Assessing exposure to phthalates - the human biomonitoring approach.

    Science.gov (United States)

    Wittassek, Matthias; Koch, Holger Martin; Angerer, Jürgen; Brüning, Thomas

    2011-01-01

    Some phthalates are developmental and reproductive toxicants in animals. Exposure to phthalates is considered to be potentially harmful to human health as well. Based on a comprehensive literature research, we present an overview of the sources of human phthalate exposure and results of exposure assessments with special focus on human biomonitoring data. Among the general population, there is widespread exposure to a number of phthalates. Foodstuff is the major source of phthalate exposure, particularly for the long-chain phthalates such as di(2-ethylhexyl) phthalate. For short-chain phthalates such as di-n-butyl-phthalate, additional pathways are of relevance. In general, children are exposed to higher phthalate doses than adults. Especially, high exposures can occur through some medications or medical devices. By comparing exposure data with existing limit values, one can also assess the risks associated with exposure to phthalates. Within the general population, some individuals exceed tolerable daily intake values for one or more phthalates. In high exposure groups, (intensive medical care, medications) tolerable daily intake transgressions can be substantial. Recent findings from animal studies suggest that a cumulative risk assessment for phthalates is warranted, and a cumulative exposure assessment to phthalates via human biomonitoring is a major step into this direction.

  5. JNK1/c-Jun and p38 alpha MAPK/ATF-2 pathways are responsible for upregulation of Fas/FasL in human chronic myeloid leukemia K562 cells upon exposure to Taiwan cobra phospholipase A2.

    Science.gov (United States)

    Chen, Ku-Chung; Chiou, Yi-Ling; Chang, Long-Sen

    2009-10-15

    Fas and FasL expression upregulation was found in human leukemia K562 cells upon exposure to Naja naja atra phospholipase A(2) (PLA(2)). PLA(2) treatment induced an increase in intracellular Ca(2+) ([Ca(2+)]i) and ROS generation levels, leading to activation of p38 MAPK and JNK. Suppression of both p38 MAPK and JNK abrogated Fas and FasL upregulation. Unlike PLA(2), catalytically inactive PLA(2) treatment did not markedly increase Fas and FasL protein expression, and p38 MAPK activation was exclusively responsible for catalytically inactive PLA(2)-induced increase in Fas and FasL protein expression. Knockdown of p38 alpha MAPK and JNK1 by siRNA proved that p38 alpha MAPK and JNK1 were involved in ATF-2 and c-Jun phosphorylation, respectively. Compared with the p38 alpha MAPK/ATF-2 pathway, the JNK1/c-Jun pathway played a crucial role in Fas/FasL upregulation. Unlike arachidonic acid, lysophosphatidylcholine mimicked the PLA(2) action in inducing Fas/FasL upregulation. Together with the previous finding that c-Jun and ATF-2 are involved in transcriptional regulation of Fas and FasL, our data suggest that PLA(2) induces Fas and FasL upregulation through p38 alpha MAPK/ATF-2 and JNK1/c-Jun pathways in K562 cells, and PLA(2) catalytic activity is involved in this action. (c) 2009 Wiley-Liss, Inc.

  6. Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

    Directory of Open Access Journals (Sweden)

    Kuei-Fang Lee

    2014-01-01

    Full Text Available Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders.

  7. A review of models for near-field exposure pathways of chemicals in consumer products

    DEFF Research Database (Denmark)

    Huang, Lei; Ernstoff, Alexi; Fantke, Peter;

    2017-01-01

    Exposure to chemicals in consumer products has been gaining increasing attention, with multiple studies showing that near-field exposures from products is high compared to far-field exposures. Regarding the numerous chemical-product combinations, there is a need for an overarching review of models...... able to quantify the multiple transfers of chemicals from products used near-field to humans. The present review therefore aims at an in-depth overview of modeling approaches for near-field chemical release and human exposure pathways associated with consumer products. It focuses on lower...... in a “human receptor compartment”. We first focus on models of physical mass transfers from the product to ‘near-field’ compartments. For transfers of chemicals from article interior, adequate modeling of in-article diffusion and of partitioning between article surface and air/skin/food is key. Modeling...

  8. Framework for Multi-Pathway Cumulative Exposure for Comparative Assessments

    DEFF Research Database (Denmark)

    McKone, Tom; Fantke, Peter

    2016-01-01

    as a framework for comparative assessment of chemicals, products, and services. We first review the development and evolution of the multimedia mass-balance approach to pollutant fate and exposure evaluation and illustrate some of the calculations used in multimedia, multi-pathway exposure assessments...... in comparative risk assessment, life-cycle assessment (LCA), and chemical alternatives assessment (CAA), multimedia fate and exposure models synthesize information about partitioning, reaction, and intermedia-transport properties of chemicals in a representative (local to regional) or generic (continental...... to global) environment with information about larger scale populations rather than specific individuals or vulnerable subgroups. Although there can be large uncertainties in this approach, it provides insight on how chemical properties and use patterns map onto population-scale metrics of exposure...

  9. Arsenic exposure disrupts the normal function of the FA/BRCA repair pathway.

    Science.gov (United States)

    Peremartí, Jana; Ramos, Facundo; Marcos, Ricard; Hernández, Alba

    2014-11-01

    Chronic arsenic exposure is known to enhance the genotoxicity/carcinogenicity of other DNA-damaging agents by inhibiting DNA repair activities. Interference with nucleotide excision repair and base excision repair are well documented, but interactions with other DNA repair pathways are poorly explored so far. The Fanconi anemia FA/BRCA pathway is a DNA repair mechanism required for maintaining genomic stability and preventing cancer. Here, interactions between arsenic compounds and the FA/BRCA pathway were explored by using isogenic FANCD2(-/-) (FA/BRCA-deficient) and FANCD2(+/+) (FA/BRCA-corrected) human fibroblasts. To study whether arsenic disrupts the normal FA/BRCA function, FANCD2(+/+) cells were preexposed to subtoxic concentrations of the trivalent arsenic compounds methylarsonous acid (MMA(III)) and arsenic trioxide (ATO) for 2 weeks. The cellular response to mitomicin-C, hydroxyurea, or diepoxybutane, typical inducers of the studied pathway, was then evaluated and compared to that of FANCD2(-/-) cells. Our results show that preexposure to the trivalent arsenicals MMA(III) and ATO induces in corrected cells, a cellular FA/BRCA-deficient phenotype characterized by hypersensitivity, enhanced accumulation in the G2/M compartment and increased genomic instability--measured as micronuclei. Overall, our data demonstrate that environmentally relevant arsenic exposures disrupt the normal function of the FA/BRCA activity, supporting a novel source of arsenic co- and carcinogenic effects. This is the first study linking arsenic exposure with the FA/BRCA DNA repair pathway.

  10. Ultraviolet Radiation: Human Exposure and Health Risks.

    Science.gov (United States)

    Tenkate, Thomas D.

    1998-01-01

    Provides an overview of human exposure to ultraviolet radiation and associated health effects as well as risk estimates for acute and chronic conditions resulting from such exposure. Demonstrates substantial reductions in health risk that can be achieved through preventive actions. Also includes a risk assessment model for skin cancer. Contains 36…

  11. Community Engagement in Observational Human Exposure Studies

    Science.gov (United States)

    Although observational human exposure studies do not deliberately expose participants to chemicals or environmental conditions, merely involving people as research participants and conducting research inside homes raises ethical issues. Community engagement offers a promising st...

  12. PARTNERING TO IMPROVE HUMAN EXPOSURE METHODS

    Science.gov (United States)

    Methods development research is an application-driven scientific area that addresses programmatic needs. The goals are to reduce measurement uncertainties, address data gaps, and improve existing analytical procedures for estimating human exposures. Partnerships have been develop...

  13. Understanding pathways of exposure using site-specific habits surveys, particularly new pathways and methodologies

    Energy Technology Data Exchange (ETDEWEB)

    Grzechnik, M.; McTaggart, K.; Clyne, F. [Centre for Environment, Fisheries and Aquaculture Science, Lowestoft (United Kingdom)

    2006-07-01

    Full text of publication follows: UK policy on the control of radiation exposure via routine discharges from nuclear licensed sites has long been based on ICRP recommendations that embody the principles of justification of practices, optimisation of protection, and dose limitation. Radiological protection of the public is based on the concept of a critical group of individuals. This group is defined as those people who, as a result of the area they reside and their habits, receive the highest radiation dose due to the operations of a site. Therefore, if the dose to this critical group is acceptable in relation to relevant dose limits and constraints, then other members of the public will receive lower doses. Thus, the principle of critical groups provides overall protection for the public. Surveys to determine local habits involve an integrated methodology, whereby the potential radioactive exposure pathways from liquid and gaseous discharges and direct radiation from the site are investigated. Surveys to identify these habits must be undertaken rigorously for consistency, and have been known to reveal unexpected pathways of radiation exposure. Pathways typically include consumption of local foodstuffs and external exposure. Furthermore, a number of critical groups ma y be identified within a single survey area if the habits of one group do not adequately describe those of the other inhabitants of the area. Survey preparation involves the initial identification of high producers and consumers of local foods in a geographically defined area surrounding the nuclear facility. Pathways can be broken down into three general groups, which include exposure arising from; 1) Terrestrial (gaseous) discharges surveyed within 5 km of the site 2) Direct radiation surveyed within 1 km of the site 3) Aquatic (liquid) discharges surveyed within local areas affected by the discharges, including seas, rivers and sewage works. The survey fieldwork involves interviewing members of the

  14. Multi-pathway exposure modelling of chemicals in cosmetics ...

    Science.gov (United States)

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based on the chemical mass originally applied via a product, multiplied by the product intake fractions (PiF, the fraction of a chemical in a product that is taken in by exposed persons) to yield intake rates. The average PiFs for the evaluated chemicals in shampoo ranged from 3 × 10− 4 up to 0.3 for rapidly absorbed ingredients. Average intake rates ranged between nano- and micrograms per kilogram bodyweight per day; the order of chemical prioritization was strongly affected by the ingredient concentration in shampoo. Dermal intake and inhalation (for 20% of the evaluated chemicals) during use dominated exposure, while the skin permeation coefficient dominated the estimated uncertainties. The fraction of chemical taken in by a shampoo user often exceeded, by orders of magnitude, the aggregated fraction taken in by the population through post-use environmental emissions. Chemicals with relatively high octanol-water partitioning and/or volatility, and low molecular weight tended to have higher use stage exposure. Chemicals with low intakes during use (< 1%) and subsequent high post-use emissions, however, may yield comparable intake for a member of the general population. The pre

  15. Multi-Omics Reveals that Lead Exposure Disturbs Gut Microbiome Development, Key Metabolites and Metabolic Pathways.

    Science.gov (United States)

    Gao, Bei; Chi, Liang; Mahbub, Ridwan; Bian, Xiaoming; Tu, Pengcheng; Ru, Hongyu; Lu, Kun

    2017-02-24

    Lead exposure remains as a global public health issue and recent Flint water crisis has again raised concern about lead toxicity in the public. The toxicity of lead has been well established in a variety of systems and organs. It has been increasingly appreciated that gut microbiome is highly involved in many critical physiological processes, such as food digestion, immune system development, and metabolic homeostasis, etc. However, despite the key role of gut microbiome in human health, the functional impact of lead exposure on gut microbiome has not been studied yet. This study aims at defining gut microbiome toxicity induced by lead exposure in C57BL/6 mice by multi-omics approaches including 16S rRNA sequencing, whole genome metagenomics sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics profiling. 16S rRNA sequencing revealed that lead exposure altered the gut microbiome trajectory and phylogenetic diversity. Metagenomics sequencing and metabolomics profiling showed that numerous metabolic pathways, including vitamin E and bile acids, nitrogen metabolism, energy metabolism, oxidative stress and defense/detoxification mechanism, were significantly disturbed by lead exposure. These perturbed molecules and pathways may have important implications in lead toxicity in the host. Taken together, we have demonstrated that lead exposure not only alters the gut microbiome community structures/diversity, but also largely affects its metabolic functions, leading to gut microbiome toxicity.

  16. Human exposure to organic arsenic species from seafood.

    Science.gov (United States)

    Taylor, Vivien; Goodale, Britton; Raab, Andrea; Schwerdtle, Tanja; Reimer, Ken; Conklin, Sean; Karagas, Margaret R; Francesconi, Kevin A

    2017-02-15

    Seafood, including finfish, shellfish, and seaweed, is the largest contributor to arsenic (As) exposure in many human populations. In contrast to the predominance of inorganic As in water and many terrestrial foods, As in marine-derived foods is present primarily in the form of organic compounds. To date, human exposure and toxicological assessments have focused on inorganic As, while organic As has generally been considered to be non-toxic. However, the high concentrations of organic As in seafood, as well as the often complex As speciation, can lead to complications in assessing As exposure from diet. In this report, we evaluate the presence and distribution of organic As species in seafood, and combined with consumption data, address the current capabilities and needs for determining human exposure to these compounds. The analytical approaches and shortcomings for assessing these compounds are reviewed, with a focus on the best practices for characterization and quantitation. Metabolic pathways and toxicology of two important classes of organic arsenicals, arsenolipids and arsenosugars, are examined, as well as individual variability in absorption of these compounds. Although determining health outcomes or assessing a need for regulatory policies for organic As exposure is premature, the extensive consumption of seafood globally, along with the preliminary toxicological profiles of these compounds and their confounding effect on assessing exposure to inorganic As, suggests further investigations and process-level studies on organic As are needed to fill the current gaps in knowledge.

  17. Modelling Human Exposure to Chemicals in Food

    NARCIS (Netherlands)

    Slob W

    1993-01-01

    Exposure to foodborne chemicals is often estimated using the average consumption pattern in the human population. To protect the human population instead of the average individual, however, interindividual variability in consumption behaviour must be taken into account. This report shows how food

  18. Immunogenic tumor cell death for optimal anticancer therapy: the calreticulin exposure pathway.

    Science.gov (United States)

    Zitvogel, Laurence; Kepp, Oliver; Senovilla, Laura; Menger, Laurie; Chaput, Nathalie; Kroemer, Guido

    2010-06-15

    In response to some chemotherapeutic agents such as anthracyclines and oxaliplatin, cancer cells undergo immunogenic apoptosis, meaning that their corpses are engulfed by dendritic cells and that tumor cell antigens are presented to tumor-specific CD8(+) T cells, which then control residual tumor cells. One of the peculiarities of immunogenic apoptosis is the early cell surface exposure of calreticulin (CRT), a protein that usually resides in the lumen of the endoplasmic reticulum (ER). When elicited by anthracyclines or oxaliplatin, the CRT exposure pathway is activated by pre-apoptotic ER stress and the phosphorylation of the eukaryotic translation initiation factor eIF2alpha by the kinase PERK, followed by caspase-8-mediated proteolysis of the ER-sessile protein BAP31, activation of the pro-apoptotic proteins Bax and Bak, anterograde transport of CRT from the ER to the Golgi apparatus and exocytosis of CRT-containing vesicles, finally resulting in CRT translocation onto the plasma membrane surface. Interruption of this complex pathway abolishes CRT exposure, annihilates the immunogenicity of apoptosis, and reduces the immune response elicited by anticancer chemotherapies. We speculate that human cancers that are incapable of activating the CRT exposure pathway are refractory to the immune-mediated component of anticancer therapies.

  19. Assessment of Human Exposure to ENMs.

    Science.gov (United States)

    Jiménez, Araceli Sánchez; van Tongeren, Martie

    2017-01-01

    Human exposure assessment of engineered nanomaterials (ENMs) is hampered, among other factors, by the difficulty to differentiate ENM from other nanomaterials (incidental to processes or naturally occurring) and the lack of a single metric that can be used for health risk assessment. It is important that the exposure assessment is carried out throughout the entire life-cycle as releases can occur at the different stages of the product life-cycle, from the synthesis, manufacture of the nano-enable product (occupational exposure) to the professional and consumer use of nano-enabled product (consumer exposure) and at the end of life.Occupational exposure surveys should follow a tiered approach, increasing in complexity in terms of instruments used and sampling strategy applied with higher tiers in order tailor the exposure assessment to the specific materials used and workplace exposure scenarios and to reduce uncertainty in assessment of exposure. Assessment of consumer exposure and of releases from end-of-life processes currently relies on release testing of nano-enabled products in laboratory settings.

  20. Atmospheric Ionizing Radiation and Human Exposure

    Science.gov (United States)

    Wilson, John W.; Mertens, Christopher J.; Goldhagen, Paul; Friedberg, W.; DeAngelis, G.; Clem, J. M.; Copeland, K.; Bidasaria, H. B.

    2005-01-01

    Atmospheric ionizing radiation is of interest, apart from its main concern of aircraft exposures, because it is a principal source of human exposure to radiations with high linear energy transfer (LET). The ionizing radiations of the lower atmosphere near the Earth s surface tend to be dominated by the terrestrial radioisotopes. especially along the coastal plain and interior low lands, and have only minor contributions from neutrons (11 percent). The world average is substantially larger but the high altitude cities especially have substantial contributions from neutrons (25 to 45 percent). Understanding the world distribution of neutron exposures requires an improved understanding of the latitudinal, longitudinal, altitude and spectral distribution that depends on local terrain and time. These issues are being investigated in a combined experimental and theoretical program. This paper will give an overview of human exposures and describe the development of improved environmental models.

  1. Perspectives for integrating human and environmental exposure assessments.

    Science.gov (United States)

    Ciffroy, P; Péry, A R R; Roth, N

    2016-10-15

    Integrated Risk Assessment (IRA) has been defined by the EU FP7 HEROIC Coordination action as "the mutual exploitation of Environmental Risk Assessment for Human Health Risk Assessment and vice versa in order to coherently and more efficiently characterize an overall risk to humans and the environment for better informing the risk analysis process" (Wilks et al., 2015). Since exposure assessment and hazard characterization are the pillars of risk assessment, integrating Environmental Exposure assessment (EEA) and Human Exposure assessment (HEA) is a major component of an IRA framework. EEA and HEA typically pursue different targets, protection goals and timeframe. However, human and wildlife species also share the same environment and they similarly inhale air and ingest water and food through often similar overlapping pathways of exposure. Fate models used in EEA and HEA to predict the chemicals distribution among physical and biological media are essentially based on common properties of chemicals, and internal concentration estimations are largely based on inter-species (i.e. biota-to-human) extrapolations. Also, both EEA and HEA are challenged by increasing scientific complexity and resources constraints. Altogether, these points create the need for a better exploitation of all currently existing data, experimental approaches and modeling tools and it is assumed that a more integrated approach of both EEA and HEA may be part of the solution. Based on the outcome of an Expert Workshop on Extrapolations in Integrated Exposure Assessment organized by the HEROIC project in January 2014, this paper identifies perspectives and recommendations to better harmonize and extrapolate exposure assessment data, models and methods between Human Health and Environmental Risk Assessments to support the further development and promotion of the concept of IRA. Ultimately, these recommendations may feed into guidance showing when and how to apply IRA in the regulatory decision

  2. Variation in calculated human exposure. Comparison of calculations with seven European human exposure models

    NARCIS (Netherlands)

    Swartjes F; ECO

    2003-01-01

    Twenty scenarios, differing with respect to land use, soil type and contaminant, formed the basis for calculating human exposure from soil contaminants with the use of models contributed by seven European countries (one model per country). Here, the human exposures to children and children

  3. Exploring consumer exposure pathways and patterns of use for chemicals in the environment

    Directory of Open Access Journals (Sweden)

    Kathie L. Dionisio

    Full Text Available •To assign use-related information to chemicals to help prioritize which will be given more scrutiny relative to human exposure potential.•Categorical chemical use and functional information are presented through the Chemical/Product Categories Database (CPCat.•CPCat contains information on >43,000 unique chemicals mapped to ∼800 terms categorizing their usage or function.•The CPCat database is useful for modeling and prioritizing human chemical exposures.Humans are exposed to thousands of chemicals in the workplace, home, and via air, water, food, and soil. A major challenge in estimating chemical exposures is to understand which chemicals are present in these media and microenvironments. Here we describe the Chemical/Product Categories Database (CPCat, a new, publically available (http://actor.epa.gov/cpcat database of information on chemicals mapped to “use categories” describing the usage or function of the chemical. CPCat was created by combining multiple and diverse sources of data on consumer- and industrial-process based chemical uses from regulatory agencies, manufacturers, and retailers in various countries. The database uses a controlled vocabulary of 833 terms and a novel nomenclature to capture and streamline descriptors of chemical use for 43,596 chemicals from the various sources. Examples of potential applications of CPCat are provided, including identifying chemicals to which children may be exposed and to support prioritization of chemicals for toxicity screening. CPCat is expected to be a valuable resource for regulators, risk assessors, and exposure scientists to identify potential sources of human exposures and exposure pathways, particularly for use in high-throughput chemical exposure assessment. keywords: ACToR,Aggregated Computational Toxicology Resource,AICS,Australian Inventory of Chemical Substances,CAS RN,Chemical Abstracts Service Registry Number,CDR,Chemical Data Reporting Rule

  4. Protecting Critical Infrastructure by Identifying Pathways of Exposure to Risk

    Directory of Open Access Journals (Sweden)

    Philip O’Neill

    2013-08-01

    Full Text Available Increasingly, our critical infrastructure is managed and controlled by computers and the information networks that connect them. Cyber-terrorists and other malicious actors understand the economic and social impact that a successful attack on these systems could have. While it is imperative that we defend against such attacks, it is equally imperative that we realize how best to react to them. This article presents the strongest-path method of analyzing all potential pathways of exposure to risk – no matter how indirect or circuitous they may be – in a network model of infrastructure and operations. The method makes direct use of expert knowledge about entities and dependency relationships without the need for any simulation or any other models. By using path analysis in a directed graph model of critical infrastructure, planners can model and assess the effects of a potential attack and develop resilient responses.

  5. Exploring consumer exposure pathways and patterns of use for chemicals in the environment.

    Science.gov (United States)

    Dionisio, Kathie L; Frame, Alicia M; Goldsmith, Michael-Rock; Wambaugh, John F; Liddell, Alan; Cathey, Tommy; Smith, Doris; Vail, James; Ernstoff, Alexi S; Fantke, Peter; Jolliet, Olivier; Judson, Richard S

    2015-01-01

    Humans are exposed to thousands of chemicals in the workplace, home, and via air, water, food, and soil. A major challenge in estimating chemical exposures is to understand which chemicals are present in these media and microenvironments. Here we describe the Chemical/Product Categories Database (CPCat), a new, publically available (http://actor.epa.gov/cpcat) database of information on chemicals mapped to "use categories" describing the usage or function of the chemical. CPCat was created by combining multiple and diverse sources of data on consumer- and industrial-process based chemical uses from regulatory agencies, manufacturers, and retailers in various countries. The database uses a controlled vocabulary of 833 terms and a novel nomenclature to capture and streamline descriptors of chemical use for 43,596 chemicals from the various sources. Examples of potential applications of CPCat are provided, including identifying chemicals to which children may be exposed and to support prioritization of chemicals for toxicity screening. CPCat is expected to be a valuable resource for regulators, risk assessors, and exposure scientists to identify potential sources of human exposures and exposure pathways, particularly for use in high-throughput chemical exposure assessment.

  6. Gene networks and toxicity pathways induced by acute cadmium exposure in adult largemouth bass (Micropterus salmoides)

    Energy Technology Data Exchange (ETDEWEB)

    Mehinto, Alvine C., E-mail: alvinam@sccwrp.org [Southern California Coastal Water Research Project, Costa Mesa, CA 92626 (United States); Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Prucha, Melinda S. [Department of Human Genetics, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322 (United States); Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Colli-Dula, Reyna C.; Kroll, Kevin J.; Lavelle, Candice M.; Barber, David S. [Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Vulpe, Christopher D. [Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720 (United States); Denslow, Nancy D. [Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States)

    2014-07-01

    Highlights: • Low-level acute cadmium exposure elicited tissue-specific gene expression changes. • Molecular initiating events included oxidative stress and disruption of DNA repair. • Metallothionein, a marker of metal exposure, was not significantly affected. • We report effects of cadmium on cholesterol metabolism and steroid synthesis. • Diabetic complications and impaired reproduction are potential adverse outcomes. - Abstract: 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 20 μg/kg of cadmium chloride (mean exposure level – 2.6 μg of cadmium per fish) and microarray analyses were conducted in the liver and testis 48 h 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 48 h 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

  7. Alterations in Cell Signaling Pathways in Breast Cancer Cells after Environmental Exposure

    Energy Technology Data Exchange (ETDEWEB)

    Kulp, K; McCutcheon-Maloney, S M; Bennett, L M

    2003-02-01

    Recent human epidemiological studies suggest that up to 75% of human cancers can be attributed to environmental exposures. Understanding the biologic impact of being exposed to a lifetime of complex environmental mixtures that may not be fully characterized is currently a major challenge. Functional endpoints may be used to assess the gross health consequences of complex mixture exposures from groundwater contamination, superfund sites, biologic releases, or nutritional sources. Such endpoints include the stimulation of cell growth or the induction of a response in an animal model. An environmental exposure that upsets normal cell growth regulation may have important ramifications for cancer development. Stimulating cell growth may alter an individual's cancer risk by changing the expression of genes and proteins that have a role in growth regulatory pathways within cells. Modulating the regulation of these genes and their products may contribute to the initiation, promotion or progression of disease in response to environmental exposure. We are investigating diet-related compounds that induce cell proliferation in breast cancer cell lines. These compounds, PhIP, Flor-Essence{reg_sign} and Essiac{reg_sign}, may be part of an everyday diet. PhIP is a naturally occurring mutagen that is formed in well-cooked muscle meats. PhIP consistently causes dose-dependent breast tumor formation in rats and consumption of well-done meat has been linked to increased risk of breast cancer in women. Flor-Essence{reg_sign} and Essiac{reg_sign} herbal tonics are complementary and alternative medicines used by women who have been diagnosed with breast cancer as an alternative therapy for disease treatment and prevention. The long-term goal of this work is to identify those cellular pathways that are altered by a chemical or biologic environmental exposure and understand how those changes correlate with and or predict changes in human health risk. This project addressed this goal

  8. Human biological monitoring of occupational genotoxic exposures

    DEFF Research Database (Denmark)

    Knudsen, Lisbeth E.; Sorsa, M

    1993-01-01

    ) occupational exposure limit value of styrene in ambient air. The consideration of ethical issues in human genetic monitoring is an important but often overlooked aspect. This includes the scientific and preventional relevance of performing a test on individuals, pre- and post study information of donors......Human biological monitoring is a valuable tool for exposure assessment in groups of persons occupationally exposed to genotoxic agents. If the monitoring activity covers genetic material the term genetic monitoring is used. The methods used for genetic monitoring are either substance specific, e...... for and the biomonitoring results should preferentially be linked with accurate ambient air monitoring. In persons occupationally exposed to styrene the endpoints of DNA-damage and DNA-repair in genetic monitoring are methods of choice in exposure situations above the current Danish (25 ppm) or Finnish (20 ppm...

  9. A translatable predictor of human radiation exposure.

    Directory of Open Access Journals (Sweden)

    Joseph Lucas

    Full Text Available Terrorism using radiological dirty bombs or improvised nuclear devices is recognized as a major threat to both public health and national security. In the event of a radiological or nuclear disaster, rapid and accurate biodosimetry of thousands of potentially affected individuals will be essential for effective medical management to occur. Currently, health care providers lack an accurate, high-throughput biodosimetric assay which is suitable for the triage of large numbers of radiation injury victims. Here, we describe the development of a biodosimetric assay based on the analysis of irradiated mice, ex vivo-irradiated human peripheral blood (PB and humans treated with total body irradiation (TBI. Interestingly, a gene expression profile developed via analysis of murine PB radiation response alone was inaccurate in predicting human radiation injury. In contrast, generation of a gene expression profile which incorporated data from ex vivo irradiated human PB and human TBI patients yielded an 18-gene radiation classifier which was highly accurate at predicting human radiation status and discriminating medically relevant radiation dose levels in human samples. Although the patient population was relatively small, the accuracy of this classifier in discriminating radiation dose levels in human TBI patients was not substantially confounded by gender, diagnosis or prior exposure to chemotherapy. We have further incorporated genes from this human radiation signature into a rapid and high-throughput chemical ligation-dependent probe amplification assay (CLPA which was able to discriminate radiation dose levels in a pilot study of ex vivo irradiated human blood and samples from human TBI patients. Our results illustrate the potential for translation of a human genetic signature for the diagnosis of human radiation exposure and suggest the basis for further testing of CLPA as a candidate biodosimetric assay.

  10. A Review of Health Risks and Pathways for Exposure to Wastewater Use in Agriculture

    Science.gov (United States)

    Dickin, Sarah K.; Schuster-Wallace, Corinne J.; Qadir, Manzoor; Pizzacalla, Katherine

    2016-01-01

    Background: Wastewater is increasingly being used in the agricultural sector to cope with the depletion of freshwater resources as well as water stress linked to changing climate conditions. As wastewater irrigation expands, research focusing on the human health risks is critical because exposure to a range of contaminants must be weighed with the benefits to food security, nutrition and livelihoods. Objectives: The goal of this paper was to review research examining health risks and exposure pathways associated with wastewater irrigation to identify research trends and gaps. Methods: We conducted a review of the literature and identified a total of 126 studies published from 1995 to 2013. Findings were summarized based on several themes including types of exposure pathways, wastewater contaminants, methodological approaches and the geographical distribution of research. Results: Only 23 studies used epidemiological methods, while most research applied alternative methods to estimate risk, such as quantitative risk assessment models or comparisons of crop contamination to established guidelines for wastewater reuse. A geographic breakdown demonstrated a focus on microbiological contaminants in specific regions such as sub-Saharan Africa and Southeast Asia, despite growing chemical risks associated with rapid urbanization and industrialization that may change the types and distribution of wastewater contaminants. Conclusions: To provide a more comprehensive understanding of the health risks of wastewater use in agriculture, future research should consider multiple exposure routes, long-term health implications, and increase the range of contaminants studied, particularly in regions heavily dependent on wastewater irrigation. Citation: Dickin SK, Schuster-Wallace CJ, Qadir M, Pizzacalla K. 2016. A review of health risks and pathways for exposure to wastewater use in agriculture. Environ Health Perspect 124:900–909; http://dx.doi.org/10.1289/ehp.1509995 PMID

  11. Multi-pathway exposure modelling of chemicals in cosmetics with application to shampoo

    DEFF Research Database (Denmark)

    Ernstoff, Alexi S.; Fantke, Peter; Csiszar, Susan A.

    2016-01-01

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based...... and critical advancement for life cycle assessments and high-throughput exposure screening of chemicals in cosmetic products demonstrating the importance of consistent consideration of near- and far-field multi-pathway exposures....

  12. ASSESSMENT OF HUMAN EXPOSURE TO TOLUENE DIISOCYANATE

    Directory of Open Access Journals (Sweden)

    OLIVIA ANCA RUSU

    2011-03-01

    Full Text Available Assessment of human exposure to toluene diisocyanate. Toluene diisocyanate (TDI, an aromatic compound, may be dangerous for human health. Diisocyanates have wide industrial use in the fabrication of flexible and rigid foams, fibers, elastomers, and coatings such as paints and varnishes. Isocyanates are known skin and respiratory sensitizers, and proper engineering controls should be in place to prevent exposure to isocyanate liquid and vapor; exposure to TDI vapors is well documented to increase asthma risk. The study focused on the exposure of workers and nearby populations to toluene diisocyanate in a Polyurethane Foam Factory located in Baia Mare, Romania. Workplace air measurements were performed in different departments of the plant, after sampling either in fixed points or as personal monitoring. Sampling in four different locations of Baia Mare town was carried out, - during and after the foaming process. TDI sampling was performed on silica cartridge followed by GC-MS analysis. TDI concentration at workplace was lower than 0,035 mg/m³, which represents the permissible exposure limit, while in the city the TDI concentration had shown values below 0,20 μg/m³. Health assessment of a group of 49 workers was based on questionnaire interview, determination of TDI antibodies and lung function tests. Data collected until this stage do not show any negative effects of TDI on the employees health. Since this plant had only recently begun operating, continuous workplace and ambient air TDI monitoring, along with workers health surveillance, is deemed necessary.

  13. Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G.; Tan, Yu-Mei; Edwards, Stephen W.; Leonard, Jeremy A.; Anderson, Kim A.; Corley, Richard A.; Kile, Molly L.; Simonich, Staci M.; Stone, David; Tanguay, Robert L.; Waters, Katrina M.; Harper, Stacey L.; Williams, David E.

    2016-05-03

    Driven by major scientific advances in analytical methods, biomonitoring, and computational exposure assessment, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the computationally enabled “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. The AEP framework offers an intuitive approach to successful organization of exposure science data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathway and adverse outcome pathways, completing the source to outcome continuum and setting the stage for more efficient integration of exposure science and toxicity testing information. Together these frameworks form and inform a decision making framework with the flexibility for risk-based, hazard-based or exposure-based decisions.

  14. Phylogenetic conservation of the preapoptotic calreticulin exposure pathway from yeast to mammals.

    Science.gov (United States)

    Madeo, Frank; Durchschlag, Michael; Kepp, Oliver; Panaretakis, Theocharis; Zitvogel, Laurence; Fröhlich, Kai-Uwe; Kroemer, Guido

    2009-02-15

    The pre-apoptotic exposure of calreticulin (CRT) on the cell surface determines the efficient engulfment of mouse or human tumor cells by antigen-presenting dendritic cells. CRT exposure is rapidly induced by anthracyclins and ionizing irradiation and follows a complex signal transduction pathway that is interrupted by depletion of PERK, caspase-8, BAP31, Bax, Bak or SNAREs, as well as by knock-in mutation of eIF2alpha (to make it non-phosphorylable by PERK) or BAP31 (to render it uncleavable by caspase-8). Here, we show that yeast (Saccharomyces cerevisiae) can expose the CRT orthologue CNE1 on the surface in response to cell death induced by the anthracylin mitoxantrone (MTX). This MTX-triggered CNE1 translocation is abolished by knockout of the yeast orthologues of PERK (Gcn2), BAP31 (Yet3) and SNAREs (Nyv1, Sso1). Altogether, our data point to the existence of an ancestral and cell death-related CRT exposure pathway with conserved elements shared between unicellular fungi and mammals.

  15. Space Radiation and Human Exposures, A Primer.

    Science.gov (United States)

    Nelson, Gregory A

    2016-04-01

    The space radiation environment is a complex field comprised primarily of charged particles spanning energies over many orders of magnitude. The principal sources of these particles are galactic cosmic rays, the Sun and the trapped radiation belts around the earth. Superimposed on a steady influx of cosmic rays and a steady outward flux of low-energy solar wind are short-term ejections of higher energy particles from the Sun and an 11-year variation of solar luminosity that modulates cosmic ray intensity. Human health risks are estimated from models of the radiation environment for various mission scenarios, the shielding of associated vehicles and the human body itself. Transport models are used to propagate the ambient radiation fields through realistic shielding levels and materials to yield radiation field models inside spacecraft. Then, informed by radiobiological experiments and epidemiology studies, estimates are made for various outcome measures associated with impairments of biological processes, losses of function or mortality. Cancer-associated risks have been formulated in a probabilistic model while management of non-cancer risks are based on permissible exposure limits. This article focuses on the various components of the space radiation environment and the human exposures that it creates.

  16. [Human exposure to trihalomethanes in drinking water].

    Science.gov (United States)

    Tominaga, M Y; Midio, A F

    1999-08-01

    Halogenated hydrocarbon compounds, some of them recognized as carcinogenic to different animal species can be found in drinking water. Chloroform, bromodichloromethane, dibromochloromethane and bromoform are the most important trihalomethanes found in potable water. They are produced in natural waters during chlorinated desinfection by the halogenation of precursors, specially humic and fulvic compounds. The review, in the MEDLINE covers the period from 1974 to 1998, presents the general aspects of the formation of trihalomethanes, sources of human exposure and their toxicological meaning for exposed organisms: toxicokinetic disposition and spectrum of toxic effects (carcinogenic, mutagenic and teratogenic).

  17. Comparative genomic analyses identify common molecular pathways modulated upon exposure to low doses of arsenic and cadmium

    Directory of Open Access Journals (Sweden)

    Fry Rebecca C

    2011-04-01

    Full Text Available Abstract Background Exposure to the toxic metals arsenic and cadmium is associated with detrimental health effects including cancers of various organs. While arsenic and cadmium are well known to cause adverse health effects at high doses, the molecular impact resulting from exposure to environmentally relevant doses of these metals remains largely unexplored. Results In this study, we examined the effects of in vitro exposure to either arsenic or cadmium in human TK6 lymphoblastoid cells using genomics and systems level pathway mapping approaches. A total of 167 genes with differential expression were identified following exposure to either metal with surprisingly no overlap between the two. Real-time PCR was used to confirm target gene expression changes. The gene sets were overlaid onto protein-protein interaction maps to identify metal-induced transcriptional networks. Interestingly, both metal-induced networks were significantly enriched for proteins involved in common biological processes such as tumorigenesis, inflammation, and cell signaling. These findings were further supported by gene set enrichment analysis. Conclusions This study is the first to compare the transcriptional responses induced by low dose exposure to cadmium and arsenic in human lymphoblastoid cells. These results highlight that even at low levels of exposure both metals can dramatically influence the expression of important cellular pathways.

  18. Puerarin Suppress Apoptosis of Human Osteoblasts via ERK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Ling-juan Liu

    2013-01-01

    Full Text Available Puerarin, the main isoflavone glycoside extracted from Radix Puerariae, is an isoflavone traditional Chinese herb. Previous studies have demonstrated that puerarin could regulate osteoblast proliferation and differentiation to promote bone formation. However, the effect of puerarin on the process of human osteoblasts (hOBs apoptosis is still unclear. In this study, we detected the function of puerarin on serum-free-induced cell apoptosis using ELISA and TUNEL arrays and then found that the mortality of hOBs was significantly decreased after exposure to 10−10–10−6 M puerarin and reached the maximal antiapoptotic effect at the concentration of 10−8 M. In addition, compared with the control group, puerarin notably increased the Bcl-2 protein levels while it decreased the Bax protein levels in the hOBs in a dose-dependent way. 10−7 M puerarin decreased the Bax/Bcl-2 ratio with a maximal decrease to 0.08. Moreover, puerarin activated ERK signaling pathways in hOBs, and the antiapoptotic effect induced by puerarin was abolished by incubation of ERK inhibitor PD98059. Similarly, the estrogen receptor antagonist ICI182780 also suppressed the inhibitory effect of puerarin on hOBs apoptosis. In conclusion, puerarin could prevent hOBs apoptosis via ERK signaling pathway, which might be effective in providing protection against bone loss and bone remolding associated with osteoporosis.

  19. Acute Exposure to Pacific Ciguatoxin Reduces Electroencephalogram Activity and Disrupts Neurotransmitter Metabolic Pathways in Motor Cortex.

    Science.gov (United States)

    Kumar, Gajendra; Au, Ngan Pan Bennett; Lei, Elva Ngai Yu; Mak, Yim Ling; Chan, Leanne Lai Hang; Lam, Michael Hon Wah; Chan, Leo Lai; Lam, Paul Kwan Sing; Ma, Chi Him Eddie

    2016-09-10

    Ciguatera fish poisoning (CFP) is a common human food poisoning caused by consumption of ciguatoxin (CTX)-contaminated fish affecting over 50,000 people worldwide each year. CTXs are classified depending on their origin from the Pacific (P-CTXs), Indian Ocean (I-CTXs), and Caribbean (C-CTXs). P-CTX-1 is the most toxic CTX known and the major source of CFP causing an array of neurological symptoms. Neurological symptoms in some CFP patients last for several months or years; however, the underlying electrophysiological properties of acute exposure to CTXs remain unknown. Here, we used CTX purified from ciguatera fish sourced in the Pacific Ocean (P-CTX-1). Delta and theta electroencephalography (EEG) activity was reduced remarkably in 2 h and returned to normal in 6 h after a single exposure. However, second exposure to P-CTX-1 induced not only a further reduction in EEG activities but also a 2-week delay in returning to baseline EEG values. Ciguatoxicity was detected in the brain hours after the first and second exposure by mouse neuroblastoma assay. The spontaneous firing rate of single motor cortex neuron was reduced significantly measured by single-unit recording with high spatial resolution. Expression profile study of neurotransmitters using targeted profiling approach based on liquid chromatography-tandem mass spectrometry revealed an imbalance between excitatory and inhibitory neurotransmitters in the motor cortex. Our study provides a possible link between the brain oscillations and neurotransmitter release after acute exposure to P-CTX-1. Identification of EEG signatures and major metabolic pathways affected by P-CTX-1 provides new insight into potential biomarker development and therapeutic interventions.

  20. Characterization of changes in gene expression and biochemical pathways at low levels of benzene exposure

    NARCIS (Netherlands)

    Thomas, Reuben; Hubbard, Alan E.; McHale, Cliona M.; Zhang, Luoping; Rappaport, Stephen M.; Lan, Qing; Rothman, Nathaniel; Vermeulen, Roel; Guyton, Kathryn Z.; Jinot, Jennifer; Sonawane, Babasaheb R.; Smith, Martyn T.

    2014-01-01

    Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across

  1. Characterization of changes in gene expression and biochemical pathways at low levels of benzene exposure

    NARCIS (Netherlands)

    Thomas, Reuben; Hubbard, Alan E.; McHale, Cliona M.; Zhang, Luoping; Rappaport, Stephen M.; Lan, Qing; Rothman, Nathaniel; Vermeulen, Roel; Guyton, Kathryn Z.; Jinot, Jennifer; Sonawane, Babasaheb R.; Smith, Martyn T.

    2014-01-01

    Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across

  2. RESRAD benchmarking against six radiation exposure pathway models

    Energy Technology Data Exchange (ETDEWEB)

    Faillace, E.R.; Cheng, J.J.; Yu, C.

    1994-10-01

    A series of benchmarking runs were conducted so that results obtained with the RESRAD code could be compared against those obtained with six pathway analysis models used to determine the radiation dose to an individual living on a radiologically contaminated site. The RESRAD computer code was benchmarked against five other computer codes - GENII-S, GENII, DECOM, PRESTO-EPA-CPG, and PATHRAE-EPA - and the uncodified methodology presented in the NUREG/CR-5512 report. Estimated doses for the external gamma pathway; the dust inhalation pathway; and the soil, food, and water ingestion pathways were calculated for each methodology by matching, to the extent possible, input parameters such as occupancy, shielding, and consumption factors.

  3. Human internal and external exposure to PBDEs - A review of levels and sources

    DEFF Research Database (Denmark)

    Frederiksen, Marie; Vorkamp, Katrin; Thomsen, Marianne

    2009-01-01

    ingest more dust than adults. Infants are also exposed to PBDEs via breast milk. Internal human exposure has generally been found to be one order of magnitude larger in North America than in Europe and Asia. These differences cannot solely be explained by the dietary intake as meat products are the only......This paper reviews the existing literature on human exposure to polybrominated diphenyl ethers (PBDEs), with particular focus on external exposure routes (e.g. dust, diet, and air) and the resulting internal exposure to PBDEs (e.g. breast milk and blood). Being lipophilic and persistent organic...... compounds, PBDEs accumulate in lipid-rich tissues. Consequently, food items like fish from high trophic levels or lipid-rich oils have been found to contain relatively high concentrations of PBDEs, thus presenting an important exposure pathway to humans. The presence of PBDEs in various products of everyday...

  4. Coal seam gas water: potential hazards and exposure pathways in Queensland.

    Science.gov (United States)

    Navi, Maryam; Skelly, Chris; Taulis, Mauricio; Nasiri, Shahram

    2015-01-01

    The extraction of coal seam gas (CSG) produces large volumes of potentially contaminated water. It has raised concerns about the environmental health impacts of the co-produced CSG water. In this paper, we review CSG water contaminants and their potential health effects in the context of exposure pathways in Queensland's CSG basins. The hazardous substances associated with CSG water in Queensland include fluoride, boron, lead and benzene. The exposure pathways for CSG water are (1) water used for municipal purposes; (2) recreational water activities in rivers; (3) occupational exposures; (4) water extracted from contaminated aquifers; and (5) indirect exposure through the food chain. We recommend mapping of exposure pathways into communities in CSG regions to determine the potentially exposed populations in Queensland. Future efforts to monitor chemicals of concern and consolidate them into a central database will build the necessary capability to undertake a much needed environmental health impact assessment.

  5. Human Exposure and Health Effects of Inorganic and Elemental Mercury

    Science.gov (United States)

    Zheng, Wei

    2012-01-01

    Mercury is a toxic and non-essential metal in the human body. Mercury is ubiquitously distributed in the environment, present in natural products, and exists extensively in items encountered in daily life. There are three forms of mercury, i.e., elemental (or metallic) mercury, inorganic mercury compounds, and organic mercury compounds. This review examines the toxicity of elemental mercury and inorganic mercury compounds. Inorganic mercury compounds are water soluble with a bioavailability of 7% to 15% after ingestion; they are also irritants and cause gastrointestinal symptoms. Upon entering the body, inorganic mercury compounds are accumulated mainly in the kidneys and produce kidney damage. In contrast, human exposure to elemental mercury is mainly by inhalation, followed by rapid absorption and distribution in all major organs. Elemental mercury from ingestion is poorly absorbed with a bioavailability of less than 0.01%. The primary target organs of elemental mercury are the brain and kidney. Elemental mercury is lipid soluble and can cross the blood-brain barrier, while inorganic mercury compounds are not lipid soluble, rendering them unable to cross the blood-brain barrier. Elemental mercury may also enter the brain from the nasal cavity through the olfactory pathway. The blood mercury is a useful biomarker after short-term and high-level exposure, whereas the urine mercury is the ideal biomarker for long-term exposure to both elemental and inorganic mercury, and also as a good indicator of body burden. This review discusses the common sources of mercury exposure, skin lightening products containing mercury and mercury release from dental amalgam filling, two issues that happen in daily life, bear significant public health importance, and yet undergo extensive debate on their safety. PMID:23230464

  6. Multi-pathway exposure modelling of chemicals in cosmetics with application to shampoo

    Science.gov (United States)

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quant...

  7. EFFECTS OF ARSENIC EXPOSURE IN HUMAN HEALTH

    Directory of Open Access Journals (Sweden)

    Aline Sueli de Lima Rodrigues

    2008-10-01

    Full Text Available In recent years, ingestion of inorganic arsenic from drinking water has emerged as an important public health concern. It enters drinking water supplies from natural deposits in the earth or from agricultural and industrial practices, mainly the mining. The health consequences of chronic arsenic exposure include increased risk for various forms of cancer and numerous pathologic effects, such as cutaneous effects (hyperpigmentation and hyperkeratoses, gastrointestinal effects, vascular effects, diabetes mellitus, and peripheral neuropathy. This way, this study presents through a critical revision of the literature, the more relevant current aspects on the immunological consequences, carcinogenic and resulting genetics of the human intoxication for arsenic. They were identified and analyzed 50 works published on the subject among the years of 1979 and 2008, being used as main sources LILACS-BIREME MEDLINE/Index Medicus, SciELO and PubMed. The specific Arsênio e saúde humana effects of the intoxication for arsenic about the human health are not still completely elucidated. Thus, is possible that this element affects functions still unknown, becoming important the scientificexploration on the subject.

  8. Interferon alpha regulates MAPK and STAT1 pathways in human hepatoma cells

    Directory of Open Access Journals (Sweden)

    Ren Hao

    2011-04-01

    Full Text Available Abstract Background Signaling events triggered by interferon (IFN account for the molecular mechanisms of antiviral effect. JAK-STAT pathway plays a critical role in IFN signaling, and other pathways are also implicated in IFN-mediated antiviral effect. Changes in mitogen-activated protein kinase (MAPK and STAT1 pathways were evaluated in human hepatoma cells Huh7 and HepG2 upon IFN alpha treatment. Results Phosphorylation of ERK was significantly and specifically up-regulated, whereas enhanced phosphorylation of upstream kinase MEK was unobservable upon IFN alpha treatment. A mild increase in p38 MAPK, SAPK/JNK and downstream target ATF-2 phosphorylation was detectable after exposure to IFN alpha, indicating differential up-regulation of the MAPK signaling cascades. Moreover, STAT1 phosphorylation was strongly enhanced by IFN alpha. Conclusion IFN alpha up-regulates MAPK and STAT1 pathways in human hepatoma cells, and may provide useful information for understanding the IFN signaling.

  9. Exposure pathways and biological receptors: baseline data for the canyon uranium mine, Coconino County, Arizona

    Science.gov (United States)

    Hinck, Jo E.; Linder, Greg L.; Darrah, Abigail J.; Drost, Charles A.; Duniway, Michael C.; Johnson, Matthew J.; Méndez-Harclerode, Francisca M.; Nowak, Erika M.; Valdez, Ernest W.; Van Riper, Charles; Wolff, S.W.

    2014-01-01

    Recent restrictions on uranium mining within the Grand Canyon watershed have drawn attention to scientific data gaps in evaluating the possible effects of ore extraction to human populations as well as wildlife communities in the area. Tissue contaminant concentrations, one of the most basic data requirements to determine exposure, are not available for biota from any historical or active uranium mines in the region. The Canyon Uranium Mine is under development, providing a unique opportunity to characterize concentrations of uranium and other trace elements, as well as radiation levels in biota, found in the vicinity of the mine before ore extraction begins. Our study objectives were to identify contaminants of potential concern and critical contaminant exposure pathways for ecological receptors; conduct biological surveys to understand the local food web and refine the list of target species (ecological receptors) for contaminant analysis; and collect target species for contaminant analysis prior to the initiation of active mining. Contaminants of potential concern were identified as arsenic, cadmium, chromium, copper, lead, mercury, nickel, selenium, thallium, uranium, and zinc for chemical toxicity and uranium and associated radionuclides for radiation. The conceptual exposure model identified ingestion, inhalation, absorption, and dietary transfer (bioaccumulation or bioconcentration) as critical contaminant exposure pathways. The biological survey of plants, invertebrates, amphibians, reptiles, birds, and small mammals is the first to document and provide ecological information on .200 species in and around the mine site; this study also provides critical baseline information about the local food web. Most of the species documented at the mine are common to ponderosa pine Pinus ponderosa and pinyon–juniper Pinus–Juniperus spp. forests in northern Arizona and are not considered to have special conservation status by state or federal agencies; exceptions

  10. SPIKE: a database of highly curated human signaling pathways.

    Science.gov (United States)

    Paz, Arnon; Brownstein, Zippora; Ber, Yaara; Bialik, Shani; David, Eyal; Sagir, Dorit; Ulitsky, Igor; Elkon, Ran; Kimchi, Adi; Avraham, Karen B; Shiloh, Yosef; Shamir, Ron

    2011-01-01

    The rapid accumulation of knowledge on biological signaling pathways and their regulatory mechanisms has highlighted the need for specific repositories that can store, organize and allow retrieval of pathway information in a way that will be useful for the research community. SPIKE (Signaling Pathways Integrated Knowledge Engine; http://www.cs.tau.ac.il/&~spike/) is a database for achieving this goal, containing highly curated interactions for particular human pathways, along with literature-referenced information on the nature of each interaction. To make database population and pathway comprehension straightforward, a simple yet informative data model is used, and pathways are laid out as maps that reflect the curator’s understanding and make the utilization of the pathways easy. The database currently focuses primarily on pathways describing DNA damage response, cell cycle, programmed cell death and hearing related pathways. Pathways are regularly updated, and additional pathways are gradually added. The complete database and the individual maps are freely exportable in several formats. The database is accompanied by a stand-alone software tool for analysis and dynamic visualization of pathways.

  11. Human exposure to soil contaminants in subarctic Ontario, Canada

    Directory of Open Access Journals (Sweden)

    Ellen Stephanie Reyes

    2015-05-01

    Full Text Available Background: Chemical contaminants in the Canadian subarctic present a health risk with exposures primarily occurring via the food consumption. Objective: Characterization of soil contaminants is needed in northern Canada due to increased gardening and agricultural food security initiatives and the presence of known point sources of pollution. Design: A field study was conducted in the western James Bay Region of Ontario, Canada, to examine the concentrations of polychlorinated biphenyls, dichlorodiphenyltrichloroethane and its metabolites (ΣDDT, other organochlorines, and metals/metalloids in potentially contaminated agriculture sites. Methods: Exposure pathways were assessed by comparing the estimated daily intake to acceptable daily intake values. Ninety soil samples were collected at random (grid sampling from 3 plots (A, B, and C in Fort Albany (on the mainland, subarctic Ontario, Canada. The contaminated-soil samples were analysed by gas chromatography with an electron capture detector or inductively coupled plasma mass spectrometer. Results: The range of ΣDDT in 90 soil samples was below the limit of detection to 4.19 mg/kg. From the 3 soil plots analysed, Plot A had the highest ΣDDT mean concentration of 1.12 mg/kg, followed by Plot B and Plot C which had 0.09 and 0.01 mg/kg, respectively. Concentrations of other organic contaminants and metals in the soil samples were below the limit of detection or found in low concentrations in all plots and did not present a human health risk. Conclusions: Exposure analyses showed that the human risk was below regulatory thresholds. However, the ΣDDT concentration in Plot A exceeded soil guidelines set out by the Canadian Council of Ministers of the Environment of 0.7 mg/kg, and thus the land should not be used for agricultural or recreational purposes. Both Plots B and C were below threshold limits, and this land can be used for agricultural purposes.

  12. Responses of the insulin signaling pathways in the brown adipose tissue of rats following cold exposure.

    Science.gov (United States)

    Wang, Xiaofei; Wahl, Richard

    2014-01-01

    The insulin signaling pathway is critical for the control of blood glucose levels. Brown adipose tissue (BAT) has also been implicated as important in glucose homeostasis. The effect of short-term cold exposure on this pathway in BAT has not been explored. We evaluated the effect of 4 hours of cold exposure on the insulin pathway in the BAT of rats. Whole genomic microarray chips were used to examine the transcripts of the pathway in BAT of rats exposed to 4°C and 22°C for 4 hours. The 4 most significantly altered pathways following 4 hours of cold exposure were the insulin signaling pathway, protein kinase A, PI3K/AKT and ERK/MAPK signaling. The insulin signaling pathway was the most affected. In the documented 142 genes of the insulin pathway, 42 transcripts (29.6%) responded significantly to this cold exposure with the least false discovery rate (Benjamini-Hochberg Multiple Testing: -log10 (p-value)  = 7.18). Twenty-seven genes (64%) were up-regulated, including the insulin receptor (Insr), insulin substrates 1 and 2 (Irs1 and Irs2). Fifteen transcripts (36%) were down-regulated. Multiple transcripts of the primary target and secondary effector targets for the insulin signaling were also up-regulated, including those for carbohydrate metabolism. Using western blotting, we demonstrated that the cold induced higher Irs2, Irs1, and Akt-p protein levels in the BAT than in the BAT of controls maintained at room temperature, and higher Akt-p protein level in the muscle. this study demonstrated that 4 hours of cold exposure stimulated the insulin signaling pathway in the BAT and muscle of overnight fasted rats. This raises the possibility that acute cold stimulation may have potential to improve glucose clearance and insulin sensitivity.

  13. Signaling pathways in failing human heart muscle cells.

    Science.gov (United States)

    Drexler, H; Hasenfuss, G; Holubarsch, C

    1997-07-01

    Experimental studies have delineated important signaling pathways in cardiomyocytes and their alterations in heart failure; however, there is now evidence that these observations are not necessarily applicable to human cardiac muscle cells. For example, angiotensin II (A II) does not exert positive inotropic effects in human ventricular muscle cells, in contrast to observation in rats. Thus, it is important to elucidate cardiac signaling pathways in humans in order to appreciate the functional role of neurohumoral or mechanical stimulation in human myocardium in health and disease. In the present article, we review signal pathways in the failing human heart based on studies in human cardiac tissues and in vivo physiological studies related to A II, nitric oxide, and β-adrenergic stimulation. (Trends Cardiovasc Med 1997; 7:151-160). © 1997, Elsevier Science Inc.

  14. Prenatal alcohol and other early childhood adverse exposures: Direct and indirect pathways to adolescent drinking

    Science.gov (United States)

    Cornelius, Marie D.; De Genna, Natacha M.; Goldschmidt, Lidush; Larkby, Cynthia; Day, Nancy L.

    2016-01-01

    We examined direct and indirect pathways between adverse environmental exposures during gestation and childhood and drinking in mid-adolescence. Mothers and their offspring (n = 917 mother/child dyads) were followed prospectively from second trimester to a 16-year follow-up assessment. Interim assessments occurred at delivery, 6, 10, and 14 years. Adverse environmental factors included gestational exposures to alcohol, tobacco, and marijuana, exposures to childhood maltreatment and violence, maternal psychological symptoms, parenting practices, economic and home environments, and demographic characteristics of the mother and child. Indirect effects of early child behavioral characteristics including externalizing, internalizing activity, attention, and impulsivity were also examined. Polytomous logistic regression analyses were used to evaluate direct effects of adverse environmental exposures with level of adolescent drinking. Structural equation modeling (SEM) was applied to simultaneously estimate the relation between early adversity variables, childhood characteristics, and drinking level at age 16 while controlling for significant covariates. Level of drinking among the adolescent offspring was directly predicted by prenatal exposure to alcohol, less parental strictness, and exposures to maltreatment and violence during childhood. Whites and offspring with older mothers were more likely to drink at higher levels. There was a significant indirect effect between childhood exposure to violence and adolescent drinking via childhood externalizing behavior problems. All other hypothesized indirect pathways were not significant. Thus most of the early adversity measures directly predicted adolescent drinking and did not operate via childhood behavioral dysregulation characteristics. These results highlight the importance of adverse environmental exposures on pathways to adolescent drinking. PMID:26994529

  15. MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways

    Energy Technology Data Exchange (ETDEWEB)

    Simões, Maylla Ronacher, E-mail: yllars@hotmail.com [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Aguado, Andrea [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Fiorim, Jonaína; Silveira, Edna Aparecida; Azevedo, Bruna Fernandes; Toscano, Cindy Medice [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Zhenyukh, Olha; Briones, Ana María [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Alonso, María Jesús [Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón (Spain); Vassallo, Dalton Valentim [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Health Science Center of Vitória-EMESCAM, Vitória, ES CEP 29045-402 (Brazil); Salaices, Mercedes, E-mail: mercedes.salaices@uam.es [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain)

    2015-03-01

    Chronic exposure to low lead concentration produces hypertension; however, the underlying mechanisms remain unclear. We analyzed the role of oxidative stress, cyclooxygenase-2-dependent pathways and MAPK in the vascular alterations induced by chronic lead exposure. Aortas from lead-treated Wistar rats (1st dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g, intramuscular, 30 days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20 μg/dL) were used. Lead blood levels of treated rats attained 21.7 ± 2.38 μg/dL. Lead exposure increased systolic blood pressure and aortic ring contractile response to phenylephrine, reduced acetylcholine-induced relaxation and did not affect sodium nitroprusside relaxation. Endothelium removal and L-NAME left-shifted the response to phenylephrine more in untreated than in lead-treated rats. Apocynin and indomethacin decreased more the response to phenylephrine in treated than in untreated rats. Aortic protein expression of gp91(phox), Cu/Zn-SOD, Mn-SOD and COX-2 increased after lead exposure. In cultured VSMCs lead 1) increased superoxide anion production, NADPH oxidase activity and gene and/or protein levels of NOX-1, NOX-4, Mn-SOD, EC-SOD and COX-2 and 2) activated ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized superoxide anion production, NADPH oxidase activity and mRNA levels of NOX-1, NOX-4 and COX-2. Blockade of the ERK1/2 and p38 signaling pathways abolished lead-induced NOX-1, NOX-4 and COX-2 expression. Results show that lead activation of the MAPK signaling pathways activates inflammatory proteins such as NADPH oxidase and COX-2, suggesting a reciprocal interplay and contribution to vascular dysfunction as an underlying mechanisms for lead-induced hypertension. - Highlights: • Lead-exposure increases oxidative stress, COX-2 expression and vascular reactivity. • Lead exposure activates MAPK signaling pathway. • ROS and COX-2 activation by

  16. Developmental and reproductive outcomes in humans and animals after glyphosate exposure: a critical analysis.

    Science.gov (United States)

    Williams, Amy Lavin; Watson, Rebecca E; DeSesso, John M

    2012-01-01

    Glyphosate is the active ingredient of several widely used herbicide formulations. Glyphosate targets the shikimate metabolic pathway, which is found in plants but not in animals. Despite the relative safety of glyphosate, various adverse developmental and reproductive problems have been alleged as a result of exposure in humans and animals. To assess the developmental and reproductive safety of glyphosate, an analysis of the available literature was conducted. Epidemiological and animal reports, as well as studies on mechanisms of action related to possible developmental and reproductive effects of glyphosate, were reviewed. An evaluation of this database found no consistent effects of glyphosate exposure on reproductive health or the developing offspring. Furthermore, no plausible mechanisms of action for such effects were elucidated. Although toxicity was observed in studies that used glyphosate-based formulations, the data strongly suggest that such effects were due to surfactants present in the formulations and not the direct result of glyphosate exposure. To estimate potential human exposure concentrations to glyphosate as a result of working directly with the herbicide, available biomonitoring data were examined. These data demonstrated extremely low human exposures as a result of normal application practices. Furthermore, the estimated exposure concentrations in humans are >500-fold less than the oral reference dose for glyphosate of 2 mg/kg/d set by the U.S. Environmental Protection Agency (U.S. EPA 1993). In conclusion, the available literature shows no solid evidence linking glyphosate exposure to adverse developmental or reproductive effects at environmentally realistic exposure concentrations.

  17. Bioreactor Transient Exposure Activates Specific Neurotrophic Pathway in Cortical Neurons

    Science.gov (United States)

    Zimmitti, V.; Benedetti, E.; Caracciolo, V.; Sebastiani, P.; Di Loreto, S.

    2010-02-01

    Altered gravity forces might influence neuroplasticity and can provoke changes in biochemical mechanisms. In this contest, neurotrophins have a pivotal role, particularly nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). A suspension of dissociated cortical cells from rat embryos was exposed to 24 h of microgravity before plating in normal adherent culture system. Expression and transductional signalling pathways of NGF and BDNF were assessed at the end of maturational process (8-10 days in vitro). Rotating wall vessel bioreactor (RWV) pre-exposition did not induce changes in NGF expression and its high affinity receptor TrkA. On the contrary both BDNF expression and its high affinity receptor TrkB were strongly up-regulated, inducing Erk-5, but not Erk-1/2 activation and, in turn, MEF2C over-expression and activation. According to our previous and present results, we postulate that relatively short microgravitational stimuli, applied to neural cells during the developmental stage, exert a long time activation of specific neurotrophic pathways.

  18. Human exposure to bovine polyomavirus: a zoonosis

    Energy Technology Data Exchange (ETDEWEB)

    Parry, J.V.; Gardner, S.D.

    1986-01-01

    A competitive-type solid phase radioimmunoassay (RIA) was developed for the detection of antibody to bovine polyomavirus. Comparison of RIA and counter-immunoelectrophoresis (CIE) results on 273 cattle sera indicated that both techniques were detecting antibody of like specificity. Human sera from 256 blood donors, 219 people recently vaccinated against polio, rubella or rabies, 50 immunosuppressed patients and 472 people with various occupational exposure to cattle were tested for antibody to bovine polyomavirus, the foetal rhesus monkey kidney strain, (anti-FRKV) by RIA. Apart from one blood donor and one of 108 rabies vaccinees only those in close contact with cattle possessed anti-FRKV. Compared with 62 per cent seropositive in the natural hosts, cattle, 71 per cent of veterinary surgeons, 50 per cent of cattle farmers, 40 per cent of abattoir workers, 16 per cent of veterinary institute technical staff and 10 per cent of veterinary students were anti-FRKV positive. Our findings indicate that the theoretical hazard of FRKV infection from undetected contamination of current tissue culture derived vaccines may, in practice, be remote. Proposed wider use of primate kidney cells as substrates for new vaccines may increase this risk.

  19. Characterization of changes in gene expression and biochemical pathways at low levels of benzene exposure.

    Directory of Open Access Journals (Sweden)

    Reuben Thomas

    Full Text Available Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML. Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC, we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from 10 ppm compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings.

  20. Progress in human exposure assessment for biocidal products

    NARCIS (Netherlands)

    Hemmen, J.J. van

    2004-01-01

    An important shortcoming in our present knowledge required for risk assessment of biocidal products is the assessment of human exposure. This knowledge gap has been filled in a preliminary fashion with the TNsG on human exposure to biocidal products (available from the ECB website). Explicit User gu

  1. Human exposure assessment: Approaches for chemicals (REACH) and biocides (BPD)

    NARCIS (Netherlands)

    Hemmen, J.J. van; Gerritsen-Ebben, R.

    2008-01-01

    The approaches that are indicated in the various guidance documents for the assessment of human exposure for chemicals and biocides are summarised. This reflects the TNsG (Technical notes for Guidance) version 2: human exposure assessment for biocidal products (1) under the BPD (Biocidal Products Di

  2. Differentially Expressed Genes and Signature Pathways of Human Prostate Cancer.

    Directory of Open Access Journals (Sweden)

    Jennifer S Myers

    Full Text Available Genomic technologies including microarrays and next-generation sequencing have enabled the generation of molecular signatures of prostate cancer. Lists of differentially expressed genes between malignant and non-malignant states are thought to be fertile sources of putative prostate cancer biomarkers. However such lists of differentially expressed genes can be highly variable for multiple reasons. As such, looking at differential expression in the context of gene sets and pathways has been more robust. Using next-generation genome sequencing data from The Cancer Genome Atlas, differential gene expression between age- and stage- matched human prostate tumors and non-malignant samples was assessed and used to craft a pathway signature of prostate cancer. Up- and down-regulated genes were assigned to pathways composed of curated groups of related genes from multiple databases. The significance of these pathways was then evaluated according to the number of differentially expressed genes found in the pathway and their position within the pathway using Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis. The "transforming growth factor-beta signaling" and "Ran regulation of mitotic spindle formation" pathways were strongly associated with prostate cancer. Several other significant pathways confirm reported findings from microarray data that suggest actin cytoskeleton regulation, cell cycle, mitogen-activated protein kinase signaling, and calcium signaling are also altered in prostate cancer. Thus we have demonstrated feasibility of pathway analysis and identified an underexplored area (Ran for investigation in prostate cancer pathogenesis.

  3. [Advances on research of human exposure to triclosan].

    Science.gov (United States)

    Jin, Chenye; Chen, Yiming; Zhang, Peiqi; Xiong, Zhezhen; Wang, Caifeng; Tian, Ying

    2016-03-01

    Triclosan, a broad-spectrum antimicrobial agent, was reported to have been widely detected in various human biological samples such as urine, blood and human milk among foreign populations. In China, limited reports have been found on human exposure to triclosan, and the reported urinary triclosan concentrations were significantly lower than that of American populations. Besides, the potential influencing factors still remain unclear regarding human exposure to triclosan, but evidences suggest that those in middle age and with higher household income and higher social class tend to have higher urinary triclosan concentrations. Furthermore, triclosan exposure tend to differ by sex, geography, heredity, metabolism and life style.

  4. Modularized study of human calcium signalling pathway

    Indian Academy of Sciences (India)

    Losiana Nayak; Rajat K De

    2007-08-01

    Signalling pathways are complex biochemical networks responsible for reg ulation of numerous cellular functions. These networks function by serial and successive interactions among a large number of vital biomolecules and chemical compounds. For deciphering and analysing the underlying mechanism of such networks, a modularized study is quite helpful. Here we propose an algorithm for modularization of calcium signalling pathway of H. sapiens. The idea that ``a node whose function is dependant on maximum number of other nodes tends to be the center of a sub network” is used to divide a large signalling network into smaller sub networks. Inclusion of node(s) into sub networks(s) is dependant on the outdegree of the node(s). Here outdegree of a node refers to the number of re lations of the considered node lying outside the constructed sub network. Node(s) having more than c relations lying outside the expanding subnetwork have to be excluded from it. Here is a specified variable based on user preference, which is finally fixed during adjustments of created subnetworks, so that certain biological significance can be conferred on them.

  5. DEGAS: de novo discovery of dysregulated pathways in human diseases.

    Directory of Open Access Journals (Sweden)

    Igor Ulitsky

    Full Text Available BACKGROUND: Molecular studies of the human disease transcriptome typically involve a search for genes whose expression is significantly dysregulated in sick individuals compared to healthy controls. Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals. However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals. While a pathway is usually defined as a set of genes known to share a specific function, pathway boundaries are frequently difficult to assign, and methods that rely on such definition cannot discover novel pathways. Protein interaction networks can potentially be used to overcome these problems. METHODOLOGY/PRINCIPAL FINDINGS: We present DEGAS (DysrEgulated Gene set Analysis via Subnetworks, a method for identifying connected gene subnetworks significantly enriched for genes that are dysregulated in specimens of a disease. We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases. In Parkinson's disease, we provide novel evidence for involvement of mRNA splicing, cell proliferation, and the 14-3-3 complex in the disease progression. DEGAS is available as part of the MATISSE software package (http://acgt.cs.tau.ac.il/matisse. CONCLUSIONS/SIGNIFICANCE: The subnetworks identified by DEGAS can provide a signature of the disease potentially useful for diagnosis, pinpoint possible pathways affected by the disease, and suggest targets for drug intervention.

  6. The Aggregate Exposure Pathway (AEP): A conceptual framework for advancing exposure science research and applications

    Science.gov (United States)

    Historically, risk assessment has relied upon toxicological data to obtain hazard-based reference levels, which are subsequently compared to exposure estimates to determine whether an unacceptable risk to public health may exist. Recent advances in analytical methods, biomarker ...

  7. Transcriptomic analysis in the developing zebrafish embryo after compound exposure: Individual gene expression and pathway regulation

    Energy Technology Data Exchange (ETDEWEB)

    Hermsen, Sanne A.B., E-mail: Sanne.Hermsen@rivm.nl [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht (Netherlands); Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.178, 3508 TD, Utrecht (Netherlands); Pronk, Tessa E. [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht (Netherlands); Brandhof, Evert-Jan van den [Centre for Environmental Quality, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Ven, Leo T.M. van der [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Piersma, Aldert H. [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.178, 3508 TD, Utrecht (Netherlands)

    2013-10-01

    The zebrafish embryotoxicity test is a promising alternative assay for developmental toxicity. Classically, morphological assessment of the embryos is applied to evaluate the effects of compound exposure. However, by applying differential gene expression analysis the sensitivity and predictability of the test may be increased. For defining gene expression signatures of developmental toxicity, we explored the possibility of using gene expression signatures of compound exposures based on commonly expressed individual genes as well as based on regulated gene pathways. Four developmental toxic compounds were tested in concentration-response design, caffeine, carbamazepine, retinoic acid and valproic acid, and two non-embryotoxic compounds, D-mannitol and saccharin, were included. With transcriptomic analyses we were able to identify commonly expressed genes, which were mostly development related, after exposure to the embryotoxicants. We also identified gene pathways regulated by the embryotoxicants, suggestive of their modes of action. Furthermore, whereas pathways may be regulated by all compounds, individual gene expression within these pathways can differ for each compound. Overall, the present study suggests that the use of individual gene expression signatures as well as pathway regulation may be useful starting points for defining gene biomarkers for predicting embryotoxicity. - Highlights: • The zebrafish embryotoxicity test in combination with transcriptomics was used. • We explored two approaches of defining gene biomarkers for developmental toxicity. • Four compounds in concentration-response design were tested. • We identified commonly expressed individual genes as well as regulated gene pathways. • Both approaches seem suitable starting points for defining gene biomarkers.

  8. Exposure to 1950-MHz TD-SCDMA electromagnetic fields affects the apoptosis of astrocytes via caspase-3-dependent pathway.

    Directory of Open Access Journals (Sweden)

    Yu-xiao Liu

    Full Text Available The usage of mobile phone increases globally. However, there is still a paucity of data about the impact of electromagnetic fields (EMF on human health. This study investigated whether EMF radiation would alter the biology of glial cells and act as a tumor-promoting agent. We exposed rat astrocytes and C6 glioma cells to 1950-MHz TD-SCDMA for 12, 24 and 48 h respectively, and found that EMF exposure had differential effects on rat astroctyes and C6 glioma cells. A 48 h of exposure damaged the mitochondria and induced significant apoptosis of astrocytes. Moreover, caspase-3, a hallmark of apoptosis, was highlighted in astrocytes after 48 h of EMF exposure, accompanied by a significantly increased expression of bax and reduced level of bcl-2. The tumorigenicity assays demonstrated that astrocytes did not form tumors in both control and exposure groups. In contrast, the unexposed and exposed C6 glioma cells show no significant differences in both biological feature and tumor formation ability. Therefore, our results implied that exposure to the EMF of 1950-MHz TD-SCDMA may not promote the tumor formation, but continuous exposure damaged the mitochondria of astrocytes and induce apoptosis through a caspase-3-dependent pathway with the involvement of bax and bcl-2.

  9. Human exposures to parabens in cosmetics - a literature study

    OpenAIRE

    Aarflot, Ragnhild Lønseth

    2013-01-01

    A literature study was performed in order to assess and compare evidence of human exposure to parabens in cosmetics. The focus of the thesis is on human concentrations, the rate of dermal absorption, metabolism and excretion; in order to increase our understanding of human exposures to endocrine disrupting chemicals in cosmetics. High detection rates of native and total parabens in blood and urine were identified. GMs of native parabens were lower than total paraben levels in urine as expecte...

  10. Gene expression profiling and pathway analysis of human bronchial epithelial cells exposed to airborne particulate matter collected from Saudi Arabia

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Hong [Department of Environmental Medicine, NYU School of Medicine, Tuxedo, NY (United States); Shamy, Magdy [Department of Environmental Sciences, Faculty of Meteorology, Environment and Arid Land Agriculture, King Abdulaziz University, Jeddah (Saudi Arabia); Kluz, Thomas; Muñoz, Alexandra B.; Zhong, Mianhua; Laulicht, Freda [Department of Environmental Medicine, NYU School of Medicine, Tuxedo, NY (United States); Alghamdi, Mansour A.; Khoder, Mamdouh I. [Department of Environmental Sciences, Faculty of Meteorology, Environment and Arid Land Agriculture, King Abdulaziz University, Jeddah (Saudi Arabia); Chen, Lung-Chi [Department of Environmental Medicine, NYU School of Medicine, Tuxedo, NY (United States); Costa, Max, E-mail: Max.Costa@nyumc.org [Department of Environmental Medicine, NYU School of Medicine, Tuxedo, NY (United States)

    2012-12-01

    Epidemiological studies have established a positive correlation between human mortality and increased concentration of airborne particulate matters (PM). However, the mechanisms underlying PM related human diseases, as well as the molecules and pathways mediating the cellular response to PM, are not fully understood. This study aims to investigate the global gene expression changes in human cells exposed to PM{sub 10} and to identify genes and pathways that may contribute to PM related adverse health effects. Human bronchial epithelial cells were exposed to PM{sub 10} collected from Saudi Arabia for 1 or 4 days, and whole transcript expression was profiled using the GeneChip human gene 1.0 ST array. A total of 140 and 230 genes were identified that significantly changed more than 1.5 fold after PM{sub 10} exposure for 1 or 4 days, respectively. Ingenuity Pathway Analysis revealed that different exposure durations triggered distinct pathways. Genes involved in NRF2-mediated response to oxidative stress were up-regulated after 1 day exposure. In contrast, cells exposed for 4 days exhibited significant changes in genes related to cholesterol and lipid synthesis pathways. These observed changes in cellular oxidative stress and lipid synthesis might contribute to PM related respiratory and cardiovascular disease. -- Highlights: ► PM exposure modulated gene expression and associated pathways in BEAS-2B cells. ► One-day exposure to PM induced genes involved in responding to oxidative stress. ► 4-day exposure to PM changed genes associated to cholesterol and lipid synthesis.

  11. Internodal pathways in the human atria: a model study.

    Science.gov (United States)

    Kafer, C J

    1991-12-01

    An electrophysical/anatomical computer model of human atrial excitation was used to investigate the controversy over specialized internodal pathways. The only atrial pathways that have been thoroughly described in the literature are those that connect the sinoatrial (SA) and atrioventricular (AV) nodes, and the right and left atria. By incorporating pathways of rapid propagation representing the internodal and interatrial tracts, anisotropy was introduced into an otherwise isotropic atrial model. Simulated epicardial isochrone maps, heart vector loops, and electrograms were calculated for both the isotropic and anisotropic atrial models, and the simulations were compared with observed normal data. Although the simulations using the anisotropic model compare more favorably with real data, the results suggest that there are more pathways of rapid propagation in the atria than those described and that a global anisotropy based on morphology and fiber direction is a more likely explanation than rapid propagation confined to a few specialized pathways.

  12. Wood smoke in a controlled exposure experiment with human volunteers.

    Science.gov (United States)

    Riddervold, I S; Bønløkke, J H; Mølhave, L; Massling, A; Jensen, B; Grønborg, T K; Bossi, R; Forchhammer, L; Kjærgaard, S K; Sigsgaard, T

    2011-04-01

    Exposure to wood smoke in the general population is increasing and concurrently, also our awareness. This article describes a wood-smoke generating system for studying human exposure to wood smoke and symptoms related to this exposure. Twenty nonsmoking atopic human participants with normal lung function and normal bronchial reactivity were randomly exposed for 3 h at three different exposure conditions; clean filtered air (control exposure) and wood smoke with a characteristic particulate matter (PM) concentration of 200 µg/m³ (low) and 400 µg/m³ (high) under controlled environmental conditions. The range for PM₂.₅ load observed for single experiments was 165-303 µg/m³ for the low exposure and 205-662 µg/m³ for the high exposure, whereas particle loads during clean air exposure most often were below the detection limit (humans. The knowledge gained in this study on subjective-rated symptoms may be important for understanding human response to wood-smoke exposure.

  13. Exposure Pathways, Biomarkers and the Exposome: Predictions, Insight, and Uncertainty (SOT presentation - CE lecture)

    Science.gov (United States)

    The risk posed to human health by any of the thousands of untested anthropogenic chemicals in our environment is a function of both the hazard presented by the chemical and the extent of exposure. However, many chemicals lack estimates of exposure intake, limiting the understandi...

  14. Exposure Pathways, Biomarkers and the Exposome: Predictions, Insight, and Uncertainty (SOT presentation - CE lecture)

    Science.gov (United States)

    The risk posed to human health by any of the thousands of untested anthropogenic chemicals in our environment is a function of both the hazard presented by the chemical and the extent of exposure. However, many chemicals lack estimates of exposure intake, limiting the understandi...

  15. Exploring Exposure Pathways with Chemical/Product Categorical CPCat)Data

    Science.gov (United States)

    Humans are exposed to thousands of chemicals over our lifetimes. A major challenge to risk assessors is to understand how and when chemical exposures occur, and which “exposure pathways” contribute the most. An informatics-driven approach to assigning “product-use” categories to ...

  16. Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver

    Science.gov (United States)

    Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver D.B. Johnson, 1 W.O. Ward, 2 V.L. Bass, 2 M.C.J. Schladweiler, 2A.D. Ledbetter, 2 D. Andrews, and U.P. Kodavanti 2 1 Curriculum in Toxicology, UNC School of Medicine, Cha...

  17. Inhale while Dreaming: Human Exposure to Pollutants while Sleeping

    DEFF Research Database (Denmark)

    Corsi, Richard; Spilak, Michal; Boor, E., Brandon

    2012-01-01

    Humans spend approximately 1/3 of their total life asleep, typically on a mattress or other bedding. Despite the fact that there is no other location where most of humanity spends more time, this microenvironment has received little attention from the standpoint of human exposure to a wide range ...

  18. Signaling pathway networks mined from human pituitary adenoma proteomics data

    Directory of Open Access Journals (Sweden)

    Zhan Xianquan

    2010-04-01

    Full Text Available Abstract Background We obtained a series of pituitary adenoma proteomic expression data, including protein-mapping data (111 proteins, comparative proteomic data (56 differentially expressed proteins, and nitroproteomic data (17 nitroproteins. There is a pressing need to clarify the significant signaling pathway networks that derive from those proteins in order to clarify and to better understand the molecular basis of pituitary adenoma pathogenesis and to discover biomarkers. Here, we describe the significant signaling pathway networks that were mined from human pituitary adenoma proteomic data with the Ingenuity pathway analysis system. Methods The Ingenuity pathway analysis system was used to analyze signal pathway networks and canonical pathways from protein-mapping data, comparative proteomic data, adenoma nitroproteomic data, and control nitroproteomic data. A Fisher's exact test was used to test the statistical significance with a significance level of 0.05. Statistical significant results were rationalized within the pituitary adenoma biological system with literature-based bioinformatics analyses. Results For the protein-mapping data, the top pathway networks were related to cancer, cell death, and lipid metabolism; the top canonical toxicity pathways included acute-phase response, oxidative-stress response, oxidative stress, and cell-cycle G2/M transition regulation. For the comparative proteomic data, top pathway networks were related to cancer, endocrine system development and function, and lipid metabolism; the top canonical toxicity pathways included mitochondrial dysfunction, oxidative phosphorylation, oxidative-stress response, and ERK/MAPK signaling. The nitroproteomic data from a pituitary adenoma were related to cancer, cell death, lipid metabolism, and reproductive system disease, and the top canonical toxicity pathways mainly related to p38 MAPK signaling and cell-cycle G2/M transition regulation. Nitroproteins from a

  19. Wood smoke in a controlled exposure experiment with human volunteers

    DEFF Research Database (Denmark)

    Riddervold, Ingunn Skogstad; Bønløkke, Jakob Hjort; Mølhave, Lars

    2011-01-01

    Exposure to wood smoke in the general population is increasing and concurrently, also our awareness. This article describes a wood-smoke generating system for studying human exposure to wood smoke and symptoms related to this exposure. Twenty nonsmoking atopic human participants with normal lung...... function and normal bronchial reactivity were randomly exposed for 3h at three different exposure conditions; clean filtered air (control exposure) and wood smoke with a characteristic particulate matter (PM) concentration of 200 µg/m3 (low) and 400 µg/m3 (high) under controlled environmental conditions.......0007), “irritative body perceptions” (p = 0.0127), “psychological/neurological effects” (p = 0.0075) and “weak inflammatory responses” (p = 0.0003). Furthermore, significant effects (p = 0.0192) on self-reported general mucosa irritation were found. In conclusion, exposure to wood smoke affected symptom rating...

  20. The Use of Signal-Transduction and Metabolic Pathways to Predict Human Disease Targets from Electric and Magnetic Fields Using in vitro Data in Human Cell Lines

    Science.gov (United States)

    Parham, Fred; Portier, Christopher J.; Chang, Xiaoqing; Mevissen, Meike

    2016-01-01

    Using in vitro data in human cell lines, several research groups have investigated changes in gene expression in cellular systems following exposure to extremely low frequency (ELF) and radiofrequency (RF) electromagnetic fields (EMF). For ELF EMF, we obtained five studies with complete microarray data and three studies with only lists of significantly altered genes. Likewise, for RF EMF, we obtained 13 complete microarray datasets and 5 limited datasets. Plausible linkages between exposure to ELF and RF EMF and human diseases were identified using a three-step process: (a) linking genes associated with classes of human diseases to molecular pathways, (b) linking pathways to ELF and RF EMF microarray data, and (c) identifying associations between human disease and EMF exposures where the pathways are significantly similar. A total of 60 pathways were associated with human diseases, mostly focused on basic cellular functions like JAK–STAT signaling or metabolic functions like xenobiotic metabolism by cytochrome P450 enzymes. ELF EMF datasets were sporadically linked to human diseases, but no clear pattern emerged. Individual datasets showed some linkage to cancer, chemical dependency, metabolic disorders, and neurological disorders. RF EMF datasets were not strongly linked to any disorders but strongly linked to changes in several pathways. Based on these analyses, the most promising area for further research would be to focus on EMF and neurological function and disorders. PMID:27656641

  1. Organophosphate pesticides exposure among farmworkers: pathways and risk of adverse health effects.

    Science.gov (United States)

    Suratman, Suratman; Edwards, John William; Babina, Kateryna

    2015-01-01

    Organophosphate (OP) compounds are the most widely used pesticides with more than 100 OP compounds in use around the world. The high-intensity use of OP pesticides contributes to morbidity and mortality in farmworkers and their families through acute or chronic pesticides-related illnesses. Many factors contributing to adverse health effects have been investigated by researchers to determine pathways of OP-pesticide exposure among farmers in developed and developing countries. Factors like wind/agricultural pesticide drift, mixing and spraying pesticides, use of personal protective equipment (PPE), knowledge, perceptions, washing hands, taking a shower, wearing contaminated clothes, eating, drinking, smoking, and hot weather are common in both groups of countries. Factors including low socioeconomic status areas, workplace conditions, duration of exposure, pesticide safety training, frequency of applying pesticides, spraying against the wind, and reuse of pesticide containers for storage are specific contributors in developing countries, whereas housing conditions, social contextual factors, and mechanical equipment were specific pathways in developed countries. This paper compares existing research in environmental and behavioural exposure modifying factors and biological monitoring between developing and developed countries. The main objective of this review is to explore the current depth of understanding of exposure pathways and factors increasing the risk of exposure potentially leading to adverse health effects specific to each group of countries.

  2. Environmental chemical exposures and human epigenetics

    Science.gov (United States)

    Hou, Lifang; Zhang, Xiao; Wang, Dong; Baccarelli, Andrea

    2012-01-01

    Every year more than 13 million deaths worldwide are due to environmental pollutants, and approximately 24% of diseases are caused by environmental exposures that might be averted through preventive measures. Rapidly growing evidence has linked environmental pollutants with epigenetic variations, including changes in DNA methylation, histone modifications and microRNAs. Environ mental chemicals and epigenetic changes All of these mechanisms are likely to play important roles in disease aetiology, and their modifications due to environmental pollutants might provide further understanding of disease aetiology, as well as biomarkers reflecting exposures to environmental pollutants and/or predicting the risk of future disease. We summarize the findings on epigenetic alterations related to environmental chemical exposures, and propose mechanisms of action by means of which the exposures may cause such epigenetic changes. We discuss opportunities, challenges and future directions for future epidemiology research in environmental epigenomics. Future investigations are needed to solve methodological and practical challenges, including uncertainties about stability over time of epigenomic changes induced by the environment, tissue specificity of epigenetic alterations, validation of laboratory methods, and adaptation of bioinformatic and biostatistical methods to high-throughput epigenomics. In addition, there are numerous reports of epigenetic modifications arising following exposure to environmental toxicants, but most have not been directly linked to disease endpoints. To complete our discussion, we also briefly summarize the diseases that have been linked to environmental chemicals-related epigenetic changes. PMID:22253299

  3. Probabilistic integrated risk assessment of human exposure risk to environmental bisphenol A pollution sources.

    Science.gov (United States)

    Fu, Keng-Yen; Cheng, Yi-Hsien; Chio, Chia-Pin; Liao, Chung-Min

    2016-10-01

    Environmental bisphenol A (BPA) exposure has been linked to a variety of adverse health effects such as developmental and reproductive issues. However, establishing a clear association between BPA and the likelihood of human health is complex yet fundamentally uncertain. The purpose of this study was to assess the potential exposure risks from environmental BPA among Chinese population based on five human health outcomes, namely immune response, uterotrophic assay, cardiovascular disease (CVD), diabetes, and behavior change. We addressed these health concerns by using a stochastic integrated risk assessment approach. The BPA dose-dependent likelihood of effects was reconstructed by a series of Hill models based on animal models or epidemiological data. We developed a physiologically based pharmacokinetic (PBPK) model that allows estimation of urinary BPA concentration from external exposures. Here we showed that the daily average exposure concentrations of BPA and urinary BPA estimates were consistent with the published data. We found that BPA exposures were less likely to pose significant risks for infants (0-1 year) and adults (male and female >20 years) with human long-term BPA susceptibility in relation to multiple exposure pathways, and for informing the public of the negligible magnitude of environmental BPA pollution impacts on human health.

  4. Human Health Effects Associated with Exposure to Toxic Cyanobacteria

    Science.gov (United States)

    Reports of toxic cyanobacteria blooms are increasing worldwide. Warming and eutrophic surface water systems support the development of blooms. We examine the evidence for adverse human health effects associated with exposure to toxic blooms in drinking water, recreational water a...

  5. Knowledge of human immunodeficiency virus post-exposure ...

    African Journals Online (AJOL)

    Knowledge of human immunodeficiency virus post-exposure prophylaxis among doctors in a Nigerian tertiary hospital. ... of PEP policy in the hospital. The level of knowledge concerning the high-risk fluid and three drugs used in PEP is high.

  6. Human Health Effects Associated with Exposure to Toxic Cyanobacteria

    Science.gov (United States)

    Reports of toxic cyanobacteria blooms are increasing worldwide. Warming and eutrophic surface water systems support the development of blooms. We examine the evidence for adverse human health effects associated with exposure to toxic blooms in drinking water, recreational water a...

  7. Parabens as Urinary Biomarkers of Exposure in Humans

    OpenAIRE

    Ye, Xiaoyun; Bishop, Amber M.; Reidy, John A; Needham, Larry L.; Calafat, Antonia M

    2006-01-01

    Background Parabens appear frequently as antimicrobial preservatives in cosmetic products, in pharmaceuticals, and in food and beverage processing. In vivo and in vitro studies have revealed weak estrogenic activity of some parabens. Widespread use has raised concerns about the potential human health risks associated with paraben exposure. Objectives Assessing human exposure to parabens usually involves measuring in urine the conjugated or free species of parabens or their metabolites. In ani...

  8. Dynamics of the transcriptome response of cultured human embryonic stem cells to ionizing radiation exposure

    Energy Technology Data Exchange (ETDEWEB)

    Sokolov, Mykyta V., E-mail: sokolovm@mail.nih.gov [Nuclear Medicine Division, Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892 (United States); Panyutin, Irina V., E-mail: ipanyutinv@mail.nih.gov [Nuclear Medicine Division, Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892 (United States); Panyutin, Igor G., E-mail: igorp@helix.nih.gov [Nuclear Medicine Division, Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892 (United States); Neumann, Ronald D., E-mail: rneumann@mail.nih.gov [Nuclear Medicine Division, Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892 (United States)

    2011-05-10

    One of the key consequences of exposure of human cells to genotoxic agents is the activation of DNA damage responses (DDR). While the mechanisms underpinning DDR in fully differentiated somatic human cells have been studied extensively, molecular signaling events and pathways involved in DDR in pluripotent human embryonic stem cells (hESC) remain largely unexplored. We studied changes in the human genome-wide transcriptome of H9 hESC line following exposures to 1 Gy of gamma-radiation at 2 h and 16 h post-irradiation. Quantitative real-time PCR was performed to verify the expression data for a subset of genes. In parallel, the cell growth, DDR kinetics, and expression of pluripotency markers in irradiated hESC were monitored. The changes in gene expression in hESC after exposure to ionizing radiation (IR) are substantially different from those observed in somatic human cell lines. Gene expression patterns at 2 h post-IR showed almost an exclusively p53-dependent, predominantly pro-apoptotic, signature with a total of only 30 up-regulated genes. In contrast, the gene expression patterns at 16 h post-IR showed 354 differentially expressed genes, mostly involved in pro-survival pathways, such as increased expression of metallothioneins, ubiquitin cycle, and general metabolism signaling. Cell growth data paralleled trends in gene expression changes. DDR in hESC followed the kinetics reported for human somatic differentiated cells. The expression of pluripotency markers characteristic of undifferentiated hESC was not affected by exposure to IR during the time course of our analysis. Our data on dynamics of transcriptome response of irradiated hESCs may provide a valuable tool to screen for markers of IR exposure of human cells in their most naive state; thus unmasking the key elements of DDR; at the same time, avoiding the complexity of interpreting distinct cell type-dependent genotoxic stress responses of terminally differentiated cells.

  9. The meaning of aluminium exposure on human health and aluminium-related diseases.

    Science.gov (United States)

    Crisponi, Guido; Fanni, Daniela; Gerosa, Clara; Nemolato, Sonia; Nurchi, Valeria M; Crespo-Alonso, Miriam; Lachowicz, Joanna I; Faa, Gavino

    2013-02-01

    The aim of this review is to attempt to answer extremely important questions related to aluminium-related diseases. Starting from an overview on the main sources of aluminium exposure in everyday life, the principal aspects of aluminium metabolism in humans have been taken into consideration in an attempt to enlighten the main metabolic pathways utilised by trivalent metal ions in different organs. The second part of this review is focused on the available evidence concerning the pathogenetic consequences of aluminium overload in human health, with particular attention to its putative role in bone and neurodegenerative human diseases.

  10. Gene expression and pathway analysis of human hepatocellular carcinoma cells treated with cadmium

    Science.gov (United States)

    Cartularo, Laura; Laulicht, Freda; Sun, Hong; Kluz, Thomas; Freedman, Jonathan H.; Costa, Max

    2015-01-01

    Cadmium (Cd) is a toxic and carcinogenic metal naturally occurring in the earth’s crust. A common route of human exposure is via diet and cadmium accumulates in the liver. The effects of Cd exposure on gene expression in human hepatocellular carcinoma (HepG2) cells were examined in this study. HepG2 cells were acutely-treated with 0.1, 0.5, or 1.0 μM Cd for 24 hours; or chronically-treated with 0.01, 0.05, or 0.1 μM Cd for three weeks and gene expression analysis was performed using Affymetrix GeneChip® Human Gene 1.0 ST Arrays. Acute and chronic exposures significantly altered the expression of 333 and 181 genes, respectively. The genes most upregulated by acute exposure included several metallothioneins. Downregulated genes included the monooxygenase CYP3A7, involved in drug and lipid metabolism. In contrast, CYP3A7 was upregulated by chronic Cd exposure, as was DNAJB9, an anti-apoptotic J protein. Genes downregulated following chronic exposure included the transcriptional regulator early growth response protein 1. Ingenuity Pathway Analysis revealed that the top networks altered by acute exposure were lipid metabolism, small molecule biosynthesis, and cell morphology, organization, and development; while top networks altered by chronic exposure were organ morphology, cell cycle, cell signaling, and renal and urological diseases/cancer. Many of the dysregulated genes play important roles in cellular growth, proliferation, and apoptosis, and may be involved in carcinogenesis. In addition to gene expression changes, HepG2 cells treated with cadmium for 24 hours indicated a reduction in global levels of histone methylation and acetylation that persisted 72 hours post-treatment. PMID:26314618

  11. Repair pathways evident in human liver organ slices

    NARCIS (Netherlands)

    Vickers, Alison E. M.; Fisher, Robyn; Olinga, Peter; Dial, Sharon

    2011-01-01

    The extension of human liver slice culture viability for several days broadens the potential of this ex vivo model for characterizing pathways of organ injury and repair, and allows for the multiple dosing of compounds. Extended viability is demonstrated by continued synthesis of GSH and ATP, and ma

  12. Chronic boron exposure and human semen parameters.

    Science.gov (United States)

    Robbins, Wendie A; Xun, Lin; Jia, Juan; Kennedy, Nola; Elashoff, David A; Ping, Liu

    2010-04-01

    Boron found as borates in soil, food, and water has important industrial and medical applications. A panel reviewing NTP reproductive toxicants identified boric acid as high priority for occupational studies to determine safe versus adverse reproductive effects. To address this, we collected boron exposure/dose measures in workplace inhalable dust, dietary food/fluids, blood, semen, and urine from boron workers and two comparison worker groups (n=192) over three months and determined correlations between boron and semen parameters (total sperm count, sperm concentration, motility, morphology, DNA breakage, apoptosis and aneuploidy). Blood boron averaged 499.2 ppb for boron workers, 96.1 and 47.9 ppb for workers from high and low environmental boron areas (pBoron concentrated in seminal fluid. No significant correlations were found between blood or urine boron and adverse semen parameters. Exposures did not reach those causing adverse effects published in animal toxicology work but exceeded those previously published for boron occupational groups.

  13. Susceptibility of human populations to environmental exposure to organic contaminants.

    Science.gov (United States)

    Undeman, Emma; Brown, Trevor N; Wania, Frank; McLachlan, Michael S

    2010-08-15

    Environmental exposure to organic contaminants is a complex function of environmental conditions, food chain characteristics, and chemical properties. In this study the susceptibility of various human populations to environmental exposure to neutral organic contaminants was compared. An environmental fate model and a linked bioaccumulation model were parametrized to describe ecosystems in different climatic regions (temperate, arctic, tropical, and steppe). The human body burden resulting from constant emissions of hypothetical chemicals was estimated for each region. An exposure susceptibility index was defined as the body burden in the region of interest normalized to the burden of the same chemical in a reference human from the temperate region eating an average diet. For most persistent chemicals emitted to air, the Arctic had the highest susceptibility index (max 520). Susceptibility to exposure was largely determined by the food web properties. The properties of the physical environment only had a marked effect when air or water, not food, was the dominant source of human exposure. Shifting the mode of emission markedly changed the relative susceptibility of the ecosystems in some cases. The exposure arising from chemical use clearly varies between ecosystems, which makes an understanding of ecosystem susceptibility to exposure important for chemicals management.

  14. A comprehensive assessment of human exposure to phthalates from environmental media and food in Tianjin, China.

    Science.gov (United States)

    Ji, Yaqin; Wang, Fumei; Zhang, Leibo; Shan, Chunyan; Bai, Zhipeng; Sun, Zengrong; Liu, Lingling; Shen, Boxiong

    2014-08-30

    A total of 448 samples including foodstuffs (rice, steamed bun, vegetables, meat, poultry, fish, milk and fruits), ambient PM10, drinking water, soil, indoor PM10 and indoor dust samples from Tianjin were obtained to determine the distribution of six priority phthalates (PAEs) and assess the human exposure to them. The results indicated that DBP and DEHP were the most frequently detected PAEs in these samples. The concentrations of PAEs in environmental media were higher than those in food. We estimated the daily intake (DI) of PAEs via ingestion, inhalation and dermal absorption from five sources (food, water, air, dust and soil). Dietary intake was the main exposure source to DEP, BBP, DEHP and DOP, whereas water ingestion/absorption was the major source of exposure to DBP, DEHP and DOP. Although food and water were the overwhelmingly predominant sources of PAEs intake by Tianjin population, contaminated air was another important source of DMP, DEP and DBP contributing to up to 45% of the exposure. The results of this study will help in understanding the major pathways of human exposure to PAEs. These findings also suggest that human exposure to phthalate esters via the environment should not be overlooked.

  15. A review of human exposure to polybrominated diphenyl ethers (PBDEs) in China.

    Science.gov (United States)

    Ni, Kun; Lu, Yonglong; Wang, Tieyu; Kannan, Kurunthachalam; Gosens, Jorrit; Xu, Li; Li, Qiushuang; Wang, Lin; Liu, Shijie

    2013-11-01

    This paper reviews recent studies on human exposure to polybrominated diphenyl ethers (PBDEs) in China, with particular focus on external exposure routes (e.g. diet and dust ingestion, inhalation of air) and internal doses based on biomonitoring studies of PBDEs (e.g. breast milk, blood and hair). PBDE concentrations reported for fish samples collected from electronic waste (e-waste) recycling sites, PBDE manufacturing sites, local markets in selected cities and estuarine areas in China have been compiled. House dust has been a significant contributor to human exposure to PBDEs in many countries. This is especially true for toddlers, who are exposed to significantly higher doses of PBDEs than adults. Infants are also exposed to high levels of PBDEs via breast-feeding. The general population's inhalation exposure to PBDEs from household products is likely a less significant source into the indoor environment. In addition, the contribution of several exposure pathways to PBDEs among various age groups was analyzed. We found that house dust contributed most to the daily exposure to PBDEs for both toddlers and adults in urban areas of China. Furthermore, workers and residents in and around electronic recycling and PBDE manufacturing sites are exposed to the highest PBDE levels among all populations studied thus far. For the occupationally exposed populations, BDE209 was the dominant congener, in most cases. Rigorous pollution prevention and occupational protection measures are needed in China to mitigate potential health effects associated with PBDE exposures.

  16. Migration of Beryllium via Multiple Exposure Pathways among Work Processes in Four Different Facilities.

    Science.gov (United States)

    Armstrong, Jenna L; Day, Gregory A; Park, Ji Young; Stefaniak, Aleksandr B; Stanton, Marcia L; Deubner, David C; Kent, Michael S; Schuler, Christine R; Virji, M Abbas

    2014-01-01

    Inhalation of beryllium is associated with the development of sensitization; however, dermal exposure may also be important. The primary aim of this study was to elucidate relationships among exposure pathways in four different manufacturing and finishing facilities. Secondary aims were to identify jobs with increased levels of beryllium in air, on skin, and on surfaces; identify potential discrepancies in exposure pathways, and determine if these are related to jobs with previously identified risk. Beryllium was measured in air, on cotton gloves, and on work surfaces. Summary statistics were calculated and correlations among all three measurement types were examined at the facility and job level. Exposure ranking strategies were used to identify jobs with higher exposures. The highest air, glove, and surface measurements were observed in beryllium metal production and beryllium oxide ceramics manufacturing jobs that involved hot processes and handling powders. Two finishing and distribution facilities that handle solid alloy products had lower exposures than the primary production facilities, and there were differences observed among jobs. For all facilities combined, strong correlations were found between air-surface (rp ≥ 0.77), glove-surface (rp ≥ 0.76), and air-glove measurements (rp ≥ 0.69). In jobs where higher risk of beryllium sensitization or disease has been reported, exposure levels for all three measurement types were higher than in jobs with lower risk, though they were not the highest. Some jobs with low air concentrations had higher levels of beryllium on glove and surface wipe samples, suggesting a need to further evaluate the causes of the discrepant levels. Although such correlations provide insight on where beryllium is located throughout the workplace, they cannot identify the direction of the pathways between air, surface, or skin. Ranking strategies helped to identify jobs with the highest combined air, glove, and/or surface exposures

  17. Human-induced trophic cascades along the fecal detritus pathway.

    Directory of Open Access Journals (Sweden)

    Elizabeth Nichols

    Full Text Available Human presence and activity in tropical forest is thought to exert top-down regulation over the various 'green-world' pathways of plant-based foodwebs. However, these effects have never been explored for the 'brown-world' pathways of fecal-detritus webs. The strong effects of humans on tropical game mammals are likely to indirectly influence fecal detritivores (including Scarabaeine dung beetles, with subsequent indirect impacts on detrivore-mediated and plant-facilitating detrital processes. Across a 380-km gradient of human influence in the western Brazilian Amazon, we conducted the first landscape-level assessment of human-induced cascade effects on the fecal detritus pathway, by coupling data on human impact, game mammal and detritivore community structure, and rate measurements of a key detritus process (i.e. dung beetle-mediated secondary seed dispersal. We found evidence that human impact indirectly influences both the diversity and biomass of fecal detritivores, but not detritivore-mediated processes. Cascade strength varied across detritivore groups defined by species' traits. We found smaller-bodied dung beetles were at higher risk of local decline in areas of human presence, and that body size was a better predictor of cascade structure than fecal resource manipulation strategy. Cascade strength was also stronger in upland, unflooded forests, than in seasonally flooded forests. Our results suggest that the impact of human activity in tropical forest on fecal-detritus food web structure is mediated by both species' traits and habitat type. Further research will be required to determine the conditions under which these cascade effects influence fecal-detritus web function.

  18. A GM-CSF/IL-33 pathway facilitates allergic airway responses to sub-threshold house dust mite exposure.

    Directory of Open Access Journals (Sweden)

    Alba Llop-Guevara

    Full Text Available Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM, we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b(+ DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.

  19. Current issues in human lead exposure and regulation of lead.

    Science.gov (United States)

    Davis, J M; Elias, R W; Grant, L D

    1993-01-01

    Concern about lead as a significant public health problem has increased as epidemiological and experimental evidence has mounted regarding adverse health effects at successively lower levels of lead exposure. This concern has led to downward revision of criteria for acceptable blood lead concentrations to the 10 micrograms/dL mark now designated by EPA as a target level for regulatory development and enforcement/clean-up purposes. Much progress has been made in reducing lead exposures during the past 10-15 years, with marked declines evident both in air lead and blood lead concentrations in parallel to the phase-down of lead in gasoline and notable decreases in food lead exposure due to elimination of lead soldered cans by U.S. food processors. With the lessening of exposure from these sources, the importance of other components of multimedia exposure pathways has grown and stimulated increasing regulatory attention and abatement efforts to reduce health risks associated with lead exposure from drinking water, from lead-based paint, and from household dust and soil contaminated by deteriorating paint, smelter emissions, or various other sources. Increasing attention is also being accorded to reduction of occupational lead exposures (including those related to lead abatement activities), with particular concern for protection of men and women during their reproductive years.

  20. Cigarette smoke exposure triggers the autophagic cascade via activation of the AMPK pathway in mice.

    Science.gov (United States)

    Furlong, Hayley C; Stämpfli, Martin R; Gannon, Anne M; Foster, Warren G

    2015-10-01

    We previously demonstrated that cigarette smoke (CS) exposure decreases primordial follicle counts and induces autophagy in ovarian granulosa cells in preference to apoptosis. Therefore, the objective of this study was to investigate molecular targets underlying smoke-induced activation of the reparative autophagy pathway in the ovary. Briefly, ovarian homogenates were prepared from adult female mice exposed to mainstream CS twice daily for 8 wk, using a whole-body exposure system. A gene array revealed that CS exposure induced a greater than 2-fold significant increase in the expression of proautophagic genes Cdkn1b, Map1lc3a, Bad, and Sqstm1/p62. A significant increase in Prkaa2, Pik3c3, and Maplc31b expression, as well as a significant decrease in Akt1 and Mtor expression, was detected by quantitative PCR. The 5'-AMP-activated protein kinase catalytic subunit (AMPK) alpha1 + alpha2 and ATG7 protein expression was significantly increased, whereas AKT1, mTOR, CDKN1B/p27, and CXCR4 proteins were significantly decreased in CS exposed versus control ovaries. Up-regulation of AMPK alpha1 + alpha2, a known initiator of autophagic signaling, and ATG7 further suggests activation of the autophagy cascade. Two prosurvival factors, AKT and mTOR, were decreased in expression, an outcome that favors induction of the autophagy pathway, whereas decreased levels of CDKN1B is suggestive of cell cycle dysregulation. In summary, our data suggest that CS exposure induces ovarian follicle loss through induction of the autophagic cascade via the AMPK pathway together with inhibition of antiautophagic markers AKT and mTOR. We further postulate that toxicant-induced dysregulation of reparative autophagy is a novel pathway central to impaired follicle development and subfertility. © 2015 by the Society for the Study of Reproduction, Inc.

  1. Exposure pathway-dependent effects of the fungicide epoxiconazole on a decomposer-detritivore system.

    Science.gov (United States)

    Feckler, Alexander; Goedkoop, Willem; Zubrod, Jochen P; Schulz, Ralf; Bundschuh, Mirco

    2016-11-15

    Shredders play a central role in the breakdown of leaf material in aquatic systems. These organisms and the ecological function they provide may, however, be affected by chemical stressors either as a consequence of direct waterborne exposure or through alterations in food-quality (indirect pathway). To unravel the biological relevance of these effect pathways, we applied a 2×2-factorial test design. Leaf material was microbially colonized for 10days in absence or presence of the fungicide epoxiconazole (15μg/L) and subsequently fed to the shredder Asellus aquaticus under exposure to epoxiconazole (15μg/L) or in fungicide-free medium over a 28-day period (n=40). Both effect pathways caused alterations in asselids' food processing, physiological fitness, and growth, although not always statistically significantly: assimilation either increased or remained at a similar level relative to the control suggesting compensatory behavior of A. aquaticus to cope with the enhanced energy demand for detoxification processes and decreased nutritional quality of the food. The latter was driven by lowered microbial biomasses and the altered composition of fatty acids associated with the leaf material. Even with increased assimilation, direct and indirect effects caused decreases in the growth and lipid (fatty acid) content of A. aquaticus with relative effect sizes between 10 and 40%. Moreover, the concentrations of two essential polyunsaturated fatty acids (i.e., arachidonic acid and eicosapentaenoic acid) were non-significantly reduced (up to ~15%) in asselids. This effect was, however, independent of the exposure pathway. Although waterborne effects were generally stronger than the diet-related effects, results suggest impaired functioning of A. aquaticus via both effect pathways.

  2. Biomonitoring human exposure to environmental carcinogenic chemicals

    DEFF Research Database (Denmark)

    Farmer, P.B.; Sepai, O.; Lawrence, R.

    1996-01-01

    aberrations and sister chromatid exchanges) and mutation frequency was estimated at a number of loci including the hprt gene and genes involving in cancer development. Blood and urine samples from individuals exposed to urban pollution were collected. Populations exposed through occupational or medical......A coordinated study was carried out on the development, evaluation and application of biomonitoring procedures for populations exposed to environmental genotoxic pollutants. The procedures used involved both direct measurement of DNA or protein damage (adducts) and assessment of second biological...... for detecting carcinogen-induced damage to DNA and proteins, and subsequent biological effects. These methods were validated with the occupational exposures, which showed evidence of DNA and/or protein and/or chromosome damage in workers in a coke oven plant, garage workers exposed to diesel exhaust and workers...

  3. Cigarette smoke exposure reveals a novel role for the MEK/ERK1/2 MAPK pathway in regulation of CFTR.

    Science.gov (United States)

    Xu, Xiaohua; Balsiger, Robert; Tyrrell, Jean; Boyaka, Prosper N; Tarran, Robert; Cormet-Boyaka, Estelle

    2015-06-01

    Cystic fibrosis transmembrane conductance regulator plays a key role in maintenance of lung fluid homeostasis. Cigarette smoke decreases CFTR expression in the lung but neither the mechanisms leading to CFTR loss, nor potential ways to prevent its loss have been identified to date. The molecular mechanisms leading to down-regulation of CFTR by cigarette smoke were determined using pharmacologic inhibitors and silencing ribonucleic acids (RNAs). Using human bronchial epithelial cells, here we show that cigarette smoke induces degradation of CFTR that is attenuated by lysosomal inhibitors, but not proteasome inhibitors. Cigarette smoke can activate multiple signaling pathways in airway epithelial cells, including the MEK/Erk1/2 MAPK (MEK: mitogen-activated protein kinase/ERK kinase Erk1/2: extracellular signal-regulated kinase 1/2 MAPK: Mitogen-activated protein kinase) pathway regulating cell survival. Interestingly, pharmacological inhibition of the MEK/Erk1/2 MAPK pathway prevented the loss of plasma membrane CFTR upon cigarette smoke exposure. Similarly, decreased expression of Erk1/2 using silencing RNAs prevented the suppression of CFTR protein by cigarette smoke. Conversely, specific inhibitors of the c-Jun N-terminal kinase (JNK) or p38 MAPK pathways had no effect on CFTR decrease after cigarette smoke exposure. In addition, inhibition of the MEK/Erk1/2 MAPK pathway prevented the reduction of the airway surface liquid observed upon cigarette smoke exposure of primary human airway epithelial cells. Finally, addition of the antioxidant N-acetylcysteine inhibited activation of Erk1/2 by cigarette smoke and precluded the cigarette smoke-induced decrease of CFTR. These results show that the MEK/Erk1/2 MAPK pathway regulates plasma membrane CFTR in human airway cells. The MEK/Erk1/2 MAPK pathway should be considered as a target for strategies to maintain/restore CFTR expression in the lung of smokers. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Insulin and GH Signaling in Human Skeletal Muscle In Vivo following Exogenous GH Exposure: Impact of an Oral Glucose Load

    OpenAIRE

    Thomas Krusenstjerna-Hafstrøm; Michael Madsen; Vendelbo, Mikkel H.; Pedersen, Steen B.; Christiansen, Jens S.; Niels Møller; Niels Jessen; Jørgensen, Jens O.L.

    2011-01-01

    INTRODUCTION: GH induces acute insulin resistance in skeletal muscle in vivo, which in rodent models has been attributed to crosstalk between GH and insulin signaling pathways. Our objective was to characterize time course changes in signaling pathways for GH and insulin in human skeletal muscle in vivo following GH exposure in the presence and absence of an oral glucose load. METHODS: Eight young men were studied in a single-blinded randomized crossover design on 3 occasions: 1) after an int...

  5. Human reproductive system disturbances and pesticide exposure in Brazil

    OpenAIRE

    Sergio Koifman; Rosalina Jorge Koifman; Armando Meyer

    2002-01-01

    The observation of reproductive disturbances in humans and in the wildlife has been reported in the last decade in different countries. Exposure to different chemicals possibly acting in the endocrine system or endocrine disruptors, including pesticides, has been a hypothesis raised to explain the observed changes. This paper aimed to present results of an epidemiological ecologic study carried out to explore population data on pesticides exposure in selected Brazilian states in the eighties ...

  6. Developing human health exposure scenarios for petroleum substances under REACH

    Energy Technology Data Exchange (ETDEWEB)

    Carter, M.; De Wilde, P.; Maksimainen, K.; Margary, A.; Money, C.; Pizzella, G.; Svanehav, T.; Tsang, W.; Urbanus, J.; Rohde, A.

    2012-12-15

    This report describes the approaches that were adopted by CONCAWE to prepare the human exposure estimates in the chemical safety assessments of the REACH registration dossiers for petroleum substances based on all applicable regulatory guidance. Separate exposure estimates were developed for workers and for consumers and included inhalation and dermal routes. The complex nature of petroleum substances required various scientifically justified refinements of the regulatory guidance.

  7. Cadmium exposure pathways in a population living near a battery plant

    Energy Technology Data Exchange (ETDEWEB)

    Hellstroem, Lennart [Department of Environmental Medicine and Public Health, County Council of Kalmar, Oskarshamn (Sweden) and Division of Occupational and Environmental Medicine, Department of Molecular and Clinical Medicine, Faculty of Health Sciences, Linkoeping University, Linkoeping (Sweden)]. E-mail: lennarth@ltkalmar.se; Persson, Bodil [Department of Occupational and Environmental Medicine, University Hospital, Linkoeping (Sweden); Brudin, Lars [Department of Clinical Physiology, County Council of Kalmar, Kalmar (Sweden); Grawe, Kierstin Petersson [Toxicology Division, RD Department, National Food Administration, Uppsala (Sweden); Oborn, Ingrid [Department of Soil Sciences, Swedish University of Agricultural Sciences, Uppsala (Sweden); Jaerup, Lars [Department of Epidemiology and Public Health, Imperial College, London (United Kingdom); Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden)

    2007-02-15

    Objectives: The objectives of the present study were to assess the relative impact of different pathways of environmental cadmium (Cd) exposure and to evaluate the contribution from locally produced vegetables and root crops to the total dietary intake of Cd. Methods: Cadmium in urine was determined for 492 individuals living near a closed down battery factory in Sweden. For each individual we created an environmental exposure-index based on Cd emissions to ambient air and number of years living at various distances from the plant. This information as well as dietary data were collected via questionnaires. Samples of soil, carrots and/or potatoes were collected from 37 gardens and analysed for Cd concentration. Results: Eating homegrown vegetables/potatoes, environmental Cd-exposure-index, female gender, age above 30 years and smoking more than one pack of cigarettes daily for at least 10 years were found to be significantly associated with increased urine concentrations of Cd (UCd > 1.0 nmol/mmol creatinine). We found a statistically significant relation between Cd in urine and environmental Cd-exposure-index in persons eating homegrown vegetables/potatoes regularly. Cd concentrations in homegrown carrots, potatoes and in garden soil were highest in the area closest to the factory. Daily consumption of potatoes and vegetables cultivated in the vicinity of the closed battery factory was estimated to increase Cd intake by 18-38%. Conclusion: The present study shows that consumption of locally grown vegetables and root crops was an important exposure pathway, in subjects living near a nickel-cadmium battery plant, whereas direct exposure via ambient air was less important.

  8. Multi-pathway exposure modeling of chemicals in cosmetics with application to shampoo.

    Science.gov (United States)

    Ernstoff, Alexi S; Fantke, Peter; Csiszar, Susan A; Henderson, Andrew D; Chung, Susie; Jolliet, Olivier

    2016-01-01

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based on the chemical mass originally applied via a product, multiplied by the product intake fractions (PiF, the fraction of a chemical in a product that is taken in by exposed persons) to yield intake rates. The average PiFs for the evaluated chemicals in shampoo ranged from 3×10(-4) up to 0.3 for rapidly absorbed ingredients. Average intake rates ranged between nano- and micrograms per kilogram bodyweight per day; the order of chemical prioritization was strongly affected by the ingredient concentration in shampoo. Dermal intake and inhalation (for 20% of the evaluated chemicals) during use dominated exposure, while the skin permeation coefficient dominated the estimated uncertainties. The fraction of chemical taken in by a shampoo user often exceeded, by orders of magnitude, the aggregated fraction taken in by the population through post-use environmental emissions. Chemicals with relatively high octanol-water partitioning and/or volatility, and low molecular weight tended to have higher use stage exposure. Chemicals with low intakes during use (<1%) and subsequent high post-use emissions, however, may yield comparable intake for a member of the general population. The presented PiF based framework offers a novel and critical advancement for life cycle assessments and high-throughput exposure screening of chemicals in cosmetic products demonstrating the importance of consistent consideration of near- and far-field multi-pathway exposures.

  9. Human solvent exposure. Factors influencing the pharmacokinetics and acute toxicity

    DEFF Research Database (Denmark)

    Bælum, Jesper

    1991-01-01

    exposed to mixtures of solvents experience an increased frequency of work related irritative and neurological symptoms although the exposure has been far below the occupational exposure limits. A series of controlled human exposure studies was carried out. Different groups of persons were exposed...... to the most frequent solvent, toluene. Toluene in alveolar air and the urinary excretion of the metabolites were measured and the acute effects of toluene were assessed by the performance in a series of test of the perceptual and psychomotor functions as well as a standardized registration of annoyance...

  10. Multifaceted pathways protect human skin from UV radiation.

    Science.gov (United States)

    Natarajan, Vivek T; Ganju, Parul; Ramkumar, Amrita; Grover, Ritika; Gokhale, Rajesh S

    2014-07-01

    The recurrent interaction of skin with sunlight is an intrinsic constituent of human life, and exhibits both beneficial and detrimental effects. The apparent robust architectural framework of skin conceals remarkable mechanisms that operate at the interface between the surface and environment. In this Review, we discuss three distinct protective mechanisms and response pathways that safeguard skin from deleterious effects of ultraviolet (UV) radiation. The unique stratified epithelial architecture of human skin along with the antioxidant-response pathways constitutes the important defense mechanisms against UV radiation. The intricate pigmentary system and its intersection with the immune-system cytokine axis delicately balance tissue homeostasis. We discuss the relationship among these networks in the context of an unusual depigmenting disorder, vitiligo. The elaborate tunable mechanisms, elegant multilayered architecture and evolutionary selection pressures involved in skin and sunlight interaction makes this a compelling model to understand biological complexity.

  11. Acrolein and Human Disease: Untangling the Knotty Exposure Scenarios Accompanying Several Diverse Disorders.

    Science.gov (United States)

    Burcham, Philip C

    2017-01-17

    Acrolein is a highly toxic electrophile that participates in many diseases, yet efforts to delineate its precise mechanistic contributions to specific conditions are complicated by its wide distribution within human environments. This Perspective develops the proposal that due to its mixed status as environmental pollutant, metabolic byproduct, and endotoxicant which forms via ubiquitous pathophysiological processes, many diseases likely involve acrolein released from multiple sources. Although the category boundaries are indistinct, at least four identifiable exposure scenarios are identifiable. First, in some syndromes, such as those accompanying chronic or acute intoxication with smoke, whatever role acrolein plays in disease pathogenesis mainly traces to exogenous sources such as the combustion of tobacco or other organic matter. A second exposure category involves xenobiotics that undergo metabolism within the body to release acrolein. Still other health conditions, however, involve acrolein that forms via several endogenous pathways, some of which are activated upon intoxication with xenobiotics (i.e., Exposure Category 3), while still others accompany direct physical trauma to body tissues (Exposure Category 4). Further complicating efforts to clarify the role of endogenous acrolein in human disease is the likelihood that many such syndromes are complex phenomena that resemble "chemical mixture exposures" by involving multiple toxic substances simultaneously. This Perspective contends that while recent decades have witnessed much progress in describing the deleterious effects of acrolein at the cellular and molecular levels, more work is needed to define the contributions of different acrolein sources to "real-world" health conditions in human subjects.

  12. Occupational and environmental exposure to pesticides and cytokine pathways in chronic diseases (Review).

    Science.gov (United States)

    Gangemi, Silvia; Gofita, Eliza; Costa, Chiara; Teodoro, Michele; Briguglio, Giusi; Nikitovic, Dragana; Tzanakakis, George; Tsatsakis, Aristides M; Wilks, Martin F; Spandidos, Demetrios A; Fenga, Concettina

    2016-10-01

    Pesticides can exert numerous effects on human health as a consequence of both environmental and occupational exposures. The available knowledge base suggests that exposure to pesticides may result in detrimental reproductive changes, neurological dysfunction and several chronic disorders, which are defined by slow evolution and long-term duration. Moreover, an ever increasing amount of data have identified an association between exposure to pesticides and the harmful effects on the immune system. The real impact of alterations in humoral cytokine levels on human health, in particular in the case of chronic diseases, is still unclear. To date, studies have suggested that although exposure to pesticides can affect the immune system functionally, the development of immune disorders depends on the dose and duration of exposure to pesticides. However, many of the respective studies exhibit limitations, such as a lack of information on exposure levels, differences in the pesticide administration procedures, difficulty in characterizing a prognostic significance to the weak modifications often observed and the interpretation of obtained results. The main challenge is not just to understand the role of individual pesticides and their combinations, but also to determine the manner and the duration of exposure, as the toxic effects on the immune system cannot be separated from these considerations. There is a clear need for more well‑designed and standardized epidemiological and experimental studies to recognize the exact association between exposure levels and toxic effects and to identify useful biomarkers of exposure. This review focuses on and critically discusses the immunotoxicity of pesticides and the impact of cytokine levels on health, focusing on the development of several chronic diseases.

  13. Human exposure to endocrine disruptors and breast milk.

    Science.gov (United States)

    Stefanidou, M; Maravelias, C; Spiliopoulou, C

    2009-09-01

    Endocrine system is one of the most sensitive communication networks of the human body which influences all aspects of human health and well-being, including reproductive potential, cognitive functions, thyroid and metabolism, digestion and hormonal balance. In recent years basic laboratory research has been focused on the potential relationship between environmental contaminants and cellular endocrine function. Environmental contaminants are ubiquitous in the environment, alter endocrine physiology and produce endocrine disruption without acting as classic toxicants. These endocrine disruptors (EDCs) are lipophilic and stored for long periods of time in the adipose tissue. Maternal exposure to EDCs during pregnancy and lactation has as a result the exposure of the fetus and neonate through placenta and breast milk. It has been recognized that human milk is the best natural food for neonates providing immunologic, developmental and practical advantages throughout childhood. However, contamination of human milk by the presence of environmental toxicants is widespread through the past decades due to inadequately controlled pollution. Persistent pesticides, chemical solvents and others tend to invade slowly the environment, to bioaccumulate in the food chain and to have long half-lives in animals and humans. During the past fifteen years, the scientific interest has been focused on xenoestrogens, i.e.,environmental chemicals with estrogen disrupting activity. Certain adverse health and reproductive outcomes are attributed to these chemicals in wildlife, in laboratory animals, as well as in humans. Although most toxic agents are hazardous in high doses, the human health risks associated with EDCs concern exposure to low doses. The human health risks that may be associated with these low-level but constant exposures are still largely unknown and highly controversial. In this paper, we review available data on environmental chemicals present in breast milk that may

  14. National Surveillance of Occupational Exposure to the Human Immunodeficiency Virus

    Directory of Open Access Journals (Sweden)

    Maura Ricketts

    1992-01-01

    Full Text Available In September 1985, a prospective study was initiated to monitor the occurrence of occupational exposures to human immunodeficiency virus (HIV-infected blood and body fluids in Canada. This program was coordinated by the Federal Centre for acquired immune deficiency syndrome (AIDS (now the Division of HIV/AIDS Epidemiology at the Laboratory Centre for Disease Control. The objective was to determine the risk to workers of acquiring HIV infection as a result of exposure to HIV-infected blood and other body fluids. To be eligible, a worker must have sustained a documented parenteral, mucous membrane or skin contact exposure to blood or body fluids from an HIV-infected person. A baseline specimen was collected within a week of the exposure and then at six weeks, 12 weeks, six months and 12 months. Information concerning the type of exposure, precautions used and post exposure treatment was submitted to the Federal Centre for AIDS on standard data collection forms. All information was anonymous, identified only by a code number. Guidelines for counselling an exposed employee were provided with enrollment material. As of July 29, 1991, 414 employees have been included in the study. Two hundred and thirty-seven of the 414 exposures (57% were needlestick injuries of which 167 (70% were sustained by nurses. Other exposures consisted of open wound contamination, eye splashes, scalpel wounds and skin contact with blood and body fluids. To date, there have been no seroconversions among workers enrolled in the surveillance program.

  15. Controlled human exposures to ambient pollutant particles in susceptible populations

    Directory of Open Access Journals (Sweden)

    Ghio Andrew J

    2009-07-01

    Full Text Available Abstract Epidemiologic studies have established an association between exposures to air pollution particles and human mortality and morbidity at concentrations of particles currently found in major metropolitan areas. The adverse effects of pollution particles are most prominent in susceptible subjects, including the elderly and patients with cardiopulmonary diseases. Controlled human exposure studies have been used to confirm the causal relationship between pollution particle exposure and adverse health effects. Earlier studies enrolled mostly young healthy subjects and have largely confirmed the capability of particles to cause adverse health effects shown in epidemiological studies. In the last few years, more studies involving susceptible populations have been published. These recent studies in susceptible populations, however, have shown that the adverse responses to particles appear diminished in these susceptible subjects compared to those in healthy subjects. The present paper reviewed and compared control human exposure studies to particles and sought to explain the "unexpected" response to particle exposure in these susceptible populations and make recommendations for future studies. We found that the causes for the discrepant results are likely multifactorial. Factors such as medications, the disease itself, genetic susceptibility, subject selection bias that is intrinsic to many controlled exposure studies and nonspecificity of study endpoints may explain part of the results. Future controlled exposure studies should select endpoints that are more closely related to the pathogenesis of the disease and reflect the severity of particle-induced health effects in the specific populations under investigation. Future studies should also attempt to control for medications and genetic susceptibility. Using a different study design, such as exposing subjects to filtered air and ambient levels of particles, and assessing the improvement in

  16. [Natriuretic peptides: a new lipolytic pathway in human fat cells].

    Science.gov (United States)

    Sengenes, Coralie; Moro, Cédric; Galitzky, Jean; Berlan, Michel; Lafontan, Max

    2005-12-01

    Human fat cell lipolysis was considered until recently to be an exclusive cAMP/protein-kinase A (PKA)-regulated metabolic pathway under the control of catecholamines and insulin. Moreover, exercise-induced lipid mobilization in humans was considered to mainly depend on catecholamine action and interplay between fat cell beta- and alpha2-adrenergic receptors controlling adenylyl cyclase activity and cAMP production. We have recently demonstrated that natriuretic peptides stimulate lipolysis and contribute to the regulation of lipid mobilization in humans. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) stimulate lipolysis in human isolated fat cells. Activation of the adipocyte plasma membrane type A guanylyl cyclase receptor (NPR-A), increase in intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) levels and activation of hormone-sensitive lipase mediate the action of ANP. ANP does not modulate cAMP production and PKA activity. Increment of cGMP induces the phosphorylation of hormone-sensitive lipase and perilipin A via the activation of a cGMP dependent protein kinase-I (cGK-I). Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans. Physiological relevance of the ANP-dependent pathway was demonstrated in young subjects performing physical exercise. ANP plays a role in conjunction with catecholamines in the control of exercise-induced lipid mobilization. This pathway becomes of major importance when subjects are submitted to chronic treatment with a beta-blocker. Oral beta-adrenoceptor blockade suppresses the beta-adrenergic component of catecholamine action in fat cells and potentiates exercise-induced ANP release by the heart. These findings may have several implications whenever natriuretic peptide secretion is altered such as in subjects with left ventricular dysfunction, congestive heart failure and obesity.

  17. Comparative expression pathway analysis of human and canine mammary tumors

    Directory of Open Access Journals (Sweden)

    Marconato Laura

    2009-03-01

    Full Text Available Abstract Background Spontaneous tumors in dog have been demonstrated to share many features with their human counterparts, including relevant molecular targets, histological appearance, genetics, biological behavior and response to conventional treatments. Mammary tumors in dog therefore provide an attractive alternative to more classical mouse models, such as transgenics or xenografts, where the tumour is artificially induced. To assess the extent to which dog tumors represent clinically significant human phenotypes, we performed the first genome-wide comparative analysis of transcriptional changes occurring in mammary tumors of the two species, with particular focus on the molecular pathways involved. Results We analyzed human and dog gene expression data derived from both tumor and normal mammary samples. By analyzing the expression levels of about ten thousand dog/human orthologous genes we observed a significant overlap of genes deregulated in the mammary tumor samples, as compared to their normal counterparts. Pathway analysis of gene expression data revealed a great degree of similarity in the perturbation of many cancer-related pathways, including the 'PI3K/AKT', 'KRAS', 'PTEN', 'WNT-beta catenin' and 'MAPK cascade'. Moreover, we show that the transcriptional relationships between different gene signatures observed in human breast cancer are largely maintained in the canine model, suggesting a close interspecies similarity in the network of cancer signalling circuitries. Conclusion Our data confirm and further strengthen the value of the canine mammary cancer model and open up new perspectives for the evaluation of novel cancer therapeutics and the development of prognostic and diagnostic biomarkers to be used in clinical studies.

  18. Integrating population dynamics into mapping human exposure to seismic hazard

    Directory of Open Access Journals (Sweden)

    S. Freire

    2012-11-01

    Full Text Available Disaster risk is not fully characterized without taking into account vulnerability and population exposure. Assessment of earthquake risk in urban areas would benefit from considering the variation of population distribution at more detailed spatial and temporal scales, and from a more explicit integration of this improved demographic data with existing seismic hazard maps. In the present work, "intelligent" dasymetric mapping is used to model population dynamics at high spatial resolution in order to benefit the analysis of spatio-temporal exposure to earthquake hazard in a metropolitan area. These night- and daytime-specific population densities are then classified and combined with seismic intensity levels to derive new spatially-explicit four-class-composite maps of human exposure. The presented approach enables a more thorough assessment of population exposure to earthquake hazard. Results show that there are significantly more people potentially at risk in the daytime period, demonstrating the shifting nature of population exposure in the daily cycle and the need to move beyond conventional residence-based demographic data sources to improve risk analyses. The proposed fine-scale maps of human exposure to seismic intensity are mainly aimed at benefiting visualization and communication of earthquake risk, but can be valuable in all phases of the disaster management process where knowledge of population densities is relevant for decision-making.

  19. Air exchange rates and alternative vapor entry pathways to inform vapor intrusion exposure risk assessments.

    Science.gov (United States)

    Reichman, Rivka; Roghani, Mohammadyousef; Willett, Evan J; Shirazi, Elham; Pennell, Kelly G

    2016-11-12

    Vapor intrusion (VI) is a term used to describe indoor air (IA) contamination that occurs due to the migration of chemical vapors in the soil and groundwater. The overall vapor transport process depends on several factors such as contaminant source characteristics, subsurface conditions, building characteristics, and general site conditions. However, the classic VI conceptual model does not adequately account for the physics of airflow around and inside a building and does not account for chemical emissions from alternative "preferential" pathways (e.g. sewers and other utility connections) into IA spaces. This mini-review provides information about recent research related to building air exchange rates (AERs) and alternative pathways to improve the accuracy of VI exposure risk assessment practices. First, results from a recently published AER study for residential homes across the United States (US) are presented and compared to AERs recommended by the US Environmental Protection Agency (USEPA). The comparison shows considerable differences in AERs when season, location, building age, and other factors are considered. These differences could directly impact VI assessments by influencing IA concentration measurements. Second, a conceptual model for sewer gas entry into buildings is presented and a summary of published field studies is reported. The results of the field studies suggest that alternative pathways for vapors to enter indoor spaces warrant consideration. Ultimately, the information presented in this mini-review can be incorporated into a multiple-lines-of-evidence approach for assessing site-specific VI exposure risks.

  20. In Vitro Manganese Exposure Disrupts MAPK Signaling Pathways in Striatal and Hippocampal Slices from Immature Rats

    Directory of Open Access Journals (Sweden)

    Tanara Vieira Peres

    2013-01-01

    Full Text Available The molecular mechanisms mediating manganese (Mn-induced neurotoxicity, particularly in the immature central nervous system, have yet to be completely understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs and tyrosine hydroxylase (TH could represent potential targets of Mn in striatal and hippocampal slices obtained from immature rats (14 days old. The aim of this study was to evaluate if the MAPK pathways are modulated after subtoxic Mn exposure, which do not significantly affect cell viability. The concentrations of manganese chloride (MnCl2; 10–1,000 μM caused no change in cell viability in slices exposed for 3 or 6 hours. However, Mn exposure significantly increased extracellular signal-regulated kinase (ERK 1/2, as well as c-Jun N-terminal kinase (JNK 1/2/3 phosphorylation at both 3 and 6 hours incubations, in both brain structures. Furthermore, Mn exposure did not change the total content or phosphorylation of TH at the serine 40 site in striatal slices. Thus, Mn at concentrations that do not disrupt cell viability causes activation of MAPKs (ERK1/2 and JNK1/2/3 in immature hippocampal and striatal slices. These findings suggest that altered intracellular MAPKs signaling pathways may represent an early event concerning the effects of Mn in the immature brain.

  1. In Vitro Manganese Exposure Disrupts MAPK Signaling Pathways in Striatal and Hippocampal Slices from Immature Rats

    Science.gov (United States)

    Peres, Tanara Vieira; Pedro, Daniela Zótico; de Cordova, Fabiano Mendes; Lopes, Mark William; Gonçalves, Filipe Marques; Mendes-de-Aguiar, Cláudia Beatriz Nedel; Walz, Roger; Farina, Marcelo; Aschner, Michael; Leal, Rodrigo Bainy

    2013-01-01

    The molecular mechanisms mediating manganese (Mn)-induced neurotoxicity, particularly in the immature central nervous system, have yet to be completely understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs) and tyrosine hydroxylase (TH) could represent potential targets of Mn in striatal and hippocampal slices obtained from immature rats (14 days old). The aim of this study was to evaluate if the MAPK pathways are modulated after subtoxic Mn exposure, which do not significantly affect cell viability. The concentrations of manganese chloride (MnCl2; 10–1,000 μM) caused no change in cell viability in slices exposed for 3 or 6 hours. However, Mn exposure significantly increased extracellular signal-regulated kinase (ERK) 1/2, as well as c-Jun N-terminal kinase (JNK) 1/2/3 phosphorylation at both 3 and 6 hours incubations, in both brain structures. Furthermore, Mn exposure did not change the total content or phosphorylation of TH at the serine 40 site in striatal slices. Thus, Mn at concentrations that do not disrupt cell viability causes activation of MAPKs (ERK1/2 and JNK1/2/3) in immature hippocampal and striatal slices. These findings suggest that altered intracellular MAPKs signaling pathways may represent an early event concerning the effects of Mn in the immature brain. PMID:24324973

  2. Asymmetry of White Matter Pathways in Developing Human Brains.

    Science.gov (United States)

    Song, Jae W; Mitchell, Paul D; Kolasinski, James; Ellen Grant, P; Galaburda, Albert M; Takahashi, Emi

    2015-09-01

    Little is known about the emergence of structural asymmetry of white matter tracts during early brain development. We examined whether and when asymmetry in diffusion parameters of limbic and association white matter pathways emerged in humans in 23 brains ranging from 15 gestational weeks (GW) up to 3 years of age (11 ex vivo and 12 in vivo cases) using high-angular resolution diffusion imaging tractography. Age-related development of laterality was not observed in a limbic connectional pathway (cingulum bundle or fornix). Among the studied cortico-cortical association pathways (inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus, and arcuate fasciculus), only the ILF showed development of age-related laterality emerging as early as the second trimester. Comparisons of ages older and younger than 40 GW revealed a leftward asymmetry in the cingulum bundle volume and a rightward asymmetry in apparent diffusion coefficient and leftward asymmetry in fractional anisotropy in the ILF in ages older than 40 GW. These results suggest that morphometric asymmetry in cortical areas precedes the emergence of white matter pathway asymmetry. Future correlative studies will investigate whether such asymmetry is anatomically/genetically driven or associated with functional stimulation.

  3. Human disease resulting from exposure to electromagnetic fields.

    Science.gov (United States)

    Carpenter, David O

    2013-01-01

    Electromagnetic fields (EMFs) include everything from cosmic rays through visible light to the electric and magnetic fields associated with electricity. While the high frequency fields have sufficient energy to cause cancer, the question of whether there are human health hazards associated with communication radiofrequency (RF) EMFs and those associated with use of electricity remains controversial. The issue is more important than ever given the rapid increase in the use of cell phones and other wireless devices. This review summarizes the evidence stating that excessive exposure to magnetic fields from power lines and other sources of electric current increases the risk of development of some cancers and neurodegenerative diseases, and that excessive exposure to RF radiation increases risk of cancer, male infertility, and neurobehavioral abnormalities. The relative impact of various sources of exposure, the great range of standards for EMF exposure, and the costs of doing nothing are also discussed.

  4. Human convective boundary layer and its impact on personal exposure

    DEFF Research Database (Denmark)

    Licina, Dusan

    People spend most of their time indoors and they are constantly exposed to pollution that affects their health, comfort and productivity. Due to strong economic and environmental pressures to reduce building energy consumption, low air velocity design is gaining popularity; hence buoyancy flows...... differences in pollution concentration mean that personal exposure, rather than average space concentration, determines the risk of elevated exposure. Current room air distribution design practice does not take into account the air movement induced by the thermal flows from occupants, which often results...... in inaccurate exposure prediction. This highlights the importance of a detailed understanding of the complex air movements that take place in the vicinity of the human body and their impact on personal exposure. The two objectives of the present work are: (i) to examine the extent to which the room air...

  5. Developmental exposure to estrogen alters differentiation and epigenetic programming in a human fetal prostate xenograft model.

    Directory of Open Access Journals (Sweden)

    Camelia M Saffarini

    Full Text Available Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure.

  6. Human reproductive system disturbances and pesticide exposure in Brazil

    Directory of Open Access Journals (Sweden)

    Koifman Sergio

    2002-01-01

    Full Text Available The observation of reproductive disturbances in humans and in the wildlife has been reported in the last decade in different countries. Exposure to different chemicals possibly acting in the endocrine system or endocrine disruptors, including pesticides, has been a hypothesis raised to explain the observed changes. This paper aimed to present results of an epidemiological ecologic study carried out to explore population data on pesticides exposure in selected Brazilian states in the eighties and human reproductive outcomes in the nineties. Pearson correlation coefficients were ascertained between available data pesticides sales in eleven states in Brazil in 1985 and selected further reproductive outcomes or their surrogates. Moderate to high correlations were observed to infertility, testis, breast, prostate and ovarian cancer mortality. Despite the restrains of ecologic studies to establish cause-effect relationships, the observed results are in agreement with evidence supporting a possible association between pesticides exposure and the analyzed reproductive outcomes.

  7. Assessing Sources of Human Methylmercury Exposure Using Stable Mercury Isotopes

    DEFF Research Database (Denmark)

    Li, Miling; Sherman, Laura S; Blum, Joel D

    2014-01-01

    Seafood consumption is the primary route of methylmercury (MeHg) exposure for most populations. Inherent uncertainties in dietary survey data point to the need for an empirical tool to confirm exposure sources. We therefore explore the utility of Hg stable isotope ratios in human hair as a new...... method for discerning MeHg exposure sources. We characterized Hg isotope fractionation between humans and their diets using hair samples from Faroese whalers exposed to MeHg predominantly from pilot whales. We observed an increase of 1.75‰ in δ(202)Hg values between pilot whale muscle tissue and Faroese...... whalers' hair but no mass-independent fractionation. We found a similar offset in δ(202)Hg between consumed seafood and hair samples from Gulf of Mexico recreational anglers who are exposed to lower levels of MeHg from a variety of seafood sources. An isotope mixing model was used to estimate individual...

  8. Traditional goat husbandry may substantially contribute to human toxoplasmosis exposure

    Science.gov (United States)

    Raising goats in settings that are highly contaminated with oocysts of Toxoplasma gondii may contribute significantly to human exposure to this zoonotic parasite. Increasing consumption of young goats in Romania, where goats are typically reared in backyards that are also home to cats (the definitiv...

  9. Biocides Steering Group on human exposure assessment: A preliminary report

    NARCIS (Netherlands)

    Hemmen, J.J. van

    1999-01-01

    In a project granted by DG XI of the European Commission, it is attempted to collate experimental and theoretical data on human (workers and consumers) exposure assessment to biocidal products, and to outline the methodology for sampling and measurement. On the basis of the available evidence, appro

  10. Early Brain Response to Low-Dose Radiation Exposure Involves Molecular Networks and Pathways Associated with Cognitive Functions, Advanced Aging and Alzheimer's Disease

    Energy Technology Data Exchange (ETDEWEB)

    Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J.

    2008-06-06

    Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated network (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.

  11. Organization of the human mitochondrial hydrogen sulfide oxidation pathway.

    Science.gov (United States)

    Libiad, Marouane; Yadav, Pramod Kumar; Vitvitsky, Victor; Martinov, Michael; Banerjee, Ruma

    2014-11-07

    Sulfide oxidation is expected to play an important role in cellular switching between low steady-state intracellular hydrogen sulfide levels and the higher concentrations where the physiological effects are elicited. Yet despite its significance, fundamental questions regarding how the sulfide oxidation pathway is wired remain unanswered, and competing proposals exist that diverge at the very first step catalyzed by sulfide quinone oxidoreductase (SQR). We demonstrate that, in addition to sulfite, glutathione functions as a persulfide acceptor for human SQR and that rhodanese preferentially synthesizes rather than utilizes thiosulfate. The kinetic behavior of these enzymes provides compelling evidence for the flow of sulfide via SQR to glutathione persulfide, which is then partitioned to thiosulfate or sulfite. Kinetic simulations at physiologically relevant metabolite concentrations provide additional support for the organizational logic of the sulfide oxidation pathway in which glutathione persulfide is the first intermediate formed.

  12. Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

    Energy Technology Data Exchange (ETDEWEB)

    Ovacik, Meric A. [Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854 (United States); Sen, Banalata [National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC 27709 (United States); Euling, Susan Y. [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460 (United States); Gaido, Kevin W. [U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation, Division of Human Food Safety, Rockville, MD 20855 (United States); Ierapetritou, Marianthi G. [Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854 (United States); Androulakis, Ioannis P., E-mail: yannis@rci.rutgers.edu [Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854 (United States); Biomedical Engineering Department, Rutgers University, NJ 08854 (United States)

    2013-09-15

    Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significance analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data.

  13. Assessment of human exposure effects of nitrous acid

    Energy Technology Data Exchange (ETDEWEB)

    Rasmussen, T.R.; Kjaergaard, S.K. (University of Aarhus. Institute of Environmental and Occupational Medicine (Denmark)); Brauer, M. (Harvard School of Public Health. Department of Environmental Health, Exposure Assessment and Engineering Program (United States))

    1993-01-01

    The study aimed at an estimation of the relative contribution of nitrous acid to measurable human exposure effects in relation to indoor environments with unvented gas combustion. Fifteen medically examined totally healthy non-smoker adults aged between 22 and 57 years were exposed in a double-blind, balanced design (3x3 latin square) to clean air and nitrous acid (HONO) concentration in an empty 74 m[sup 3] climate chamber. 3 teams of 5 subjects each were randomly exposed and the latin square was selected at random. Each exposure period was 3.5 hours and preceded by a 1 hour base-line pre-exposure measurement period. After 1 hr 40 minutes the subjects exercised for ten minutes on bicycle ergometers in order to increase the uptake of HONO by increasing ventilatory rate 3-4 fold. Workloads were calculated individually and ranged from 21800-34600 kpm/h. During the 10 minutes the test subjects were mouth-breathing to encourage deeper penetration of nitrous acid in the respiratory system so as to induce a mild cooling which would increase their responsiveness to irritants. The amount of deliverable H[sup +] was estimated at 16.350 nmoles with exposure to 395 ppb HONO with subjects breathing at the rate of 5 L min[sup -1]. It was assumed that HONO is efficiently absorbed into the respiratory system. Details are given of the results. Findings were highly variable, largely negative effects of exposure to nitrous acid which appear similiar to results seen in nitrogen dioxide exposure studies. It is concluded to be unlikely that HONO exposures alone can be responsible for exposure misclassification in NO[sub 2] exposure studies. (AB) (52 refs.).

  14. Assessment of human exposure effects of nitrous acid

    Energy Technology Data Exchange (ETDEWEB)

    Rasmussen, T.R.; Kjaergaard, S.K. [University of Aarhus. Institute of Environmental and Occupational Medicine (Denmark); Brauer, M. [Harvard School of Public Health. Department of Environmental Health, Exposure Assessment and Engineering Program (United States)

    1993-01-01

    The study aimed at an estimation of the relative contribution of nitrous acid to measurable human exposure effects in relation to indoor environments with unvented gas combustion. Fifteen medically examined totally healthy non-smoker adults aged between 22 and 57 years were exposed in a double-blind, balanced design (3x3 latin square) to clean air and nitrous acid (HONO) concentration in an empty 74 m{sup 3} climate chamber. 3 teams of 5 subjects each were randomly exposed and the latin square was selected at random. Each exposure period was 3.5 hours and preceded by a 1 hour base-line pre-exposure measurement period. After 1 hr 40 minutes the subjects exercised for ten minutes on bicycle ergometers in order to increase the uptake of HONO by increasing ventilatory rate 3-4 fold. Workloads were calculated individually and ranged from 21800-34600 kpm/h. During the 10 minutes the test subjects were mouth-breathing to encourage deeper penetration of nitrous acid in the respiratory system so as to induce a mild cooling which would increase their responsiveness to irritants. The amount of deliverable H{sup +} was estimated at 16.350 nmoles with exposure to 395 ppb HONO with subjects breathing at the rate of 5 L min{sup -1}. It was assumed that HONO is efficiently absorbed into the respiratory system. Details are given of the results. Findings were highly variable, largely negative effects of exposure to nitrous acid which appear similiar to results seen in nitrogen dioxide exposure studies. It is concluded to be unlikely that HONO exposures alone can be responsible for exposure misclassification in NO{sub 2} exposure studies. (AB) (52 refs.).

  15. Developmental pathways from prenatal marijuana exposure to Cannabis Use Disorder in young adulthood.

    Science.gov (United States)

    Sonon, Kristen; Richardson, Gale A; Cornelius, Jack; Kim, Kevin H; Day, Nancy L

    Earlier studies reported an association between prenatal marijuana exposure (PME) and cognitive and behavioral problems in the offspring. A recent publication demonstrated the relation between PME and offspring marijuana use at age 22. There are no reports of the association between PME and Cannabis Use Disorder (CUD) at 22years, the age when use of marijuana and CUD peak. Subjects are from the Maternal Health Practices and Child Development Study, a longitudinal study of PME and other exposures during pregnancy. The cohort of mothers and their offspring has been followed since the fourth prenatal month through 22years of age. A path analysis was conducted on 590 mother-child pairs, representing 77% of the birth cohort, to examine potential pathways from PME to CUD in offspring at 22years of age. There is no direct effect of PME on CUD. There are, however, two indirect pathways from PME to CUD. In the first, the pathway from PME to CUD goes through offspring early age of marijuana onset. In the second, offspring depression at age 10 and early age of marijuana onset predict CUD. Although there is no direct effect of PME on CUD, there are significant indirect pathways from PME to CUD that affect the rate of CUD in the population. Thus, PME, offspring depression, and an early age of marijuana initiation, are significant points for intervention. As marijuana is legalized in more states, the rates of marijuana use will increase significantly, including during pregnancy, and the consequences of the association between PME and CUD will become even more significant from a public health perspective. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Toxicogenomic studies of human neural cells following exposure to organophosphorus chemical warfare nerve agent VX.

    Science.gov (United States)

    Gao, Xiugong; Lin, Hsiuling; Ray, Radharaman; Ray, Prabhati

    2013-05-01

    Organophosphorus (OP) compounds represent an important group of chemical warfare nerve agents that remains a significant and constant military and civilian threat. OP compounds are considered acting primarily via cholinergic pathways by binding irreversibly to acetylcholinesterase, an important regulator of the neurotransmitter acetylcholine. Many studies over the past years have suggested that other mechanisms of OP toxicity exist, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. Here we performed a microarray study in which cultured human neural cells were exposed to 0.1 or 10 μM of VX for 1 h. Global gene expression changes were analyzed 6, 24, and 72 h post exposure. Functional annotation and pathway analysis of the differentially expressed genes has revealed many genes, networks and canonical pathways that are related to nervous system development and function, or to neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In particular, the neuregulin pathway impacted by VX exposure has important implications in many nervous system diseases including schizophrenia. These results provide useful information valuable in developing suitable antidotes for more effective prevention and treatment of, as well as in developing biomarkers for, VX-induced chronic neurotoxicity.

  17. Phthalate exposure through different pathways and allergic sensitization in preschool children with asthma, allergic rhinoconjunctivitis and atopic dermatitis

    DEFF Research Database (Denmark)

    Bekö, Gabriel; Callesen, Michael; Weschler, Charles J.

    2015-01-01

    of the associations depended on accounting for a child's exposure in more than one environment (i.e., daycare facility as well as home). Significant associations were not observed between phthalate metabolites in urine, which reflected exposure from diet as well as indoor pathways, and allergic sensitization. (C...

  18. Natriuretic peptides: a new lipolytic pathway in human adipocytes.

    Science.gov (United States)

    Sengenès, C; Berlan, M; De Glisezinski, I; Lafontan, M; Galitzky, J

    2000-07-01

    Atrial natriuretic peptide (ANP) receptors have been described on rodent adipocytes and expression of their mRNA is found in human adipose tissue. However, no biological effects associated with the stimulation of these receptors have been reported in this tissue. A putative lipolytic effect of natriuretic peptides was investigated in human adipose tissue. On isolated fat cells, ANP and brain natriuretic peptide (BNP) stimulated lipolysis as much as isoproterenol, a nonselective beta-adrenergic receptor agonist, whereas C-type natriuretic peptide (CNP) had the lowest lipolytic effect. In situ microdialysis experiments confirmed the potent lipolytic effect of ANP in abdominal s.c. adipose tissue of healthy subjects. A high level of ANP binding sites was identified in human adipocytes. The potency order defined in lipolysis (ANP > BNP > CNP) and the ANP-induced cGMP production sustained the presence of type A natriuretic peptide receptor in human fat cells. Activation or inhibition of cGMP-inhibited phosphodiesterase (PDE-3B) (using insulin and OPC 3911, respectively) did not modify ANP-induced lipolysis whereas the isoproterenol effect was decreased or increased. Moreover, inhibition of adenylyl cyclase activity (using a mixture of alpha(2)-adrenergic and adenosine A1 agonists receptors) did not change ANP- but suppressed isoproterenol-induced lipolysis. The noninvolvement of the PDE-3B was finally confirmed by measuring its activity under ANP stimulation. Thus, we demonstrate that natriuretic peptides are a new pathway controlling human adipose tissue lipolysis operating via a cGMP-dependent pathway that does not involve PDE-3B inhibition and cAMP production.

  19. Human Bronchial Epithelial Cell Response to Heavy Particle Exposure

    Science.gov (United States)

    Story, Michael; Ding, Liang-Hao; Minna, John; Park, Seong-mi; Peyton, Michael; Larsen, Jill

    2012-07-01

    A battery of non-oncogenically immortalized human bronchial epithelial cells (HBECs) are being used to examine the molecular changes that lead to lung carcinogenesis after exposure to heavy particles found in the free space environment. The goal is to ultimately identify biomarkers of radioresponse that can be used for prediction of carcinogenic risk for fatal lung cancer. Our initial studies have focused on the cell line HBEC3 KT and the isogenic variant HBEC3 KTR53, which overexpresses the RASv12 mutant and where p53 has been knocked down by shRNA, and is considered to be a more oncogenically progressed variant. We have previously described the response of HBEC3 KT at the cellular and molecular level, however, the focus here is on the rate of cellular transformation after HZE radiation exposure and the molecular changes in transformed cells. When comparing the two cell lines we find that there is a maximum rate of cellular transformation at 0.25 Gy when cells are exposed to 1 GeV Fe particles, and, for the HBEC3 KTR53 there are multiple pathways upregulated that promote anchorage independent growth including the mTOR pathway, the TGF-1 pathway, RhoA signaling and the ERK/MAPK pathway as early as 2 weeks after radiation. This does not occur in the HBEC3 KT cell line. Transformed HBEC3 KT cells do not show any morphologic or phenotypic changes when grown as cell cultures. HBEC3 KTR53 cells on the other hand show substantial changes in morphology from a cobblestone epithelial appearance to a mesenchymal appearance with a lack of contact inhibition. This epithelial to mesenchymal change in morphology is accompanied by the expression of vimentin and a reduction in the expression of E-cadherin, which are hallmarks of epithelial to mesenchymal transition. Interestingly, for HBEC3 KT transformed cells there are no mutations in the p53 gene, 2 of 15 clones were found to be heterozygous for the RASV12 mutation, and 3 of 15 clones expressed high levels of BigH3, a TGFB

  20. Three dimensional visualisation of human facial exposure to solar ultraviolet.

    Science.gov (United States)

    Downs, Nathan; Parisi, Alfio

    2007-01-01

    A three dimensional computer model of the human face has been developed to represent solar ultraviolet exposures recorded by dosimeter measurements on a manikin headform under low cloud conditions and various solar zenith angles. Additionally, polysulfone dosimeters have been successfully miniaturised to provide the detailed measurements required across the face. The headform used in this research was scanned at 709 individual locations to make a wireframe mesh consisting of 18 vertical contours and 49 horizontal contours covering half the manikin's frontal facial topography. Additionally, the back of the headform and neck have also been scanned at 576 locations. Each scanned location has been used as a viable dosimeter position on the headform and represents a grid intersection point on the developed computer wireframe. A series of exposures recorded by dosimeters have been translated into three dimensional exposure ratio maps, representing ambient solar ultraviolet exposure. High dosimeter density has allowed for the development of individual topographic contour models which take into account complex variation in the face and improve upon previously employed techniques which utilise fewer dosimeters to interpolate exposure across facial contours. Exposure ratios for solar zenith angle ranges of 0 degrees -30 degrees, 30 degrees -50 degrees, and 50 degrees -80 degrees have been developed.

  1. Asbestos exposure increases human bronchial epithelial cell fibrinolytic activity.

    Science.gov (United States)

    Gross, T J; Cobb, S M; Gruenert, D C; Peterson, M W

    1993-03-01

    Chronic exposure to asbestos fibers results in fibrotic lung disease. The distal pulmonary epithelium is an early target of asbestos-mediated injury. Local plasmin activity may be important in modulating endoluminal inflammatory responses in the lung. We studied the effects of asbestos exposure on cell-mediated plasma clot lysis as a marker of pericellular plasminogen activation. Exposing human bronchial epithelial (HBE) cells to 100 micrograms/ml of asbestos fibers for 24 h resulted in increased plasma clot lysis. Fibrinolytic activity was augmented in a dose-dependent fashion, was not due to secreted protease, and occurred only when there was direct contact between the plasma clot and the epithelial monolayer. Further analysis showed that asbestos exposure increased HBE cell-associated urokinase-type plasminogen activator (uPA) activity in a time-dependent manner. The increased cell-associated PA activity could be removed by acid washing. The increase in PA activity following asbestos exposure required new protein synthesis because it was abrogated by treatment with either cycloheximide or actinomycin D. Therefore, asbestos exposure increases epithelial-mediated fibrinolysis by augmenting expression of uPA activity at the cell surface by mechanisms that require new RNA and protein synthesis. These observations suggest a novel mechanism whereby exposure of the distal epithelium to inhaled particulates may result in a chronic inflammatory response that culminates in the development of fibrotic lung disease.

  2. Parabens as Urinary Biomarkers of Exposure in Humans

    Science.gov (United States)

    Ye, Xiaoyun; Bishop, Amber M.; Reidy, John A.; Needham, Larry L.; Calafat, Antonia M.

    2006-01-01

    Background Parabens appear frequently as antimicrobial preservatives in cosmetic products, in pharmaceuticals, and in food and beverage processing. In vivo and in vitro studies have revealed weak estrogenic activity of some parabens. Widespread use has raised concerns about the potential human health risks associated with paraben exposure. Objectives Assessing human exposure to parabens usually involves measuring in urine the conjugated or free species of parabens or their metabolites. In animals, parabens are mostly hydrolyzed to p-hydroxybenzoic acid and excreted in the urine as conjugates. Still, monitoring urinary concentrations of p-hydroxybenzoic acid is not necessarily the best way to assess exposure to parabens. p-Hydroxybenzoic acid is a nonspecific biomarker, and the varying estrogenic bioactivities of parabens require specific biomarkers. Therefore, we evaluated the use of free and conjugated parent parabens as new biomarkers for human exposure to these compounds. Results We measured the urinary concentrations of methyl, ethyl, n-propyl, butyl (n- and iso-), and benzyl parabens in a demographically diverse group of 100 anonymous adults. We detected methyl and n-propyl parabens at the highest median concentrations (43.9 ng/mL and 9.05 ng/mL, respectively) in nearly all (> 96%) of the samples. We also detected other parabens in more than half of the samples (ethyl, 58%; butyl, 69%). Most important, however, we found that parabens in urine appear predominantly in their conjugated forms. Conclusions The results, demonstrating the presence of urinary conjugates of parabens in humans, suggest that such conjugated parabens could be used as exposure biomarkers. Additionally, the fact that conjugates appear to be the main urinary products of parabens may be important for risk assessment. PMID:17185273

  3. GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth

    Directory of Open Access Journals (Sweden)

    Emily F. Winterbottom

    2015-06-01

    Full Text Available Although considerable evidence suggests that in utero arsenic exposure affects children's health, these data are mainly from areas of the world where groundwater arsenic levels far exceed the World Health Organization limit of 10 μg/L. We, and others, have found that more common levels of in utero arsenic exposure may also impact children's health. However, the underlying molecular mechanisms are poorly understood. To address this issue, we analyzed the expression of key developmental genes in fetal placenta in a birth cohort of women using unregulated water supplies in a US region with elevated groundwater arsenic. We identified several genes whose expression associated with maternal arsenic exposure in a fetal sex-specific manner. In particular, expression of the HEDGEHOG pathway component, GLI3, in female placentae was both negatively associated with arsenic exposure and positively associated with infant birth weight. This suggests that modulation of GLI3 in the fetal placenta, and perhaps in other fetal tissues, contributes to arsenic's detrimental effects on fetal growth. We showed previously that arsenic-exposed NIH3T3 cells have reduced GLI3 repressor protein. Together, these studies identify GLI3 as a key signaling node that is affected by arsenic, mediating a subset of its effects on developmental signaling and fetal health.

  4. GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth.

    Science.gov (United States)

    Winterbottom, Emily F; Fei, Dennis L; Koestler, Devin C; Giambelli, Camilla; Wika, Eric; Capobianco, Anthony J; Lee, Ethan; Marsit, Carmen J; Karagas, Margaret R; Robbins, David J

    2015-06-01

    Although considerable evidence suggests that in utero arsenic exposure affects children's health, these data are mainly from areas of the world where groundwater arsenic levels far exceed the World Health Organization limit of 10 μg/L. We, and others, have found that more common levels of in utero arsenic exposure may also impact children's health. However, the underlying molecular mechanisms are poorly understood. To address this issue, we analyzed the expression of key developmental genes in fetal placenta in a birth cohort of women using unregulated water supplies in a US region with elevated groundwater arsenic. We identified several genes whose expression associated with maternal arsenic exposure in a fetal sex-specific manner. In particular, expression of the HEDGEHOG pathway component, GLI3, in female placentae was both negatively associated with arsenic exposure and positively associated with infant birth weight. This suggests that modulation of GLI3 in the fetal placenta, and perhaps in other fetal tissues, contributes to arsenic's detrimental effects on fetal growth. We showed previously that arsenic-exposed NIH3T3 cells have reduced GLI3 repressor protein. Together, these studies identify GLI3 as a key signaling node that is affected by arsenic, mediating a subset of its effects on developmental signaling and fetal health.

  5. Whole-genome gene expression modifications associated with nitrosamine exposure and micronucleus frequency in human blood cells

    DEFF Research Database (Denmark)

    Hebels, Dennie G A J; Jennen, Danyel G J; van Herwijnen, Marcel H M

    2011-01-01

    association between MN frequency and urinary NOCs (r = 0.41, P = 0.025) and identified modifications in among others cytoskeleton remodeling, cell cycle, apoptosis and survival, signal transduction, immune response, G-protein signaling and development pathways, which indicate a response to NOC......N-nitroso compounds (NOCs) are suspected human carcinogens and relevant in human exposure. NOCs also induce micronuclei (MN) formation in vivo. Since lymphocytic MN represent a validated biomarker of human cancer risk, establishing a link between NOC exposure and MN frequency in humans...... for analysing such potentially carcinogenic gene expression and MN formation events in target organs. To assess NOC exposure, urine samples were analysed for marker nitrosamines. NOC excretion levels and MN frequency were subsequently linked to peripheral blood transcriptomics. We demonstrated a significant...

  6. Analyzing the regulation of metabolic pathways in human breast cancer

    Directory of Open Access Journals (Sweden)

    Schramm Gunnar

    2010-09-01

    Full Text Available Abstract Background Tumor therapy mainly attacks the metabolism to interfere the tumor's anabolism and signaling of proliferative second messengers. However, the metabolic demands of different cancers are very heterogeneous and depend on their origin of tissue, age, gender and other clinical parameters. We investigated tumor specific regulation in the metabolism of breast cancer. Methods For this, we mapped gene expression data from microarrays onto the corresponding enzymes and their metabolic reaction network. We used Haar Wavelet transforms on optimally arranged grid representations of metabolic pathways as a pattern recognition method to detect orchestrated regulation of neighboring enzymes in the network. Significant combined expression patterns were used to select metabolic pathways showing shifted regulation of the aggressive tumors. Results Besides up-regulation for energy production and nucleotide anabolism, we found an interesting cellular switch in the interplay of biosynthesis of steroids and bile acids. The biosynthesis of steroids was up-regulated for estrogen synthesis which is needed for proliferative signaling in breast cancer. In turn, the decomposition of steroid precursors was blocked by down-regulation of the bile acid pathway. Conclusion We applied an intelligent pattern recognition method for analyzing the regulation of metabolism and elucidated substantial regulation of human breast cancer at the interplay of cholesterol biosynthesis and bile acid metabolism pointing to specific breast cancer treatment.

  7. Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells

    Science.gov (United States)

    Nikiforov, Andrey; Dölle, Christian; Niere, Marc; Ziegler, Mathias

    2011-01-01

    NAD is a vital redox carrier, and its degradation is a key element of important regulatory pathways. NAD-mediated functions are compartmentalized and have to be fueled by specific biosynthetic routes. However, little is known about the different pathways, their subcellular distribution, and regulation in human cells. In particular, the route(s) to generate mitochondrial NAD, the largest subcellular pool, is still unknown. To visualize organellar NAD changes in cells, we targeted poly(ADP-ribose) polymerase activity into the mitochondrial matrix. This activity synthesized immunodetectable poly(ADP-ribose) depending on mitochondrial NAD availability. Based on this novel detector system, detailed subcellular enzyme localizations, and pharmacological inhibitors, we identified extracellular NAD precursors, their cytosolic conversions, and the pathway of mitochondrial NAD generation. Our results demonstrate that, besides nicotinamide and nicotinic acid, only the corresponding nucleosides readily enter the cells. Nucleotides (e.g. NAD and NMN) undergo extracellular degradation resulting in the formation of permeable precursors. These precursors can all be converted to cytosolic and mitochondrial NAD. For mitochondrial NAD synthesis, precursors are converted to NMN in the cytosol. When taken up into the organelles, NMN (together with ATP) serves as substrate of NMNAT3 to form NAD. NMNAT3 was conclusively localized to the mitochondrial matrix and is the only known enzyme of NAD synthesis residing within these organelles. We thus present a comprehensive dissection of mammalian NAD biosynthesis, the groundwork to understand regulation of NAD-mediated processes, and the organismal homeostasis of this fundamental molecule. PMID:21504897

  8. Review of the chronic exposure pathways models in MACCS (MELCOR Accident Consequence Code System) and several other well-known probabilistic risk assessment models

    Energy Technology Data Exchange (ETDEWEB)

    Tveten, U. (Institutt for Energiteknikk, Kjeller (Norway))

    1990-06-01

    The purpose of this report is to document the results of the work performed by the author in connection with the following task, performed for US Nuclear Regulatory Commission, (USNRC) Office of Nuclear Regulatory Research, Division of Systems Research: MACCS Chronic Exposure Pathway Models: Review the chronic exposure pathway models implemented in the MELCOR Accident Consequence Code System (MACCS) and compare those models to the chronic exposure pathway models implemented in similar codes developed in countries that are members of the OECD. The chronic exposures concerned are via: the terrestrial food pathways, the water pathways, the long-term groundshine pathway, and the inhalation of resuspended radionuclides pathway. The USNRC has indicated during discussions of the task that the major effort should be spent on the terrestrial food pathways. There is one chapter for each of the categories of chronic exposure pathways listed above.

  9. Exploring consumer exposure pathways and patterns of use for chemicals in the environment

    OpenAIRE

    Dionisio, Kathie L.; Alicia M. Frame; Goldsmith, Michael-Rock; Wambaugh, John F.; Liddell, Alan; Cathey, Tommy; Smith, Doris; Vail, James; Ernstoff, Alexi; Fantke, Peter; Jolliet, Olivier; Judson, Richard S.

    2015-01-01

    Humans are exposed to thousands of chemicals in the workplace, home, and via air, water, food, and soil. A major challenge in estimating chemical exposures is to understand which chemicals are present in these media and microenvironments. Here we describe the Chemical/Product Categories Database (CPCat), a new, publically available (http://actor.epa.gov/cpcat) database of information on chemicals mapped to “use categories” describing the usage or function of the chemical. CPCat was created by...

  10. Exposure to bisphenol A at physiological concentrations observed in Chinese children promotes primordial follicle growth through the PI3K/Akt pathway in an ovarian culture system.

    Science.gov (United States)

    Zhao, Qian; Ma, Yan; Sun, Ning-Xia; Ye, Chen; Zhang, Qing; Sun, Shu-Han; Xu, Chen; Wang, Fang; Li, Wen

    2014-12-01

    The worldwide increase in the use of bisphenol A (BPA) has resulted in increased human exposure, which could affect human reproductive function. Few studies have investigated the effect of BPA exposure on the primordial follicle pool. In this study, we employed a neonatal ovarian culture system comprising organ obtained from female C57BL/6 pups on postnatal day 4 to assess the effect of BPA on the primordial follicle pool. Ovaries were cultured with BPA (0.1 μM, physiological concentration found in children's blood, and 1 μM, 10 μM) or vehicle for 10 days. Our study revealed that the primary follicle number increased during the early time points (⩽5 days), and we observed a reduction in the primordial follicle pool at a later time point (day 10). This reduction at day 10 was due to increased follicle activation and reduced follicle atresia, as determined by immunohistochemistry for Ki-67 and active caspase-3. Then we examined the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, which is known to be important for early follicle growth. BPA exposure induced the upregulation of the PI3K/Akt pathway, which was reversed by concomitant treatment with PI3K inhibitor. Our results reveal a novel mechanism for BPA-induced primordial follicle activation that involves the PI3K/Akt pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Global Coastal Exposure due to Sea-level Rise beyond Tipping Points with Multiple Warming Pathways

    Science.gov (United States)

    Tawatari, R.; Iseri, Y.; Kiguchi, M.; Kanae, S.

    2016-12-01

    Sea-level is observed and estimated to continue rising. In the future, the rise could be abrupt and irreversible in century to millennial timescale even if we conduct strong reduction of greenhouse gas emission. Greenland ice sheet and West Antarctic ice sheet are considered as attributable climate systems which would significantly enhance presently-projected sea-level rise by several meters if global mean temperature passes certain "Tipping points" which would exist around +1-5 degree Celsius above present temperature (1980-1999 average). Therefore, vulnerable coastal low-lying area, especially small islands, deltas or poor developing countries, would suffer from semi-permanent inundation and forced to counteract due to the enhanced sea-level rise. This study estimate range of sea-level rise until the year 2300 and 3000 considering excess of tipping points with using multiple levels of temperature scenarios which consist of excess tipping points and non-excess tipping points pathways. We extract state-of-the-art knowledge of tipping elements from paper reviewing to express reasonable relationship between temperature and abruptly-changing sea-level transition across the ages. This study also calculate coastal exposure globally as affected population, area and asset below the estimated sea-level for each countries with overlaying 30 arc-second gridded topography, population distribution and the sea-level. The result indicates which country would be critically affected if we follow overshooting pathways. Furthermore, this study visualize uncertain coastal exposure due to sea-level rise in the future from the multiple warming pathways. This estimation of possible future beyond tipping point would be useful information for decision-makers to establish new planning of defense, migration or mitigation for the future societies.

  12. Quantum dots trigger immunomodulation of the NFκB pathway in human skin cells.

    Science.gov (United States)

    Romoser, Amelia A; Chen, Patricia L; Berg, J Michael; Seabury, Christopher; Ivanov, Ivan; Criscitiello, Michael F; Sayes, Christie M

    2011-07-01

    The immunological effects of quantum dots are dependent on a variety of factors including, but not limited to, exposure time and dosing concentrations. In this study, we investigated the influence of 15 nm CdSe/ZnS-COOH quantum dot nanocrystals (QDs) on cell density, viability, and morphology in human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF). Furthermore, inflammatory and non-inflammatory immune responses were measured using protein and real time PCR array analysis from HDF cells exposed to predetermined sub-lethal concentrations of QDs. CdSe/ZnS-COOH QDs caused concentration-dependent (1-120 nM exposure concentrations) and time-dependent (8 h or 48 h) cell death, as evidenced by metabolic activity and morphological changes. QD exposure induced upregulation of apoptotic, inflammatory and immunoregulatory proteins such as TNF-α, IL-1B and IL-10. HMOX1, an indicator of stress due to reactive oxygen intermediates (ROIs) and/or metals, was upregulated at the later time point as well. QDs also caused modulation of genes known to be associated with inflammatory (IL1-β, CCL2, IRAK-2), immune (IL-1, IL-6, PGLYRP1, SERPINA1, IL-10), stress due to ROIs and/or heavy metals (HMOX1), and apoptotic (CASP1, ADORA2A) responses. Cellular effects from QD exposure were found to primarily follow the NFκB pathway. In addition, QDs induced a differential cytotoxicity in keratinocytes and fibroblasts at different exposure concentrations and time points, even at physiologically relevant dosing concentrations, thus emphasizing the need to investigate potential mechanisms of action among different cell types within the same target organ.

  13. Human physiological responses to cold exposure: Acute responses and acclimatization to prolonged exposure.

    Science.gov (United States)

    Castellani, John W; Young, Andrew J

    2016-04-01

    Cold exposure in humans causes specific acute and chronic physiological responses. This paper will review both the acute and long-term physiological responses and external factors that impact these physiological responses. Acute physiological responses to cold exposure include cutaneous vasoconstriction and shivering thermogenesis which, respectively, decrease heat loss and increase metabolic heat production. Vasoconstriction is elicited through reflex and local cooling. In combination, vasoconstriction and shivering operate to maintain thermal balance when the body is losing heat. Factors (anthropometry, sex, race, fitness, thermoregulatory fatigue) that influence the acute physiological responses to cold exposure are also reviewed. The physiological responses to chronic cold exposure, also known as cold acclimation/acclimatization, are also presented. Three primary patterns of cold acclimatization have been observed, a) habituation, b) metabolic adjustment, and c) insulative adjustment. Habituation is characterized by physiological adjustments in which the response is attenuated compared to an unacclimatized state. Metabolic acclimatization is characterized by an increased thermogenesis, whereas insulative acclimatization is characterized by enhancing the mechanisms that conserve body heat. The pattern of acclimatization is dependent on changes in skin and core temperature and the exposure duration.

  14. Linearity of dose-response relationships for human carcinogenic exposures

    Energy Technology Data Exchange (ETDEWEB)

    Smith, A.H. (Univ. of California, Berkeley (USA))

    The shape of dose-response relationships is a critical factor in considering cancer risks for the work place and environmental exposure to carcinogens. Markedly different risk estimates result from assumptions of linearity versus sublinear and threshold assumptions. This paper presents evidence that the relationship between the relative risk of development of cancer and the dose rate to carcinogenic exposures is frequently linear with no evidence for thresholds. Dose-response relationships from four studies of asbestos and lung cancer were examined, all of which were consistent with a linear relationship. Analysis of the relationship between the relative risk of lung cancer and exposure to nickel in a smelter study, selected because of relatively good exposure data, demonstrated a close agreement with a linear relationship. The relationship between the level of arsenic in drinking wter and the prevalence of skin cancer also was linear for males in the highest prevalence age group in Taiwan, although there was some evidence of sublinearity for females and younger persons. Also, the relationships between the number of cigarettes smoked per day and the relative risk of lung cancer was very close to linear in many studies. The analysis of these and other studies involving human exposure to carcinogens provides empirical evidence for linearity when the response variable is a rate ratio measure, rather than a risk difference measure. Linearity in dose-response is biologically plausible, without invoking a one-hit model. Except in special circumstances. the epidemiological evidence supports linear extrapolation of cancer relative risks.

  15. Di(2-Ethylhexyl) Phthalate Exposure In Utero Damages Sertoli Cell Differentiation Via Disturbance of Sex Determination Pathway in Fetal and Postnatal Mice.

    Science.gov (United States)

    Wang, Yongan; Yang, Qing; Liu, Wei; Yu, Mingxi; Zhang, Zhou; Cui, Xiaoyu

    2016-07-01

    Mice may share similar mechanism with human underlying reproductive toxicity induced by di(2-ethylhexyl) phthalate (DEHP), which is not supposed to be associated with decreased testicular testosterone. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposure level. After in utero DEHP exposure, loss of Sertoli cells and germ cells were observed in the male pups at postnatal days 21. And SRY-related HMG box 9 (SOX9), Fibroblast growth factor-9 (FGF9), and Double-sex and Mab-3 related transcripttion factor 1 (DMRT1) proteins were significantly downregulated by DEHP at 2 mg/kg/d and above, suggesting the depression of Sertoli cell differentiation. The repression of Sox9 genes expression was supported by whole-mount in situ hybridization and real-time real-time-quantitative PCR. The expressions of Cyp11α1 and Star were not significantly affected by in utero DEHP exposure, indicating the absence of effects on testosterone biosynthesis. Furthermore, the testosterone-independent pathway regulating Sertoli cells differentiation was disturbed in fetus by DEHP at 2 mg/kg/d and above during the critical time window of sex determination, involving Gadd45g → Gata4/Fog2 → Sry → Sox9 → Fgf9 The results suggest that in utero DEHP exposure damaged Sertoli cells in the postnatal life of mice offspring via disturbance of the differentiation regulating pathway, potentially inducing declines in spermatogenesis.

  16. HPD: an online integrated human pathway database enabling systems biology studies.

    Science.gov (United States)

    Chowbina, Sudhir R; Wu, Xiaogang; Zhang, Fan; Li, Peter M; Pandey, Ragini; Kasamsetty, Harini N; Chen, Jake Y

    2009-10-08

    Pathway-oriented experimental and computational studies have led to a significant accumulation of biological knowledge concerning three major types of biological pathway events: molecular signaling events, gene regulation events, and metabolic reaction events. A pathway consists of a series of molecular pathway events that link molecular entities such as proteins, genes, and metabolites. There are approximately 300 biological pathway resources as of April 2009 according to the Pathguide database; however, these pathway databases generally have poor coverage or poor quality, and are difficult to integrate, due to syntactic-level and semantic-level data incompatibilities. We developed the Human Pathway Database (HPD) by integrating heterogeneous human pathway data that are either curated at the NCI Pathway Interaction Database (PID), Reactome, BioCarta, KEGG or indexed from the Protein Lounge Web sites. Integration of pathway data at syntactic, semantic, and schematic levels was based on a unified pathway data model and data warehousing-based integration techniques. HPD provides a comprehensive online view that connects human proteins, genes, RNA transcripts, enzymes, signaling events, metabolic reaction events, and gene regulatory events. At the time of this writing HPD includes 999 human pathways and more than 59,341 human molecular entities. The HPD software provides both a user-friendly Web interface for online use and a robust relational database backend for advanced pathway querying. This pathway tool enables users to 1) search for human pathways from different resources by simply entering genes/proteins involved in pathways or words appearing in pathway names, 2) analyze pathway-protein association, 3) study pathway-pathway similarity, and 4) build integrated pathway networks. We demonstrated the usage and characteristics of the new HPD through three breast cancer case studies. HPD http://bio.informatics.iupui.edu/HPD is a new resource for searching, managing

  17. Arsenic Exposure and the Induction of Human Cancers

    Directory of Open Access Journals (Sweden)

    Victor D. Martinez

    2011-01-01

    Full Text Available Arsenic is a metalloid, that is, considered to be a human carcinogen. Millions of individuals worldwide are chronically exposed through drinking water, with consequences ranging from acute toxicities to development of malignancies, such as skin and lung cancer. Despite well-known arsenic-related health effects, the molecular mechanisms involved are not fully understood; however, the arsenic biotransformation process, which includes methylation changes, is thought to play a key role. This paper explores the relationship of arsenic exposure with cancer development and summarizes current knowledge of the potential mechanisms that may contribute to the neoplastic processes observed in arsenic exposed human populations.

  18. Pesticides: an update of human exposure and toxicity.

    Science.gov (United States)

    Mostafalou, Sara; Abdollahi, Mohammad

    2017-02-01

    Pesticides are a family of compounds which have brought many benefits to mankind in the agricultural, industrial, and health areas, but their toxicities in both humans and animals have always been a concern. Regardless of acute poisonings which are common for some classes of pesticides like organophosphoruses, the association of chronic and sub-lethal exposure to pesticides with a prevalence of some persistent diseases is going to be a phenomenon to which global attention has been attracted. In this review, incidence of various malignant, neurodegenerative, respiratory, reproductive, developmental, and metabolic diseases in relation to different routes of human exposure to pesticides such as occupational, environmental, residential, parental, maternal, and paternal has been systematically criticized in different categories of pesticide toxicities like carcinogenicity, neurotoxicity, pulmonotoxicity, reproductive toxicity, developmental toxicity, and metabolic toxicity. A huge body of evidence exists on the possible role of pesticide exposures in the elevated incidence of human diseases such as cancers, Alzheimer, Parkinson, amyotrophic lateral sclerosis, asthma, bronchitis, infertility, birth defects, attention deficit hyperactivity disorder, autism, diabetes, and obesity. Most of the disorders are induced by insecticides and herbicides most notably organophosphorus, organochlorines, phenoxyacetic acids, and triazine compounds.

  19. Dung biomass smoke activates inflammatory signaling pathways in human small airway epithelial cells.

    Science.gov (United States)

    McCarthy, Claire E; Duffney, Parker F; Gelein, Robert; Thatcher, Thomas H; Elder, Alison; Phipps, Richard P; Sime, Patricia J

    2016-12-01

    Animal dung is a biomass fuel burned by vulnerable populations who cannot afford cleaner sources of energy, such as wood and gas, for cooking and heating their homes. Exposure to biomass smoke is the leading environmental risk for mortality, with over 4,000,000 deaths each year worldwide attributed to indoor air pollution from biomass smoke. Biomass smoke inhalation is epidemiologically associated with pulmonary diseases, including chronic obstructive pulmonary disease (COPD), lung cancer, and respiratory infections, especially in low and middle-income countries. Yet, few studies have examined the mechanisms of dung biomass smoke-induced inflammatory responses in human lung cells. Here, we tested the hypothesis that dung biomass smoke causes inflammatory responses in human lung cells through signaling pathways involved in acute and chronic lung inflammation. Primary human small airway epithelial cells (SAECs) were exposed to dung smoke at the air-liquid interface using a newly developed, automated, and reproducible dung biomass smoke generation system. The examination of inflammatory signaling showed that dung biomass smoke increased the production of several proinflammatory cytokines and enzymes in SAECs through activation of the activator protein (AP)-1 and arylhydrocarbon receptor (AhR) but not nuclear factor-κB (NF-κB) pathways. We propose that the inflammatory responses of lung cells exposed to dung biomass smoke contribute to the development of respiratory diseases.

  20. ALIX-CHMP4 Interactions in the Human ESCRT Pathway

    Energy Technology Data Exchange (ETDEWEB)

    McCullough, J.; Fisher, R.D.; Whitby, F.G.; Sundquist, W.I.; Hill, C.P.

    2009-05-26

    The ESCRT pathway facilitates membrane fission events during enveloped virus budding, multivesicular body formation, and cytokinesis. To promote HIV budding and cytokinesis, the ALIX protein must bind and recruit CHMP4 subunits of the ESCRT-III complex, which in turn participate in essential membrane remodeling functions. Here, we report that the Bro1 domain of ALIX binds specifically to C-terminal residues of the human CHMP4 proteins (CHMP4A-C). Crystal structures of the complexes reveal that the CHMP4 C-terminal peptides form amphipathic helices that bind across the conserved concave surface of ALIX{sub Bro1}. ALIX-dependent HIV-1 budding is blocked by mutations in exposed ALIX{sub Bro1} residues that help contribute to the binding sites for three essential hydrophobic residues that are displayed on one side of the CHMP4 recognition helix (M/L/IxxLxxW). The homologous CHMP1-3 classes of ESCRT-III proteins also have C-terminal amphipathic helices, but, in those cases, the three hydrophobic residues are arrayed with L/I/MxxxLxxL spacing. Thus, the distinct patterns of hydrophobic residues provide a 'code' that allows the different ESCRT-III subunits to bind different ESCRT pathway partners, with CHMP1-3 proteins binding MIT domain-containing proteins, such as VPS4 and Vta1/LIP5, and CHMP4 proteins binding Bro1 domain-containing proteins, such as ALIX.

  1. Importance of the HIF pathway in cobalt nanoparticle-induced cytotoxicity and inflammation in human macrophages.

    Science.gov (United States)

    Nyga, Agata; Hart, Alister; Tetley, Teresa D

    2015-01-01

    Recent, unexpected high failure rates of metal-on-metal hip implants have reintroduced the issue of cobalt toxicity. An adverse reaction to cobalt ions and cobalt-induced lung injury occurs during environmental exposure and is now strictly controlled. Currently adverse reaction occurs to cobalt nanoparticles during wear and tear of metal-on-metal hip implants of which the underlying mechanism is not fully understood. The putative role of the hypoxia-inducible factor (HIF) pathway in the mechanism of cobalt nanoparticle (Co-NPs) toxicity was examined using the U937 cell line, human alveolar macrophages and monocyte-derived macrophages. Co-NPs (5-20 μg/ml)-induced cytotoxicity (viability ranged from 75% to cobalt ions (Co(II); up to 350 μM) did not. Co-NPs induced HIF-1α stabilization. Addition of ascorbic acid (100 µM) and glutathione (1 mM) both prevented the increased ROS. However, only treatment with ascorbic acid reduced HIF-1α levels and prevented cell death, indicating that a ROS-independent pathway is involved in Co-NPs-induced cytotoxicity. Replenishing intracellular ascorbate, which is crucial in preventing HIF pathway activation, modified Co-induced HIF target gene expression and the inflammatory response, by decreasing interleukin-1 beta (IL-1β) mRNA and protein expression. Addition of glutathione had no effect on Co-NPs-induced HIF target gene expression or inflammatory response. Thus, Co-NPs induce the HIF pathway by depleting intracellular ascorbate, leading to HIF stabilization and pathway activation. This suggests a strong, ROS-independent role for HIF activation in Co-NPs-induced cytotoxicity and a possible role for HIF in metal-on-metal hip implant pathology.

  2. Pathways involved in Drosophila and human cancer development: the Notch, Hedgehog, Wingless, Runt, and Trithorax pathway.

    Science.gov (United States)

    Geissler, Klaus; Zach, Otto

    2012-05-01

    Animal models are established tools to study basic questions of biology in a systematic way. They have greatly facilitated our understanding of the mechanisms by which nature forms and maintains organisms. Much of the knowledge on molecular changes underlying the development of organisms originates from research in the fruit fly model Drosophila melanogaster. Vertebrate models including the mouse and zebrafish model, but also other animal models coming from different corners of the animal kingdom have shown that much of the basic machinery of development is essentially identical, not just in all vertebrates but in all major phyla of invertebrates too. Moreover, key elements of this machinery have been demonstrated to be involved in recurrent molecular abnormalities detected in tumor-tissue from patients, indicating their implication in the genesis of human cancer. Thus, research in this field has become a common topic for both biologists and hemato-oncologists. In this review, we summarize current knowledge on some of these key elements and molecular pathways such as Notch, Hedgehog, Wingless, Runt, and Trithorax that have been originally described and studied in animal models and which seem to play a major role in the pathophysiology and targeted management of human cancer.

  3. Human performance analysis of industrial radiography radiation exposure events

    Energy Technology Data Exchange (ETDEWEB)

    Reece, W.J.; Hill, S.G.

    1995-12-01

    A set of radiation overexposure event reports were reviewed as part of a program to examine human performance in industrial radiography for the US Nuclear Regulatory Commission. Incident records for a seven year period were retrieved from an event database. Ninety-five exposure events were initially categorized and sorted for further analysis. Descriptive models were applied to a subset of severe overexposure events. Modeling included: (1) operational sequence tables to outline the key human actions and interactions with equipment, (2) human reliability event trees, (3) an application of an information processing failures model, and (4) an extrapolated use of the error influences and effects diagram. Results of the modeling analyses provided insights into the industrial radiography task and suggested areas for further action and study to decrease overexposures.

  4. Low Dose Cadmium Inhibits Proliferation of Human Renal Mesangial Cells via Activation of the JNK Pathway

    Science.gov (United States)

    Chen, Xiaocui; Li, Jing; Cheng, Zuowang; Xu, Yinghua; Wang, Xia; Li, Xiaorui; Xu, Dongmei; Kapron, Carolyn M.; Liu, Ju

    2016-01-01

    Cadmium (Cd) is a heavy metal and environmental pollutant. The kidney is the principal target organ of Cd exposure. Previously, we found that low concentration of Cd damages the integrity of the glomerular filtration barrier. However, little is known about the effects of Cd on renal mesangial cells, which provide structural support for the glomerular capillary loops and regulate intraglomerular blood flow. In this study, human renal mesangial cells (HRMCs) were cultured in the presence of serum and treated with 4 μM Cd. We found that Cd activates the c-Jun N-terminal kinase (JNK) pathway, and increases the protein levels of c-Jun and c-Fos. Cd treatment also induces a decrease in proliferation and an increase in apoptosis of HRMCs, but only the decrease in HRMC proliferation was reversed by pretreatment with SP600125, an inhibitor of the JNK pathway. In addition, Cd does not change the expression of α-smooth muscle actin and platelet-derived growth factor receptor-β, the markers of mesangial cells, or the alignment of the filamentous actin (F-actin) cytoskeleton of HRMCs. Our data indicate that the JNK pathway mediates the inhibitory effects of Cd on HRMC proliferation. PMID:27739415

  5. The “CROMa” Project: A Care Pathway for Clinical Management of Patients with Bisphosphonate Exposure

    Directory of Open Access Journals (Sweden)

    Mauro Capocci

    2014-01-01

    Full Text Available Aim. To describe 7 years of activity of “CROMa” (Coordination of Research on Osteonecrosis of the Jaws project of “Sapienza” University of Rome. Materials and Methods. A preventive and therapeutic care pathway was created for patients with bisphosphonates (BPs exposure. Demographic, social, behavioural, pharmacological, and clinical variables were registered in a dedicated database. Results. In the project, 502 patients, 403 females and 99 males, were observed. Bone pathologies were 79% osteometabolic diseases (OMD and 21% metastatic cancer (CA. Females were 90% in OMD group and 41% in CA. BP administration was 54% oral, 31% IV, and 11% IM; 89% of BPs were amino-BP and 11% non-amino-BP. Consistently with bone pathology (OMD/CA, alendronate appears to be prevalent for OMD (40% relative, while zoledronate was indicated in 92% of CA patients. Out of 502 cases collected, 28 BRONJ were detected: 17 of them were related to IV BP treatment. Preventive oral assessment was required for 50% of CA patients and by 4% of OMD patients. Conclusions. The proposed care pathway protocols for BP exposed patients appeared to be useful to meet treatment and preventive needs, in both oncological and osteometabolic diseases patients. Patients’ and physicians’ prevention awareness can be the starting point of a multilevel prevention system.

  6. The "CROMa" Project: A Care Pathway for Clinical Management of Patients with Bisphosphonate Exposure.

    Science.gov (United States)

    Capocci, Mauro; Romeo, Umberto; Cocco, Fabio; Bignozzi, Isabella; Annibali, Susanna; Ottolenghi, Livia

    2014-01-01

    Aim. To describe 7 years of activity of "CROMa" (Coordination of Research on Osteonecrosis of the Jaws) project of "Sapienza" University of Rome. Materials and Methods. A preventive and therapeutic care pathway was created for patients with bisphosphonates (BPs) exposure. Demographic, social, behavioural, pharmacological, and clinical variables were registered in a dedicated database. Results. In the project, 502 patients, 403 females and 99 males, were observed. Bone pathologies were 79% osteometabolic diseases (OMD) and 21% metastatic cancer (CA). Females were 90% in OMD group and 41% in CA. BP administration was 54% oral, 31% IV, and 11% IM; 89% of BPs were amino-BP and 11% non-amino-BP. Consistently with bone pathology (OMD/CA), alendronate appears to be prevalent for OMD (40% relative), while zoledronate was indicated in 92% of CA patients. Out of 502 cases collected, 28 BRONJ were detected: 17 of them were related to IV BP treatment. Preventive oral assessment was required for 50% of CA patients and by 4% of OMD patients. Conclusions. The proposed care pathway protocols for BP exposed patients appeared to be useful to meet treatment and preventive needs, in both oncological and osteometabolic diseases patients. Patients' and physicians' prevention awareness can be the starting point of a multilevel prevention system.

  7. Disturbed relaxin signaling pathway and testicular dysfunction in mouse offspring upon maternal exposure to simazine.

    Directory of Open Access Journals (Sweden)

    Ho-Oak Park

    Full Text Available Simazine is a triazine herbicide that is being widely applied worldwide and commonly detected in surface and groundwater. Despite its popular use in controlling weeds and algae, very limited information is available regarding its toxicity. In the present study, pregnant mice were orally exposed to low doses (0, 5, 50, or 500 µg/kg body weight per day of simazine during gestation and lactation, during which no overt maternal toxic response was detected, and their offspring was assessed. Simazine-exposed male offspring showed decreased body, testicular, and epididymis weight, increased testicular apoptosis, and decreased sperm concentrations. Differentially-expressed genes in the testes of male offspring exposed to simazine were identified by DNA microarray, revealing 775 upregulated and 791 downregulated genes; among these, the relaxin-family peptide receptor 1 (Rxfp1, which is the receptor for relaxin hormone, was significantly downregulated. In addition, the expression of target genes in the relaxin pathway, including nitric oxide synthase 2 (Nos2 and Nos3, was significantly decreased in simazine-exposed F1 testes. Moreover, simazine inhibited NO release, and knockdown of Rxfp1 blocked the inhibitory action of simazine on NO production in testicular Leydig cells. Therefore, the present study provides a better understanding of the toxicities associated with the widely used herbicide simazine at environmentally relevant doses by demonstrating that maternal exposure interferes with the pleotropic relaxin-NO signaling pathway, impairing normal development and reproductive activity of male offspring.

  8. Internal exposure dynamics drive the Adverse Outcome Pathways of synthetic glucocorticoids in fish

    Science.gov (United States)

    Margiotta-Casaluci, Luigi; Owen, Stewart F.; Huerta, Belinda; Rodríguez-Mozaz, Sara; Kugathas, Subramanian; Barceló, Damià; Rand-Weaver, Mariann; Sumpter, John P.

    2016-02-01

    The Adverse Outcome Pathway (AOP) framework represents a valuable conceptual tool to systematically integrate existing toxicological knowledge from a mechanistic perspective to facilitate predictions of chemical-induced effects across species. However, its application for decision-making requires the transition from qualitative to quantitative AOP (qAOP). Here we used a fish model and the synthetic glucocorticoid beclomethasone dipropionate (BDP) to investigate the role of chemical-specific properties, pharmacokinetics, and internal exposure dynamics in the development of qAOPs. We generated a qAOP network based on drug plasma concentrations and focused on immunodepression, skin androgenisation, disruption of gluconeogenesis and reproductive performance. We showed that internal exposure dynamics and chemical-specific properties influence the development of qAOPs and their predictive power. Comparing the effects of two different glucocorticoids, we highlight how relatively similar in vitro hazard-based indicators can lead to different in vivo risk. This discrepancy can be predicted by their different uptake potential, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. We recommend that the development phase of qAOPs should include the application of species-species uptake and physiologically-based PK/PD models. This integration will significantly enhance the predictive power, enabling a more accurate assessment of the risk and the reliable transferability of qAOPs across chemicals.

  9. DUAL ION EXPOSURE VS. SPLIT-DOSE EXPOSURES IN HUMAN CELL NEOPLASTIC TRANSFORMATION.

    Energy Technology Data Exchange (ETDEWEB)

    BENNETT, P.V.; CUTTER, N.C.; SUTHERLAND, B.M.

    2006-06-05

    Since radiation fields of space contain many-fold more protons than high atomic number, high energy (HZE) particles, cells in astronaut crews will experience on average several proton hits before an HZE hit. Thus radiation regimes of proton exposure before HZE particle exposure simulate space radiation exposure, and measurement of the frequency of neoplastic transformation of human primary cells to anchorage-independent growth simulates in initial step in cancer induction. Previously our group found that exposure to 20 cGy 1 GeV/n protons followed within about 1 hr by a HZE ion (20 cGy 1 GeV/n Fe or Ti ions) hit gave about a 3-fold increase in transformation frequency ([1]). To provide insight into the H-HZE induced increased transformation frequencies, we asked if split doses of the same ion gave similar increased transformation frequencies. However, the data show that the split dose of 20 cGy plus 20 cGy of either H or HZE ions gave about the same effect as the 40 cGy uninterrupted dose, quite different from the effect of the mixed ion H + HZE irradiation. We also asked if lower proton doses than 20 cGy followed 15 minutes later by 20 cGy of HZE ions gave greater than additive transformation frequencies. Substantial increases in transformation levels were observed for all proton doses tested, including 1 cGy. These results point to the signal importance of protons in affecting the effect of space radiation on human cells.

  10. Organophosphorus flame retardants in house dust from the Philippines: occurrence and assessment of human exposure.

    Science.gov (United States)

    Kim, Joon-Woo; Isobe, Tomohiko; Sudaryanto, Agus; Malarvannan, Govindan; Chang, Kwang-Hyeon; Muto, Mamoru; Prudente, Maricar; Tanabe, Shinsuke

    2013-02-01

    The use of organophosphorus flame retardants (PFRs) as flame retardants and plasticizers has increased due to the ban on common polybrominated diphenyl ether mixtures. However, only limited information on PFR contamination is available so far from Southeast Asia. In the present study, residual levels of PFRs in house dust and exposure through dust ingestion were investigated in the Philippines. House dust samples (n = 37) were collected from Malate (residential area) and Payatas (municipal dumping area) in the Philippines and analyzed using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. Among the targeted seven PFRs, triphenyl phosphate (TPP) was the predominant compound. Median levels of ΣPFRs in Malate (530 ng/g) were two times higher (p < 0.05) than in Payatas (240 ng/g). The estimated daily intake of PFRs in the Philippines (of areas studied) via house dust ingestion was below the guideline values. House dust may be an important contributor in the overall exposure of humans to TPP even when considering dietary sources. To our knowledge, this is a first report on PFR contamination in house dust from developing country. PFRs were ubiquitously detected in the home environments in the Philippines. Although estimated exposure levels through dust ingestion were below the guideline, it was suggested that toddlers are at higher risk. Therefore, further investigations to understand the behavior of PFRs in house and other microenvironments and overall exposure pathways for the country's populace to PFRs are necessary.

  11. Prenatal Exposure to Progesterone Affects Sexual Orientation in Humans.

    Science.gov (United States)

    Reinisch, June M; Mortensen, Erik Lykke; Sanders, Stephanie A

    2017-07-01

    Prenatal sex hormone levels affect physical and behavioral sexual differentiation in animals and humans. Although prenatal hormones are theorized to influence sexual orientation in humans, evidence is sparse. Sexual orientation variables for 34 prenatally progesterone-exposed subjects (17 males and 17 females) were compared to matched controls (M age = 23.2 years). A case-control double-blind design was used drawing on existing data from the US/Denmark Prenatal Development Project. Index cases were exposed to lutocyclin (bioidentical progesterone = C21H30O2; M W : 314.46) and no other hormonal preparation. Controls were matched on 14 physical, medical, and socioeconomic variables. A structured interview conducted by a psychologist and self-administered questionnaires were used to collect data on sexual orientation, self-identification, attraction to the same and other sex, and history of sexual behavior with each sex. Compared to the unexposed, fewer exposed males and females identified as heterosexual and more of them reported histories of same-sex sexual behavior, attraction to the same or both sexes, and scored higher on attraction to males. Measures of heterosexual behavior and scores on attraction to females did not differ significantly by exposure. We conclude that, regardless of sex, exposure appeared to be associated with higher rates of bisexuality. Prenatal progesterone may be an underappreciated epigenetic factor in human sexual and psychosexual development and, in light of the current prevalence of progesterone treatment during pregnancy for a variety of pregnancy complications, warrants further investigation. These data on the effects of prenatal exposure to exogenous progesterone also suggest a potential role for natural early perturbations in progesterone levels in the development of sexual orientation.

  12. Involvement of the kynurenine pathway in human glioma pathophysiology.

    Directory of Open Access Journals (Sweden)

    Seray Adams

    Full Text Available The kynurenine pathway (KP is the principal route of L-tryptophan (TRP catabolism leading to the production of kynurenine (KYN, the neuroprotectants, kynurenic acid (KYNA and picolinic acid (PIC, the excitotoxin, quinolinic acid (QUIN and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+. The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1, indoleamine 2,3-dioxygenase-2 (IDO-2 and tryptophan 2,3-dioxygenase (TDO-2 initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1 cultured human glioma cells and 2 plasma from patients with glioblastoma (GBM. Our data revealed that interferon-gamma (IFN-γ stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU, kynurenine hydroxylase (KMO and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD and kynurenine aminotransferase-I (KAT-I expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18 compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD(+, which is necessary for energy production and DNA repair.

  13. Large organic aerosols in a human exposure chamber : Applications in occupational dermatology and lung medicine

    OpenAIRE

    Lundgren, Lennart

    2006-01-01

    Exposure to large organic aerosol particles may cause respiratory and skin reactions. The use of human exposure chambers offers possibilities for experimental exposure challenges carried out with patients, in research and for investigations of the effects of exposure on the skin and in the respiratory tract. The present aim was to study the performance of modern human whole-body exposure chambers during generation of large organic particles, and to develop and test new me...

  14. New approach for assessing human perfluoroalkyl exposure via hair.

    Science.gov (United States)

    Alves, Andreia; Jacobs, Griet; Vanermen, Guido; Covaci, Adrian; Voorspoels, Stefan

    2015-11-01

    In the recent years hair has been increasingly used as alternative matrix in human biomonitoring (HBM) of environmental pollutants. Sampling advantages and time integration of exposure assessment seems the most attractive features of hair matrix. In the current study, a novel miniaturized method was developed and validated for measuring 15 perfluoroalkyl substances (PFAS), including perfluoro n-butanoic acid (PFBA), perfluoro n-pentanoic acid (PFPeA), perfluoro n-hexanoic acid (PFHxA), perfluoro n-heptanoic acid (PFHpA), perfluor n-octanoic acid (PFOA), perfluoro n-nonanoic acid (PFNA), perfluoro tetradecanoic acid (PFTeDA), perfluorobutane sulfonic acid (PFBS), perfluoro pentane sulfonic acid (PFPeS), perfluorohexane sulfonic acid (PFHxS), perfluoroheptane sulfonic acid (PFHpS), perfluorooctane sulfonic acid (PFOS), perfluorononane sulfonic acid (PFNS), perfluorodecane sulfonic acid (PFDS) and perfluorododecane sulfonic acid (PFDoS) in human hair by liquid chromatography tandem mass spectrometry (LC-MS/MS). After extraction using ethyl acetate, dispersive ENVI-Carb was used for clean-up. Good intra- and inter-day precision for low (LQ 5 ng/g hair) and high spike (HQ 15n g/g) levels were achieved (in general RSD hair and 3-13 pg/g hair, respectively. The method limit of quantification (LOQm) ranged between 6 and 301 pg/g hair. The PFAS levels were measured in 30 human hair samples indicating that the levels are low (14-1534 pg/g hair). Some PFAS were not present in any hair sample (e.g. PFHpA, PFTeDA, PFNA, PFPeS, PFHpS, PFOS and PFNS), while other PFAS were frequently detected (PFBA, PFPeA, PFHxA, PFOA, PFBS, PFHxS, PFOS, PFDS and PFDoS) in human hair. Although levels in general were low, there is evidence of higher human exposure to some analytes, such as PFBA, PFPeA, PFHxA, PFOA, PFBS, PFHxS, and PFDoS. The current study shows that hair is a suitable alternative non-invasive matrix for exposure assessment of PFAS.

  15. Human exposure to arsenic in groundwater from Lahore district, Pakistan.

    Science.gov (United States)

    Bibi, Mehwish; Hashmi, Muhammad Zaffar; Malik, Riffat Naseem

    2015-01-01

    In the present study we determined As concentrations in healthy volunteers from three different age groups (children, adults and old age) residing in Lahore, Pakistan to gain insight into arsenic exposure to humans via drinking water. The results revealed that the concentrations of As were significantly (p<0.05) different among different sites, while non significant trends were observed among different age classes. As concentrations in blood and nails samples showed a significant (p<0.05) positive correlation. The mean concentrations of As were higher in nails samples (1.43μg/g) followed by blood samples (1.15μg/L); urine samples (0.82μg/l) and hair samples (0.74μg/g) based on all sites. The antioxidants enzyme activities in blood samples showed a significant (p<0.01) decrease with the increase in As concentrations. The result suggests that urgent action is needed to prevent further human exposure to As.

  16. Resistance to asbestos-induced apoptosis with continuous exposure to crocidolite on a human T cell

    Energy Technology Data Exchange (ETDEWEB)

    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

  17. Transfer of oxytetracycline from swine manure to three different aquatic plants: implications for human exposure.

    Science.gov (United States)

    Boonsaner, Maliwan; Hawker, Darryl W

    2015-03-01

    Little is known regarding the potential for pharmaceuticals including antibiotics to be accumulated in edible aquatic plants and enter the human food chain. This work investigates the transfer of a widely used veterinary antibiotic, oxytetracycline (OTC), from swine manure to aquatic plants by firstly characterizing desorption from swine manure to water and fitting data to both nonlinear and linear isotherms. Bioconcentration of OTC from water was then quantified with aquatic plants of contrasting morphology and growth habit viz. watermeal (Wolffia globosa Hartog and Plas), cabomba (Cabomba caroliniana A. Gray) and water spinach (Ipomoea aquatica Forsk.). Watermeal and water spinach are widely consumed in Southeast Asia. The OTC desorption and bioconcentration data were used to provide the first quantitative estimates of human exposure to OTC from a manure-water-aquatic plant route. Results show that under certain conditions (plants growing for 15d in undiluted swine manure effluent (2% w/v solids) and an initial OTC swine manure concentration of 43mgkg(-1) (dry weight)), this pathway could provide a significant fraction (>48%) of the acceptable daily intake (ADI) for OTC. While effluent dilution, lower OTC manure concentrations and not all plant material consumed being contaminated would be expected to diminish the proportion of the ADI accumulated, uptake from aquatic plants should not be ignored when determining human exposure to antibiotics such as OTC.

  18. Complement alternative pathway activation in human nonalcoholic steatohepatitis.

    Directory of Open Access Journals (Sweden)

    Filip M Segers

    Full Text Available The innate immune system plays a major role in the pathogenesis of nonalcoholic steatohepatitis (NASH. Recently we reported complement activation in human NASH. However, it remained unclear whether the alternative pathway of complement, which amplifies C3 activation and which is frequently associated with pathological complement activation leading to disease, was involved. Here, alternative pathway components were investigated in liver biopsies of obese subjects with healthy livers (n = 10 or with NASH (n = 12 using quantitative PCR, Western blotting, and immunofluorescence staining. Properdin accumulated in areas where neutrophils surrounded steatotic hepatocytes, and colocalized with the C3 activation product C3c. C3 activation status as expressed by the C3c/native C3 ratio was 2.6-fold higher (p<0.01 in subjects with NASH despite reduced native C3 concentrations (0.94±0.12 vs. 0.57±0.09; p<0.01. Hepatic properdin levels positively correlated with levels of C3c (rs = 0.69; p<0.05 and C3c/C3 activation ratio (rs = 0.59; p<0.05. C3c, C3 activation status (C3c/C3 ratio and properdin levels increased with higher lobular inflammation scores as determined according to the Kleiner classification (C3c: p<0.01, C3c/C3 ratio: p<0.05, properdin: p<0.05. Hepatic mRNA expression of factor B and factor D did not differ between subjects with healthy livers and subjects with NASH (factor B: 1.00±0.19 vs. 0.71±0.07, p = 0.26; factor D: 1.00±0.21 vs. 0.66±0.14, p = 0.29;. Hepatic mRNA and protein levels of Decay Accelerating Factor tended to be increased in subjects with NASH (mRNA: 1.00±0.14 vs. 2.37±0.72; p = 0.22; protein: 0.51±0.11 vs. 1.97±0.67; p = 0.28. In contrast, factor H mRNA was downregulated in patients with NASH (1.00±0.09 vs. 0.71±0.06; p<0.05 and a similar trend was observed with hepatic protein levels (1.12±0.16 vs. 0.78±0.07; p = 0.08. Collectively, these data suggest a role for alternative

  19. The metabolic fingerprint of p,p'-DDE and HCB exposure in humans.

    Science.gov (United States)

    Salihovic, Samira; Ganna, Andrea; Fall, Tove; Broeckling, Corey D; Prenni, Jessica E; van Bavel, Bert; Lind, P Monica; Ingelsson, Erik; Lind, Lars

    2016-03-01

    Dichlorodiphenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB) are organochlorine pesticides with well-known endocrine disrupting properties. Exposure to p,p'-DDE and HCB concerns human populations worldwide and has been linked to metabolic disorders such as obesity and type 2 diabetes, but details about these associations in humans from the general population are largely unknown. We investigated the associations between p,p'-DDE and HCB exposure and global metabolomic profiles in serum samples from 1016 participants from the Swedish population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. HCB and p,p'-DDE levels were determined using gas chromatography coupled to high-resolution mass spectrometry (GC-HRMS). Metabolite levels were determined by using a non-targeted metabolomics approach with ultra-performance liquid chromatography coupled to time-of- flight mass spectrometry (UPLC-TOFMS). Association analyses were performed using multivariate linear regression. We found circulating levels of p,p-DDE and HCB to be significantly associated with circulating levels of 16 metabolites following adjustment for age, sex, education level, exercise habits, smoking, energy intake, and alcohol intake. The majority of the 16 metabolites belong to lipid metabolism pathways and include fatty acids, glycerophospholipids, sphingolipids, and glycerolipids. Overall, p,p'-DDE and HCB levels were found to be correlated to different metabolites, which suggests that different metabolic fingerprints may be related to circulating levels of these two pesticides. Our findings establish a link between human exposure to organochlorine pesticides and metabolites of key metabolic processes mainly related to human lipid metabolism. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Effects of electromagnetic fields exposure on plasma hormonal and inflammatory pathway biomarkers in male workers of a power plant

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Zhaopin; Fei, Ying; Liu, Hui [Zhejiang Univ., Hangzhou (China). Dept. of Epidemiology and Health Statistics; Zhejiang Univ., Hangzhou (China). Chronic Disease Research Inst.; and others

    2016-01-15

    The potential health risks of electromagnetic fields (EMFs) have currently raised considerable public concerns. The aim of this study was to evaluate the effects of EMF exposure on levels of plasma hormonal and inflammatory pathway biomarkers in male workers of an electric power plant. Seventy-seven male workers with high occupational EMF exposure and 77 male controls with low exposure, matched by age, were selected from a cross-sectional study. Moreover, high EMF exposure group was with walkie-talkies usage and exposed to power frequency EMF at the work places for a longer duration than control group. A questionnaire was applied to obtain relevant information, including sociodemographic characteristics, lifestyle factors, and EMF exposures. Plasma levels of testosterone, estradiol, melatonin, NF-KB, heat-shock protein (HSP) 70, HSP27, and TET1 were determined by an enzyme-linked immunosorbent assay. EMF exposure group had statistically significantly lower levels of testosterone (β = -0.3 nmol/L, P = 0.015), testosterone/estradiol (T/E2) ratio (β = -15.6, P = 0.037), and NF-KB (β = -20.8 ng/L, P = 0.045) than control group. Moreover, joint effects between occupational EMF exposure and employment duration, mobile phone fees, years of mobile phone usage, and electric fees on levels of testosterone and T/E2 ratio were observed. Nevertheless, no statistically significant associations of EMF exposures with plasma estradiol, melatonin, HSP70, HSP27, and TET1 were found. The findings showed that chronic exposure to EMF could decrease male plasma testosterone and T/E2 ratio, and it might possibly affect reproductive functions in males. No significant associations of EMF exposure with inflammatory pathway biomarkers were found.

  1. Effects of electromagnetic fields exposure on plasma hormonal and inflammatory pathway biomarkers in male workers of a power plant.

    Science.gov (United States)

    Wang, Zhaopin; Fei, Ying; Liu, Hui; Zheng, Shuangshuang; Ding, Zheyuan; Jin, Wen; Pan, Yifeng; Chen, Zexin; Wang, Lijuan; Chen, Guangdi; Xu, Zhengping; Zhu, Yongjian; Yu, Yunxian

    2016-01-01

    The potential health risks of electromagnetic fields (EMFs) have currently raised considerable public concerns. The aim of this study was to evaluate the effects of EMF exposure on levels of plasma hormonal and inflammatory pathway biomarkers in male workers of an electric power plant. Seventy-seven male workers with high occupational EMF exposure and 77 male controls with low exposure, matched by age, were selected from a cross-sectional study. Moreover, high EMF exposure group was with walkie-talkies usage and exposed to power frequency EMF at the work places for a longer duration than control group. A questionnaire was applied to obtain relevant information, including sociodemographic characteristics, lifestyle factors, and EMF exposures. Plasma levels of testosterone, estradiol, melatonin, NF-κB, heat-shock protein (HSP) 70, HSP27, and TET1 were determined by an enzyme-linked immunosorbent assay. EMF exposure group had statistically significantly lower levels of testosterone (β = -0.3 nmol/L, P = 0.015), testosterone/estradiol (T/E2) ratio (β = -15.6, P = 0.037), and NF-κB (β = -20.8 ng/L, P = 0.045) than control group. Moreover, joint effects between occupational EMF exposure and employment duration, mobile phone fees, years of mobile phone usage, and electric fees on levels of testosterone and T/E2 ratio were observed. Nevertheless, no statistically significant associations of EMF exposures with plasma estradiol, melatonin, HSP70, HSP27, and TET1 were found. The findings showed that chronic exposure to EMF could decrease male plasma testosterone and T/E2 ratio, and it might possibly affect reproductive functions in males. No significant associations of EMF exposure with inflammatory pathway biomarkers were found.

  2. Structural change of human hair induced by mercury exposure.

    Science.gov (United States)

    Xing, Xueqing; Du, Rong; Li, Yufeng; Li, Bai; Cai, Quan; Mo, Guang; Gong, Yu; Chen, Zhongjun; Wu, Zhonghua

    2013-10-01

    Mercury is one of the most hazardous pollutants in the environment. In this paper, the structural change of human hair induced by mercury exposure was studied. Human hair samples were, respectively, collected from the normal Beijing area and the Hg-contaminated Wanshan area of the Guizhou Province, China. Inductively coupled plasma mass spectroscopy was used to detect the element contents. A small angle X-ray scattering technique was used to probe the structural change. Three reflections with 8.8, 6.7, and 4.5 nm spacing were compared between the normal and the Hg-contaminated hair samples. The results confirm that the 4.5 nm reflection is from the ordered fibrillar structure of glycosaminoglycan (GAG) in proteoglycan (PG) that composes the matrix around the intermediate filaments. The increase of Ca content makes the regular oriented fibrillar structure of GAG transform to a random oriented one, broadening the angular extent of the reflection with 4.5 nm spacing. However, overdose Hg makes the core proteins where the ordered fibrils of GAG are attached become coiled, which destroys the ordered arrangements of fibrillar GAG in PG, resulting in the disappearance of the reflections with 4.5 nm spacing. The disappearance of the 4.5 nm reflection can be used as a bioindicator of overdose Hg contamination to the human body. A supercoiled-coil model of hair nanoscale structure and a possible mechanism of mercury effect in human hair are proposed in this paper.

  3. Pathways of inhalation exposure to manganese in children living near a ferromanganese refinery: A structural equation modeling approach.

    Science.gov (United States)

    Fulk, Florence; Succop, Paul; Hilbert, Timothy J; Beidler, Caroline; Brown, David; Reponen, Tiina; Haynes, Erin N

    2017-02-01

    Manganese (Mn) is both essential element and neurotoxicant. Exposure to Mn can occur from various sources and routes. Structural equation modeling was used to examine routes of exposure to Mn among children residing near a ferromanganese refinery in Marietta, Ohio. An inhalation pathway model to ambient air Mn was hypothesized. Data for model evaluation were obtained from participants in the Communities Actively Researching Exposure Study (CARES). These data were collected in 2009 and included levels of Mn in residential soil and dust, levels of Mn in children's hair, information on the amount of time the child spent outside, heat and air conditioning in the home and level of parent education. Hair Mn concentration was the primary endogenous variable used to assess the theoretical inhalation exposure pathways. The model indicated that household dust Mn was a significant contributor to child hair Mn (0.37). Annual ambient air Mn concentration (0.26), time children spent outside (0.24) and soil Mn (0.24) significantly contributed to the amount of Mn in household dust. These results provide a potential framework for understanding the inhalation exposure pathway for children exposed to ambient air Mn who live in proximity to an industrial emission source.

  4. Subclinical infection and asymptomatic carriage of gastrointestinal zoonoses: occupational exposure, environmental pathways, and the anonymous spread of disease.

    Science.gov (United States)

    Quilliam, R S; Cross, P; Williams, A Prysor; Edwards-Jones, G; Salmon, R L; Rigby, D; Chalmers, R M; Thomas, D Rh; Jones, D L

    2013-10-01

    Asymptomatic carriage of gastrointestinal zoonoses is more common in people whose profession involves them working directly with domesticated animals. Subclinical infections (defined as an infection in which symptoms are either asymptomatic or sufficiently mild to escape diagnosis) are important within a community as unknowing (asymptomatic) carriers of pathogens do not change their behaviour to prevent the spread of disease; therefore the public health significance of asymptomatic human excretion of zoonoses should not be underestimated. However, optimal strategies for managing diseases where asymptomatic carriage instigates further infection remain unresolved, and the impact on disease management is unclear. In this review we consider the environmental pathways associated with prolonged antigenic exposure and critically assess the significance of asymptomatic carriage in disease outbreaks. Although screening high-risk groups for occupationally acquired diseases would be logistically problematical, there may be an economic case for identifying and treating asymptomatic carriage if the costs of screening and treatment are less than the costs of identifying and treating those individuals infected by asymptomatic hosts.

  5. Exposure to atrazine affects the expression of key genes in metabolic pathways integral to energy homeostasis in Xenopus laevis tadpoles

    Energy Technology Data Exchange (ETDEWEB)

    Zaya, Renee M., E-mail: renee.zaya@wmich.edu [Great Lakes Environmental and Molecular Sciences Center, Department of Biological Sciences, 3425 Wood Hall, Western Michigan University, 1903 West Michigan Avenue, Kalamazoo, MI 49008 (United States); Amini, Zakariya, E-mail: zakariya.amini@wmich.edu [Great Lakes Environmental and Molecular Sciences Center, Department of Biological Sciences, 3425 Wood Hall, Western Michigan University, 1903 West Michigan Avenue, Kalamazoo, MI 49008 (United States); Whitaker, Ashley S., E-mail: ashley.s.whitaker@wmich.edu [Great Lakes Environmental and Molecular Sciences Center, Department of Biological Sciences, 3425 Wood Hall, Western Michigan University, 1903 West Michigan Avenue, Kalamazoo, MI 49008 (United States); Ide, Charles F., E-mail: charles.ide@wmich.edu [Great Lakes Environmental and Molecular Sciences Center, Department of Biological Sciences, 3425 Wood Hall, Western Michigan University, 1903 West Michigan Avenue, Kalamazoo, MI 49008 (United States)

    2011-08-15

    In our laboratory, Xenopus laevis tadpoles exposed throughout development to 200 or 400 {mu}g/L atrazine, concentrations reported to periodically occur in puddles, vernal ponds and runoff soon after application, were smaller and had smaller fat bodies (the tadpole's lipid storage organ) than controls. It was hypothesized that these changes were due to atrazine-related perturbations of energy homeostasis. To investigate this hypothesis, selected metabolic responses to exposure at the transcriptional and biochemical levels in atrazine-exposed tadpoles were measured. DNA microarray technology was used to determine which metabolic pathways were affected after developmental exposure to 400 {mu}g/L atrazine. From these data, genes representative of the affected pathways were selected for assay using quantitative real time polymerase chain reaction (qRT-PCR) to measure changes in expression during a 2-week exposure to 400 {mu}g/L. Finally, ATP levels were measured from tadpoles both early in and at termination of exposure to 200 and 400 {mu}g/L. Microarray analysis revealed significant differential gene expression in metabolic pathways involved with energy homeostasis. Pathways with increased transcription were associated with the conversion of lipids and proteins into energy. Pathways with decreased transcription were associated with carbohydrate metabolism, fat storage, and protein synthesis. Using qRT-PCR, changes in gene expression indicative of an early stress response to atrazine were noted. Exposed tadpoles had significant decreases in acyl-CoA dehydrogenase (AD) and glucocorticoid receptor protein (GR) mRNA after 24 h of exposure, and near-significant (p = 0.07) increases in peroxisome proliferator-activated receptor {beta} (PPAR-{beta}) mRNA by 72 h. Decreases in AD suggested decreases in fatty acid {beta}-oxidation while decreases in GR may have been a receptor desensitization response to a glucocorticoid surge. Involvement of PPAR-{beta}, an energy

  6. Reconstruction of Pathways Associated with Amino Acid Metabolism in Human Mitochondria

    Institute of Scientific and Technical Information of China (English)

    Purnima Guda; Chittibabu Guda; Shankar Subramaniam

    2007-01-01

    We have used a bioinformatics approach for the identification and reconstruction of metabolic pathways associated with amino acid metabolism in human mitochon- dria. Human mitochondrial proteins determined by experimental and computa- tional methods have been superposed on the reference pathways from the KEGG database to identify mitochondrial pathways. Enzymes at the entry and exit points for each reconstructed pathway were identified, and mitochondrial solute carrier proteins were determined where applicable. Intermediate enzymes in the mito- chondrial pathways were identified based on the annotations available from public databases, evidence in current literature, or our MITOPRED program, which pre- dicts the mitochondrial localization of proteins. Through integration of the data derived from experimental, bibliographical, and computational sources, we recon- structed the amino acid metabolic pathways in human mitochondria, which could help better understand the mitochondrial metabolism and its role in human health.

  7. Human exposure to soil contamination: a qualitative and quantitative analysis towards proposals for human toxicological intervention values (partly revised edition)

    NARCIS (Netherlands)

    Berg R van den; LBG

    1994-01-01

    In view of a revision of the Dutch Soil Protection act, proposals are presented in this report for human toxicologically based intervention values for soil and groundwater, calculated from human toxicological guideline values and human exposure. To this purpose the exposure model CSOIL is presented

  8. Phosphoproteomics Profiling of Human Skin Fibroblast Cells Reveals Pathways and Proteins Affected by Low Doses of Ionizing Radiation

    Science.gov (United States)

    Yang, Feng; Waters, Katrina M.; Miller, John H.; Gritsenko, Marina A.; Zhao, Rui; Du, Xiuxia; Livesay, Eric A.; Purvine, Samuel O.; Monroe, Matthew E.; Wang, Yingchun; Camp, David G.; Smith, Richard D.; Stenoien, David L.

    2010-01-01

    Background High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. Principal Findings We have identified 7117 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conclusions Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health. PMID:21152398

  9. Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Feng; Waters, Katrina M.; Miller, John H.; Gritsenko, Marina A.; Zhao, Rui; Du, Xiuxia; Livesay, Eric A.; Purvine, Samuel O.; Monroe, Matthew E.; Wang, Yingchun; Camp, David G.; Smith, Richard D.; Stenoien, David L.

    2010-11-30

    Background: High doses of ionizing radiation result in biological damage, however the precise relationships between long term health effects, including cancer, and low dose exposures remain poorly understood and are currently extrapolated using high dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose dependent responses to radiation. Principle Findings: We have identified 6845 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts one hour post-exposure. Dual statistical analyses based on spectral counts and peak intensities identified 287 phosphopeptides (from 231 proteins) and 244 phosphopeptides (from 182 proteins) that varied significantly following exposure to 2 and 50 cGy respectively. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatics analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role of MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conlcusions: Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provides a basis for the systems level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at

  10. Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation.

    Directory of Open Access Journals (Sweden)

    Feng Yang

    Full Text Available BACKGROUND: High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose-dependent responses to radiation. PRINCIPAL FINDINGS: We have identified 7117 unique phosphopeptides (2566 phosphoproteins from control and irradiated (2 and 50 cGy primary human skin fibroblasts 1 h post-exposure. Semi-quantitative label-free analyses were performed to identify phosphopeptides that are apparently altered by radiation exposure. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase and protein kinase A (PKA signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. CONCLUSIONS: Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health.

  11. Gene expression profiling to identify potentially relevant disease outcomes and support human health risk assessment for carbon black nanoparticle exposure.

    Science.gov (United States)

    Bourdon, Julie A; Williams, Andrew; Kuo, Byron; Moffat, Ivy; White, Paul A; Halappanavar, Sabina; Vogel, Ulla; Wallin, Håkan; Yauk, Carole L

    2013-01-07

    New approaches are urgently needed to evaluate potential hazards posed by exposure to nanomaterials. Gene expression profiling provides information on potential modes of action and human relevance, and tools have recently become available for pathway-based quantitative risk assessment. The objective of this study was to use toxicogenomics in the context of human health risk assessment. We explore the utility of toxicogenomics in risk assessment, using published gene expression data from C57BL/6 mice exposed to 18, 54 and 162 μg Printex 90 carbon black nanoparticles (CBNP). Analysis of CBNP-perturbed pathways, networks and transcription factors revealed concomitant changes in predicted phenotypes (e.g., pulmonary inflammation and genotoxicity), that correlated with dose and time. Benchmark doses (BMDs) for apical endpoints were comparable to minimum BMDs for relevant pathway-specific expression changes. Comparison to inflammatory lung disease models (i.e., allergic airway inflammation, bacterial infection and tissue injury and fibrosis) and human disease profiles revealed that induced gene expression changes in Printex 90 exposed mice were similar to those typical for pulmonary injury and fibrosis. Very similar fibrotic pathways were perturbed in CBNP-exposed mice and human fibrosis disease models. Our synthesis demonstrates how toxicogenomic profiles may be used in human health risk assessment of nanoparticles and constitutes an important step forward in the ultimate recognition of toxicogenomic endpoints in human health risk. As our knowledge of molecular pathways, dose-response characteristics and relevance to human disease continues to grow, we anticipate that toxicogenomics will become increasingly useful in assessing chemical toxicities and in human health risk assessment. Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.

  12. Simulation of biatrial conduction via different pathways during sinus rhythm with a detailed human atrial model*

    OpenAIRE

    Deng, Dong-dong; Gong, Ying-lan; Shou, Guo-fa; Jiao, Pei-feng; Zhang, Heng-gui; Ye, Xue-song; Xia, Ling

    2012-01-01

    In order to better understand biatrial conduction, investigate various conduction pathways, and compare the differences between isotropic and anisotropic conductions in human atria, we present a simulation study of biatrial conduction with known/assumed conduction pathways using a recently developed human atrial model. In addition to known pathways: (1) Bachmann’s bundle (BB), (2) limbus of fossa ovalis (LFO), and (3) coronary sinus (CS), we also hypothesize that there exist two fast conducti...

  13. Building-associated neurological damage modeled in human cells: a mechanism of neurotoxic effects by exposure to mycotoxins in the indoor environment.

    Science.gov (United States)

    Karunasena, Enusha; Larrañaga, Michael D; Simoni, Jan S; Douglas, David R; Straus, David C

    2010-12-01

    Damage to human neurological system cells resulting from exposure to mycotoxins confirms a previously controversial public health threat for occupants of water-damaged buildings. Leading scientific organizations disagree about the ability of inhaled mycotoxins in the indoor environment to cause adverse human health effects. Damage to the neurological system can result from exposure to trichothecene mycotoxins in the indoor environment. This study demonstrates that neurological system cell damage can occur from satratoxin H exposure to neurological cells at exposure levels that can be found in water-damaged buildings contaminated with fungal growth. The constant activation of inflammatory and apoptotic pathways at low levels of exposure in human brain capillary endothelial cells, astrocytes, and neural progenitor cells may amplify devastation to neurological tissues and lead to neurological system cell damage from indirect events triggered by the presence of trichothecenes.

  14. Human dermal exposure to galaxolide from personal care products.

    Science.gov (United States)

    Correia, P; Cruz, A; Santos, L; Alves, A

    2013-06-01

    Musks are synthetic fragrances applied on personal care and household products as fixatives, by retarding the release of other fragrances with higher volatility. Galaxolide is the most used polycyclic musk since the 90th decade, and it has been detected in several environmental and biological matrices, particularly in human tissues and fluids. For exposure assessment purposes, large-monitoring data need to be obtained and rapid but reliable analytical techniques are requested. The main objective of this study is to develop and validate a new and fast analytical methodology to quantify galaxolide in personal care products and to apply this method to real matrices like skin care products (creams and lotions), shower products (soap bar), hair care products (shampoo and hair conditioner) and oral care products (toothpaste), to evaluate the human dermal exposure risk. A dispersive solid-phase extraction is proposed, using QuEChERS methodology, followed by HPLC with fluorescence detection. Some extraction parameters were studied, like the ratio of sample/solvent amounts, the homogenization time, the salt addition effect and the used sorbents. The validation parameters of the developed method were the following: a linearity range of 0.005-1.002 mg kg⁻¹ sample, a limit of detection of 0.001 mg kg⁻¹ sample, repeatability between 0.7% and 11.3% (variation coefficient of six standard injections), an intermediate precision of 2.5% (variation coefficient of six independent analysis of the same sample), mean recoveries ranging from 65% (soap bar) to 95% (body cream) and 3% of global uncertainty in most of the working range. The time of analysis, including the extraction steps, is 60 min, allowing a throughput of 4 samples h⁻¹ . Galaxolide was detected in all of the seven analysed products in concentrations ranging from 0.04 ± 0.01 mg kg⁻¹ sample (toothpaste) to 280.78 ± 8.19 mg kg⁻¹ sample (perfumed body cream), which may correspond to a significant estimated

  15. Sun Exposure and Its Effects on Human Health: Mechanisms through Which Sun Exposure Could Reduce the Risk of Developing Obesity and Cardiometabolic Dysfunction

    Science.gov (United States)

    Fleury, Naomi; Geldenhuys, Sian; Gorman, Shelley

    2016-01-01

    Obesity is a significant burden on global healthcare due to its high prevalence and associations with chronic health conditions. In our animal studies, ongoing exposure to low dose ultraviolet radiation (UVR, found in sunlight) reduced weight gain and the development of signs of cardiometabolic dysfunction in mice fed a high fat diet. These observations suggest that regular exposure to safe levels of sunlight could be an effective means of reducing the burden of obesity. However, there is limited knowledge around the nature of associations between sun exposure and the development of obesity and cardiometabolic dysfunction, and we do not know if sun exposure (independent of outdoor activity) affects the metabolic processes that determine obesity in humans. In addition, excessive sun exposure has strong associations with a number of negative health consequences such as skin cancer. This means it is very important to “get the balance right” to ensure that we receive benefits without increasing harm. In this review, we detail the evidence around the cardiometabolic protective effects of UVR and suggest mechanistic pathways through which UVR could be beneficial. PMID:27727191

  16. Sun Exposure and Its Effects on Human Health: Mechanisms through Which Sun Exposure Could Reduce the Risk of Developing Obesity and Cardiometabolic Dysfunction

    Directory of Open Access Journals (Sweden)

    Naomi Fleury

    2016-10-01

    Full Text Available Obesity is a significant burden on global healthcare due to its high prevalence and associations with chronic health conditions. In our animal studies, ongoing exposure to low dose ultraviolet radiation (UVR, found in sunlight reduced weight gain and the development of signs of cardiometabolic dysfunction in mice fed a high fat diet. These observations suggest that regular exposure to safe levels of sunlight could be an effective means of reducing the burden of obesity. However, there is limited knowledge around the nature of associations between sun exposure and the development of obesity and cardiometabolic dysfunction, and we do not know if sun exposure (independent of outdoor activity affects the metabolic processes that determine obesity in humans. In addition, excessive sun exposure has strong associations with a number of negative health consequences such as skin cancer. This means it is very important to “get the balance right” to ensure that we receive benefits without increasing harm. In this review, we detail the evidence around the cardiometabolic protective effects of UVR and suggest mechanistic pathways through which UVR could be beneficial.

  17. Photosensitized rose Bengal-induced phototoxicity on human melanoma cell line under natural sunlight exposure.

    Science.gov (United States)

    Srivastav, Ajeet K; Mujtaba, Syed Faiz; Dwivedi, Ashish; Amar, Saroj K; Goyal, Shruti; Verma, Ankit; Kushwaha, Hari N; Chaturvedi, Rajnish K; Ray, Ratan Singh

    2016-03-01

    Rose Bengal (RB) is an anionic water-soluble xanthene dye, which used for many years to assess eye cornea and conjunctiva damage. RB showed strong absorption maxima (λmax) under visible light followed by UV-B and UV-A. RB under sunlight exposure showed a time-dependent photodegradation. Our results show that photosensitized RB generates (1)O2 via Type-II photodynamic pathway and induced DNA damage under sunlight/UV-R exposure. 2'dGuO degradation, micronuclei formation, and single- and double-strand breakage were the outcome of photogenotoxicity caused by RB. Quenching studies with NaN3 advocate the involvement of (1)O2 in RB photogenotoxicity. RB induced linoleic acid photoperoxidation, which was parallel to (1)O2-mediated DNA damage. Oxidative stress in A375 cell line (human melanoma cell line) was detected through DCF-DA assay. Photosensitized RB decreased maximum cellular viability under sunlight followed by UV-B and UV-A exposures. Apoptosis was detected as a pattern of cell death through the increased of caspase-3 activity, decreased mitochondrial membrane potential, and PS translocation through inner to outer plasma membrane. Increased cytosolic levels of Bax also advocate the apoptotic cell death. We propose a p53-mediated apoptosis via increased expression of Bax gene and protein. Thus, the exact mechanism behind RB phototoxicity was the involvement of (1)O2, which induced oxidative stress-mediated DNA and membrane damage, finally apoptotic cell death under natural sunlight exposure. The study suggests that after the use of RB, sunlight exposure may avoid to prevent from its harmful effects. Copyright © 2015. Published by Elsevier B.V.

  18. Mercury Human Exposure in Populations Living Around Lake Tana (Ethiopia).

    Science.gov (United States)

    Habiba, G; Abebe, G; Bravo, Andrea G; Ermias, D; Staffan, Ǻ; Bishop, K

    2017-02-01

    A survey carried out in Lake Tana in 2015 found that Hg levels in some fish species exceeded internationally accepted safe levels for fish consumption. The current study assesses human exposure to Hg through fish consumption around the Lake Tana. Of particular interest was that a dietary intake of fishes is currently a health risk for Bihar Dar residents and anglers. Hair samples were collected from three different groups: anglers, college students and teachers, and daily laborers. A questionary includes gender, age, weight, activity. Frequency of fish consumption and origin of the eaten fish were completed by each participant. Mercury concentrations in hair were significantly higher (P value mercury and age associated with mercury concentration in scalp hair. Mercury concentrations in the hair of men were on average twice the value of the women. Also, users of skin lightening soap on a daily basis had 2.5 times greater mercury in scalp hair than non-users. Despite the different sources of mercury exposure mentioned above, the mercury concentrations of the scalp hair of participants of this study were below levels deemed to pose a threat to health.

  19. Dental fluorosis linked to degassing of Ambrym volcano, Vanuatu: a novel exposure pathway.

    Science.gov (United States)

    Allibone, Rachel; Cronin, Shane J; Charley, Douglas T; Neall, Vince E; Stewart, Robert B; Oppenheimer, Clive

    2012-04-01

    Ambrym in Vanuatu is a persistently degassing island volcano whose inhabitants harvest rainwater for their potable water needs. The findings from this study indicate that dental fluorosis is prevalent in the population due to fluoride contamination of rainwater by the volcanic plume. A dental survey was undertaken of 835 children aged 6-18 years using the Dean's Index of Fluorosis. Prevalence of dental fluorosis was found to be 96% in the target area of West Ambrym, 71% in North Ambrym, and 61% in Southeast Ambrym. This spatial distribution appears to reflect the prevailing winds and rainfall patterns on the island. Severe cases were predominantly in West Ambrym, the most arid part of the island, and the most commonly affected by the volcanic plume. Over 50 km downwind, on a portion of Malakula Island, the dental fluorosis prevalence was 85%, with 36% prevalence on Tongoa Island, an area rarely affected by volcanic emissions. Drinking water samples from West Ambrym contained fluoride levels from 0.7 to 9.5 ppm F (average 4.2 ppm F, n = 158) with 99% exceeding the recommended concentration of 1.0 ppm F. The pathway of fluoride-enriched rainwater impacting upon human health as identified in this study has not previously been recognised in the aetiology of fluorosis. This is an important consideration for populations in the vicinity of degassing volcanoes, particularly where rainwater comprises the primary potable water supply for humans or animals.

  20. Human exposure to fipronil from dogs treated with frontline.

    Science.gov (United States)

    Jennings, K A; Canerdy, T D; Keller, R J; Atieh, B H; Doss, R B; Gupta, R C

    2002-10-01

    This investigation determined fipronil residues on gloves worn while petting dogs after Frontline application. Frontline contains 9.8% fipronil, which controls fleas and ticks on dogs for at least 30 d. Frontline (1.34 ml) was applied topically on adult household dogs and gloves worn for 5 min during pettingwere collected 24 hr and 1, 2, 3, 4 and 5 w post-Frontline application for fipronil residue determinations using GC/MS. The highest concentration of fipronil (589.3 +/- 205.7ppm) was detected 24 h after Frontline application and was undetectable in the gloves collected at 5w. Repeated exposure to such contamination can pose human health risks.

  1. LIPOPOLYSACCHARIDE INDUCES EXPOSURE OF FIBRINOGEN RECEPTORS ON HUMAN PLATELETS

    Institute of Scientific and Technical Information of China (English)

    于希春; 吴其夏

    1995-01-01

    The effect of lipopolysaccharide (LPS) on the exposure of platelet fibrinogen receptors was investigated.The results showed that:1)LPS increased the binding of fibrinogen-gold complexes to platelets and the labels were primarily limited to shape-changed platelets;2)LPS caused a dose-dependent rise in intracellular Ca2+ concentration in platelets;3)LPS induced the activation of platelet protein kinase C(PKC) and the phosphorylation of glycoprotein llla (GP llla) which was inhibited by H-7.All these results suggest that stimulation of platelets with LPS causes a conformational change in glycoprotein llb/Illa (GPllb/llla) through platelet shape change and/or phosphorylation of GPllla via PKC,which serves to expose the fibrinogen binding sites of GPllb/llla on human platelets.

  2. Quantifying human exposure to air pollution - moving from static monitoring to spatio-temporally resolved personal exposure assessment

    DEFF Research Database (Denmark)

    Steinle, Susanne; Reis, Stefan; Sabel, Clive E

    2013-01-01

    results from multifaceted relationships and interactions between environmental and human systems, adding complexity to the assessment process. Traditionally, approaches to quantify human exposure have relied on pollutant concentrations from fixed air quality network sites and static population...... distributions. New developments in sensor technology now enable us to monitor personal exposure to air pollutants directly while people are moving through their activity spaces and varying concentration fields. The literature review on which this paper is based on reflects recent developments in the assessment...... for the integrated assessment of human exposure to air pollutants taking into account latest technological capabilities and contextual information. Highlights ? We review and discuss recent developments and advances of research into personal exposure to air pollution. ? We emphasise the importance of personal...

  3. Prioritising risk pathways of complex human diseases based on functional profiling.

    Science.gov (United States)

    Li, Yan; Huang, Teng; Xiao, Yun; Ning, Shangwei; Wang, Peng; Wang, Qianghu; Chen, Xin; Chaohan, Xu; Sun, Donglin; Li, Xia; Li, Yixue

    2013-06-01

    Analysis of the biological pathways involved in complex human diseases is an important step in elucidating the pathogenesis and mechanism of diseases. Most pathway analysis approaches identify disease-related biological pathways using overlapping genes between pathways and diseases. However, these approaches ignore the functional biological association between pathways and diseases. In this paper, we designed a novel computational framework for prioritising disease-risk pathways based on functional profiling. The disease gene set and biological pathways were translated into functional profiles in the context of GO annotations. We then implemented a semantic similarity measurement for calculating the concordance score between a functional profile of disease genes and a functional profile of pathways (FPP); the concordance score was then used to prioritise and infer disease-risk pathways. A freely accessible web toolkit, 'Functional Profiling-based Pathway Prioritisation' (FPPP), was developed (http://bioinfo.hrbmu.edu.cn/FPPP). During validation, our method successfully identified known disease-pathway pairs with area under the ROC curve (AUC) values of 96.73 and 95.02% in tests using both pathway randomisation and disease randomisation. A robustness analysis showed that FPPP is reliable even when using data containing noise. A case study based on a dilated cardiomyopathy data set indicated that the high-ranking pathways from FPPP are well known to be linked with this disease. Furthermore, we predicted the risk pathways of 413 diseases by using FPPP to build a disease similarity landscape that systematically reveals the global modular organisation of disease associations.

  4. The fatty acid beta-oxidation pathway is important for decidualization of endometrial stromal cells in both humans and mice.

    Science.gov (United States)

    Tsai, Jui-He; Chi, Maggie M-Y; Schulte, Maureen B; Moley, Kelle H

    2014-02-01

    Embryo implantation and development requires the endometrial stromal cells (ESCs) to undergo decidualization. This differentiation process requires glucose utilization, and blockade of the pentose phosphate pathway inhibits decidualization of ESCs both in vitro and in vivo. Glucose and fatty acids are energy substrates for many cell types, and fatty acid beta-oxidation is critical for embryo implantation. Here, we investigated whether beta-oxidation is required for decidualization of ESCs. As assessed by marker gene expression, decidualization of human primary ESCs was blocked by reducing activity of carnitine calmitoyltransferase I, the rate-limiting enzyme in beta-oxidation, either by short hairpin RNA-mediated silencing or by treatment with the inhibitor etomoxir. Ranolazine (RAN), a partial beta-oxidation inhibitor, blocked early decidualization of a human ESC line. However, decidualization resumed after several days, most likely due to a compensatory up-regulation of GLUT1 expression and an increase in glucose metabolism. Simultaneous inhibition of the beta-oxidation pathway with RAN and the pentose phosphate pathway with glucosamine (GlcN) impaired in vitro decidualization of human ESCs more strongly than inhibition of either pathway alone. These findings were confirmed in murine ESCs in vitro, and exposure to RAN plus GlcN inhibited decidualization in vivo in a deciduoma model. Finally, intrauterine implantation of time-release RAN and GlcN pellets reduced pup number. Importantly, pup number returned to normal after the end of the pellet-active period. This work indicates that both fatty acids and glucose metabolism pathways are important for ESC decidualization, and suggests novel pathways to target for the design of future nonhormonal contraceptives.

  5. A test chamber for experimental hydrogen fluoride exposure in humans.

    Science.gov (United States)

    Søstrand, P; Kongerud, J; Eduard, W; Nilsen, T; Skogland, M; Boe, J

    1997-07-01

    An inhalation chamber was built to perform experimental studies with hydrogen fluoride (HF), other gases, and particulate matter. The present study sought to describe a new gas delivery system and the distribution and concentration of HF gas in the chamber. The aluminum chamber has a volume of 19.2 m3 and a variable ventilation rate of about 1 to 10 air changes per hour. The negative pressure difference between the chamber and outside air can be regulated from 0 to 300 Pa. HF was fed at concentrations of up to 4000 mg/m3 directly into the ventilation duct feeding the chamber through openings with diameters as small as 50 microns, oriented opposite to the airflow. Gas flow was varied from about 0.1 dm3/min at a pressure of 4 atm. The dilution factor of HF concentration from cylinder to chamber was on the order of 10(3) to 10(4). The standard deviation (SD) of the HF concentrations at a fixed measurement point during a 1-hour test was typically 0.05 mg/m3 at a time-weighted average (TWA) concentration of 2.66 mg/m3. The SD of the TWA HF concentrations at six locations in the chamber was typically 0.05 mg/m3 and 0.29 mg/m3 at 0.61 and 3.46 mg/m3, respectively. Human exposure could be predicted from calculations based on ventilation data, gas flow, and observed ratio between calculated and measured concentrations. When the target exposure concentration was 1.5 mg/m3, the measured mean exposure concentration was typically 1.54 mg/m3 (range: 1.4-1.7 mg/m3, SD 0.09 mg/m3, n = 8). The chamber is well-suited for inhalation studies in humans. Chamber atmosphere was controlled and has proved to be stable and homogeneous, even in tests with HF, a highly reactive gas in the class of superacids.

  6. Guide to the evaluation of human exposure to noise from large wind turbines

    Science.gov (United States)

    Stephens, D. G.; Shepherd, K. P.; Hubbard, H. H.; Grosveld, F.

    1982-01-01

    Guidance for evaluating human exposure to wind turbine noise is provided and includes consideration of the source characteristics, the propagation to the receiver location, and the exposure of the receiver to the noise. The criteria for evaluation of human exposure are based on comparisons of the noise at the receiver location with the human perception thresholds for wind turbine noise and noise-induced building vibrations in the presence of background noise.

  7. The Aggregate Exposure Pathway (AEP): A conceptual framework for advancing exposure science research and transforming risk assessment

    Science.gov (United States)

    Recent advances in analytical methods, biomarker discovery, cell-based assay development, computational tools, sensor/monitor, and omics technology have enabled new streams of exposure and toxicity data to be generated at higher volumes and speed. These new data offer the opport...

  8. Third trimester phthalate exposure is associated with DNA methylation of growth-related genes in human placenta

    Science.gov (United States)

    Zhao, Yan; Chen, Jiao; Wang, Xiu; Song, Qi; Xu, Hui-Hui; Zhang, Yun-Hui

    2016-09-01

    Strong evidence implicates maternal phthalate exposure during pregnancy in contributing to adverse birth outcomes. Recent research suggests these effects might be mediated through the improper regulation of DNA methylation in offspring tissue. In this study, we examined associations between prenatal phthalate exposure and DNA methylation in human placenta. We recruited 181 mother-newborn pairs (80 fetal growth restriction newborns, 101 normal newborns) in Wenzhou, China and measured third trimester urinary phthalate metabolite concentrations and placental DNA methylation levels of IGF2 and AHRR. We found urinary concentrations of mono (2-ethyl-5- hydroxyhexyl) phthalate (MEHHP), and mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) were significantly inversely associated with placental IGF2 DNA methylation. The associations were much more evident in fetal growth restriction (FGR) newborns than those in normal newborns. These findings suggest that changes in placental DNA methylation might be part of the underlying biological pathway between prenatal phthalate exposure and adverse fetal growth.

  9. Third trimester phthalate exposure is associated with DNA methylation of growth-related genes in human placenta

    Science.gov (United States)

    Zhao, Yan; Chen, Jiao; Wang, Xiu; Song, Qi; Xu, Hui-Hui; Zhang, Yun-Hui

    2016-01-01

    Strong evidence implicates maternal phthalate exposure during pregnancy in contributing to adverse birth outcomes. Recent research suggests these effects might be mediated through the improper regulation of DNA methylation in offspring tissue. In this study, we examined associations between prenatal phthalate exposure and DNA methylation in human placenta. We recruited 181 mother-newborn pairs (80 fetal growth restriction newborns, 101 normal newborns) in Wenzhou, China and measured third trimester urinary phthalate metabolite concentrations and placental DNA methylation levels of IGF2 and AHRR. We found urinary concentrations of mono (2-ethyl-5- hydroxyhexyl) phthalate (MEHHP), and mono (2-ethyl-5-oxohexyl) phthalate (MEOHP) were significantly inversely associated with placental IGF2 DNA methylation. The associations were much more evident in fetal growth restriction (FGR) newborns than those in normal newborns. These findings suggest that changes in placental DNA methylation might be part of the underlying biological pathway between prenatal phthalate exposure and adverse fetal growth. PMID:27653773

  10. Human exposure to piroplasms in Central and Northern Italy

    Directory of Open Access Journals (Sweden)

    Simona Gabrielli

    2014-03-01

    Full Text Available A serosurvey has been conducted in Northern and Central Italy to investigate the presence in humans of antibodies against zoonotic Babesia and Theileria species. The study focused on a total of 432 volunteers, of which 290 were persistently exposed to tick bites because of their jobs (forester employees, livestock keepers, veterinary practitioners, farmers and hunters and 142 resident in the same area less frequently exposed. An indirect fluorescent antibody test (IFAT for humans was used to detect antibodies to Babesia microti, IFAT tests for veterinary use were modified to detect reactivity to Babesia bovis, Babesia canis and Theileria equi. A laboratory-derived ELISA was employed to detect antibodies to Babesia divergens. Both reactive and 10 negative sera were analysed against plasmodial antigens to evaluate possible aspecificity. A high reactivity to piroplasm antigens was found, showing significant difference between the sera of the two groups of volunteers (24% vs 7.0%; p<0.001. No cross-reactivity was observed, while each professional group showed reactivity that would fit with the professional risk exposure. In particular, a high reactivity to B. microti and B. divergens antigens was observed in foresters and hunters (32% and 12%, respectively. This is the first report on the human seroreactivity to piroplasms in Italy; it also provides additional epidemiological information on these tick-borne zoonoses in Europe. Our findings suggest the possible occurrence of piroplasm infections in Italy and alert physicians to consider these otherwise neglected parasitic diseases when dealing with any febrile illness, especially in subjects exposed to tick bites.

  11. 'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

    Energy Technology Data Exchange (ETDEWEB)

    Jetten, Marlon J.A.; Gaj, Stan [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Ruiz-Aracama, Ainhoa [RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Kok, Theo M. de [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Delft, Joost H.M. van, E-mail: j.vandelft@maastrichtuniversity.nl [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Lommen, Arjen [RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Someren, Eugene P. van [Research Group Microbiology and Systems Biology, TNO, PO Box 360 3700 AJ Zeist (Netherlands); Jennen, Danyel G.J.; Claessen, Sandra M. [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands); Peijnenburg, Ad A.C.M. [RIKILT, Institute of Food Safety, Wageningen UR, PO Box 230, 6700 AE, Wageningen (Netherlands); Stierum, Rob H. [Research Group Microbiology and Systems Biology, TNO, PO Box 360 3700 AJ Zeist (Netherlands); Kleinjans, Jos C.S. [Department of Toxicogenomics, Maastricht University, Universitiessingel 50 6229 ER Maastricht (Netherlands)

    2012-03-15

    Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites. -- Highlights: ► 'Omics techniques

  12. Induction of apoptosis in human myeloid leukemia cells by remote exposure of resistive barrier cold plasma.

    Science.gov (United States)

    Thiyagarajan, Magesh; Anderson, Heather; Gonzales, Xavier F

    2014-03-01

    Cold atmospheric plasma (CAP), an ambient temperature ionized gas, is gaining extensive interest as a promising addition to anti-tumor therapy primarily due to the ability to generate and control delivery of electrons, ions, excited molecules, UV photons, and reactive species such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) to a specific site. The heterogeneous composition of CAP offers the opportunity to mediate several signaling pathways that regulate tumor cells. Consequently, the array of CAP generated products has limited the identification of the mechanisms of action on tumor cells. The aim of this work is to assess the cell death response of human myeloid leukemia cells by remote exposure to CAP generated RNS by utilizing a novel resistive barrier discharge system that primarily produces RNS. The effect of variable treatments of CAP generated RNS was tested in THP-1 cell (human monocytic leukemia cell line), a model for hematological malignancy. The number of viable cells was evaluated with erythrosine-B staining, while apoptosis and necrosis was assessed by endonuclease cleavage observed by agarose gel electrophoresis and detection of cells with the exclusionary dye propidium iodide and fluorescently labeled annexin-V by flow cytometry and fluorescent microscopy. Our observations indicate that treatment dosage levels of 45 s of exposure to CAP emitted RNS-induced apoptotic cell death and for higher dosage conditions of ≥50 s of exposure to CAP induced necrosis. Overall the results suggest that CAP emitted RNS play a significant role in the anti-tumor potential of CAP.

  13. Adolescent Conflict as a Developmental Process in the Prospective Pathway from Exposure to Interparental Violence to Dating Violence

    OpenAIRE

    Narayan, Angela J.; Englund, Michelle M.; Carlson, Elizabeth A.; Egeland, Byron

    2014-01-01

    Within a developmental psychopathology framework, the current study examined adolescent conflict (age 16) with families, best friends, and dating partners as mediators in the prospective pathway from exposure to interparental violence (EIPV) in early childhood (0–64 months) to dating violence perpetration and victimization in early adulthood (age 23). Adolescent conflict was predicted to partially mediate EIPV and dating violence with significant direct paths from EIPV to dating violence, giv...

  14. ASSESSING HUMAN EXPOSURE TO GRASS POLLEN IN DENMARK

    DEFF Research Database (Denmark)

    Peel, Robert George; Hertel, Ole; Herbert, Rob

    Objectives: Exposure to pollen is typically assessed using data collected at fixed roof-top monitoring stations, which give a general picture of airborne pollen concentrations over a wide region. Actual exposure levels can be obtained through personal exposure monitoring. This is typically done u...

  15. Candidate gene biodosimeters of mice and human exposure to ionizing radiation by quantitative reverse transcription polymerase chain reaction

    Directory of Open Access Journals (Sweden)

    Hamed Rezaeejam

    2015-01-01

    Full Text Available Understanding of cellular responses to ionizing radiation (IR is essential for the development of predictive markers useful for assessing human exposure. Biological markers of exposure to IR in human populations are of great interest for assessing normal tissue injury in radiation oncology and for biodosimetry in nuclear incidents and accidental radiation exposures. Traditional radiation exposure biomarkers based on cytogenetic assays (biodosimetry, are time-consuming and do not provide results fast enough and requires highly trained personnel for scoring. Hence, the development of rapid biodosimetry methods is one of the highest priorities. Exposure of cells to IR activates multiple signal transduction pathways, which result in complex alterations in gene-expression. Real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR has become the benchmark for the detection and quantification of RNA targets and is being utilized increasingly in monitoring the specific genes with more accurately and sensitively. This review evaluates the RT-qPCR as a biodosimetry method and we investigated the papers from 2000 up to now, which identified the genes-expression related the DNA repair, cell cycle checkpoint, and apoptosis induced by ionization radiation in peripheral blood and determined as biodosimeters. In conclusion, it could be say that RT-qPCR technique for determining the specific genes as biodosimeters could be a fully quantitative reliable and sensitive method. Furthermore, the results of the current review will help the researchers to recognize the most expressed genes induced by ionization radiation.

  16. A changing climate: impacts on human exposures to O3 using an integrated modeling methodology

    Science.gov (United States)

    Predicting the impacts of changing climate on human exposure to air pollution requires future scenarios that account for changes in ambient pollutant concentrations, population sizes and distributions, and housing stocks. An integrated methodology to model changes in human exposu...

  17. Cytotoxicity and inflammation in human alveolar epithelial cells following exposure to occupational levels of gold and silver nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Bachand, George D., E-mail: gdbacha@sandia.gov [Sandia National Laboratories, Center for Integrated Nanotechnologies (United States); Allen, Amy [Sandia National Laboratories, Department of Analytical Science (United States); Bachand, Marlene [Sandia National Laboratories, Department of Nanobiology (United States); Achyuthan, Komandoor E. [Sandia National Laboratories, Department of Biosensors and Nanomaterials (United States); Seagrave, Jean Clare [Lovelace Respiratory Research Institute, Applied Life Science and Toxicology Division (United States); Brozik, Susan M. [Sandia National Laboratories, Department of Biosensors and Nanomaterials (United States)

    2012-10-15

    While inhalation represents one of the most likely routes of exposure, the toxicity and response of nanoparticles at concentrations expected from such an exposure are not well understood. Here we characterized the in vitro response of human A549 adenocarcinomic alveolar epithelial cells following exposure to gold (AuNP) and silver (AgNP) nanoparticles at levels approximating an occupational exposure. Changes in neither oxidative stress nor cytotoxicity were significantly affected by exposure to AgNPs and AuNPs, regardless of NP type (Ag vs. Au), concentration, surface ligand (citrate or tannic acid), or size. An inflammatory response was, however, observed in response to 20 nm AgNPs and 20 nm AuNPs, where significant differences in the release of interleukin (IL)-8 but not IL-6 were observed. Additional data demonstrated that increased IL-8 secretion was strongly dependent on both nanoparticle size and concentration. Overall these data suggest that, while not acutely toxic, occupational exposure to AuNPs and AgNPs may trigger a significant inflammatory response in alveolar epithelium. Moreover, the differential responses in IL-8 and IL-6 secretion suggest that NPs may induce a response pathway that is distinct from those commonly elicited by allergens and pathogens.

  18. Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways

    Energy Technology Data Exchange (ETDEWEB)

    Vickers, Alison E.M., E-mail: vickers_alison@allergan.com [Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine CA 92612 (United States); Heale, Jason; Sinclair, John R.; Morris, Stephen; Rowe, Josh M. [Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine CA 92612 (United States); Fisher, Robyn L. [Vitron Inc., Tucson, AZ (United States)

    2012-04-01

    Drug induced thyroid effects were evaluated in organotypic models utilizing either a rat thyroid lobe or human thyroid slices to compare rodent and human response. An inhibition of thyroid peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. The clinically used thiourea drugs, methimazole (MMI) and 6-n-propyl-2-thioruacil (PTU), were used to evaluate thyroid drug response in these models. Inhibition of TPO occurred early as shown in rat thyroid lobes (2 h) and was sustained in both rat (24–48 h) and human (24 h) with ≥ 10 μM MMI. Thyroid from rats treated with single doses of MMI (30–1000 mg/kg) exhibited sustained TPO inhibition at 48 h. The MMI in vivo thyroid concentrations were comparable to the culture concentrations (∼ 15–84 μM), thus demonstrating a close correlation between in vivo and ex vivo thyroid effects. A compensatory response to TPO inhibition was demonstrated in the rat thyroid lobe with significant up-regulation of genes involved in the pathway of thyroid hormone synthesis (Tpo, Dio1, Slc5a5, Tg, Tshr) and the megalin release pathway (Lrp2) by 24 h with MMI (≥ 10 μM) and PTU (100 μM). Similarly, thyroid from the rat in vivo study exhibited an up-regulation of Dio1, Slc5a5, Lrp2, and Tshr. In human thyroid slices, there were few gene expression changes (Slc5a5, ∼ 2-fold) and only at higher MMI concentrations (≥ 1500 μM, 24 h). Extended exposure (48 h) resulted in up-regulation of Tpo, Dio1 and Lrp2, along with Slc5a5 and Tshr. In summary, TPO was inhibited by similar MMI concentrations in rat and human tissue, however an increased sensitivity to drug treatment in rat is indicated by the up-regulation of thyroid hormone synthesis and release gene pathways at concentrations found not to affect human tissue. -- Highlights: ► Novel model of rat thyroid or human thyroid slices to evaluate pathways of injury. ► TPO inhibition by MMI or PTU altered

  19. The mTOR Signalling Pathway in Human Cancer

    Directory of Open Access Journals (Sweden)

    Paula Soares

    2012-02-01

    Full Text Available The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin, a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.

  20. Ubiquitin/proteasome pathway regulates levels of retinoic acid receptor gamma and retinoid X receptor alpha in human keratinocytes.

    Science.gov (United States)

    Boudjelal, M; Wang, Z; Voorhees, J J; Fisher, G J

    2000-04-15

    Repeated exposure of human skin to solar UV radiation leads to premature aging (photoaging) and skin cancer. UV-induced skin damage can be ameliorated by all-trans retinoic acid treatment. The actions of retinoic acid in skin keratinocytes are mediated primarily by nuclear retinoic acid receptor gamma (RARgamma) and retinoid X receptor alpha (RXRalpha). We found that exposure of cultured primary human keratinocytes to UV irradiation (30 mJ/cm2) substantially reduced (50-90%) RARgamma and RXRalpha mRNA and protein within 8 h. The rates of disappearance of RARgamma and RXRalpha proteins after UV exposure or treatment with the protein synthesis inhibitor cycloheximide were similar. UV irradiation did not increase the rate of breakdown of RARgamma or RXRalpha but rather reduced their rate of synthesis. The addition of proteasome inhibitors MG132 and LLvL, but not the lysosomal inhibitor E64, prevented loss of RARgamma and RXRalpha proteins after exposure of keratinocytes to either UV radiation or cycloheximide. Soluble extracts from nonirradiated or UV-irradiated keratinocytes possessed similar levels of proteasome activity that degraded RARgamma and RXRalpha proteins in vitro. Furthermore, RARgamma and RXRalpha were polyubiquitinated in intact cells. RXRalpha was found to contain two proline, glutamate/aspartate, serine, and threonine (PEST) motifs, which confer rapid turnover of many short-lived regulatory proteins that are degraded by the ubiquitin/proteasome pathway. However, the PEST motifs in RXRalpha did not function to regulate its stability, because deletion of the PEST motifs individually or together did not alter ubiquitination or proteasome-mediated degradation of RXRalpha. These results demonstrate that loss of RARgamma and RXRalpha proteins after UV irradiation results from degradation via the ubiquitin/proteasome pathway. Taken together, the data here indicate that ubiquitin/proteasome-mediated breakdown is an important mechanism regulating the levels of

  1. Human Exposure to Legacy and Emerging Halogenated Flame Retardants via Inhalation and Dust Ingestion in a Norwegian Cohort.

    Science.gov (United States)

    Tay, Joo Hui; Sellström, Ulla; Papadopoulou, Eleni; Padilla-Sánchez, Juan Antonio; Haug, Line Småstuen; de Wit, Cynthia A

    2017-07-18

    In this study, we estimated human exposure to polybrominated diphenyl ethers (PBDEs), hexabromocyclododecanes (HBCDDs), and several emerging flame retardants (EFRs) via inhalation and dust ingestion. Sixty indoor stationary air samples, 13 personal air samples, and 60 settled dust samples were collected from a Norwegian cohort during winter 2013. PBDEs showed the highest median concentration in dust (1200 ng/g), followed by EFRs (730 ng/g) and HBCDDs (190 ng/g). The PBDE concentrations in dust were mainly driven by BDE-209 and those of EFRs by bis(2-ethylhexyl) tetrabromophthalate. EFRs predominated in stationary air samples, with 2-ethylhexyl 2,3,4,5-tetrabromobenzoate and 4-(1,2-dibromoethyl)-1,2-dibromocyclohexane having the highest median concentrations (150 and 25 pg/m(3) (sum of α- and β-isomers), respectively). Different profiles and concentrations were observed in personal air samples compared to the corresponding stationary air samples. In relation to inhalation exposure, dust ingestion appears to be the major exposure pathway to FRs (median total exposure 230 pg/kg bw/d, accounting for more than 65% of the total exposure) for the Norwegian cohort. The calculated exposure due to air inhalation was substantially lower when the stationary air concentrations were used rather than personal air concentrations (43 pg/kg bw/d versus 130 pg/kg bw/d). This suggests that other exposure situations (such as outdoors or in offices) contributed significantly to the overall personal exposure, which cannot be included by using only a stationary air sampling technique. The median and 95th percentile exposures for all target FRs did not exceed the reference dose.

  2. Use of international data sets to evaluate and validate pathway assessment models applicable to exposure and dose reconstruction at DOE facilities. Progress report, August 1993--January 1994

    Energy Technology Data Exchange (ETDEWEB)

    Hendrickson, S.M. [ed.] [Lawrence Livermore National Lab., CA (United States); Hoffman, F.O. [Senes Oak Ridge, Inc., TN (United States). Center for Risk Analysis

    1994-03-01

    This project, ``Use of International Data Sets to Evaluate and Validate Pathway Assessment Models Applicable to Exposure and Dose Reconstruction at DOE Facilities,`` grew out of several activities being conducted by the Principal Investigator Dr. F Owen Hoffman. One activity was originally part of the Chernobyl Studies Project and began as Task 7.1D, ``Internal Dose From Direct Contamination of Terrestrial Food Sources.`` The objective of Task 7.1D was to (1) establish a collaborative US USSR effort to improve and validate our methods of forecasting doses and dose commitments from the direct contamination of food sources, and (2) perform experiments and validation studies to improve our ability to predict rapidly and accurately the long-term internal dose from the contamination of agricultural soil. The latter was to include the consideration of remedial measures to block contamination of food grown on contaminated soil. The current objective of this project is to evaluate and validate pathway-assessment models applicable to exposure and dose reconstruction at DOE facilities through use of international data sets. This project incorporates the activity of Task 7.1D into a multinational effort to evaluate data used for the prediction of radionuclide transfer through agricultural and aquatic systems to humans. It also includes participation in two multinational studies, BIOMOVS (BIOspheric MOdel Validation Study) with the Swedish National Institute for Radiation Protection and VAMP (VAlidation of Model Predictions) with the International Atomic Energy Agency, that address testing the performance of models of radionuclide transport through foodchains.

  3. The Health Impacts of Energy Policy Pathways in Ulaanbaatar, Mongolia: A Total Exposure Assessment

    Science.gov (United States)

    Hill, L. A.; Damdinsuren, Y.; Olkhanud, P. B.; Smith, K. R.; Turner, J. R.; Edwards, R.; Odsuren, M.; Ochir, C.

    2015-12-01

    Ulaanbaatar is home to nearly half of Mongolia's 2.8 million residents. The city's rapid growth, frigid winters, valley topography, and reliance on coal-fired stoves have led to some of the worst winter pollution levels in the world. To better understand this issue, we modeled integrated PM2.5exposures and related health impacts for various city-wide heating policies through 2024. This assessment is one of the first to employ a total exposure approach and results of the 2014 Comparative Risk Assessments of the Global Burden of Disease Project (CRA/GBD) in a policy-relevant energy study. Emissions related to heating, traffic, and power generation were considered under Business as Usual, Moderate Improvement, and Max Improvement scenarios. Calibrated outdoor models were combined with indoor models, local infiltration and time activity estimates, and demographic projections to estimate PM2.5exposures in 2014 and 2024. Indoor exposures were assigned by heating type, home type, and smoking status; outdoor exposures were assigned through geocoding. Population average annual exposures were calculated and applied to local disease rates and integrated exposure-response curves (2014 CRA/GBD) to arrive at annual projections of premature deaths and DALYs. We estimate 2014 annual average exposures at 68 μg/m3, dictated almost exclusively by indoor winter exposures. Under current trends, annual exposures increase 10% to 75 μg/m3 in 2024. This is in stark contrast to the moderate and max improvement scenarios, which lead to 2024 annual exposures that are 31%, and 68% lower, respectively. Under the Moderate scenario, 2024 per capita annual DALY and death burdens drop 26% and 22%, respectively, from 2014 levels. Under the Max scenario, 2024 per capita annual DALY and death burdens drop 71% and 66%, respectively, from 2014. SHS becomes a major contributor as emissions from other sectors decrease. Reductions are dominated by cardiovascular and lower respiratory diseases in children.

  4. Comparison of PBDE congener profiles and concentration levels in human specimens from China and the US and identification of human exposure sources

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    In an effort to investigate the status of human exposure to PBDEs in China,available monitoring data in human specimens(including breast milk,serums,and blood) was collected from the general population as well as specific groups that are occupationally exposed.PBDEs exposure profiles and concentration levels were compared with their counterparts in the United States of America.It was found that PBDE burdens in general Chinese population are one order lower and have different congener profiles from that in the US,showing higher percentages of BDE-28 or BDE-153 in human specimens from China.Workers and residents in electronic wastes recycling regions or areas of commercial PBDE manufacturing have the highest PBDE exposure levels reported worldwide,which are close or higher than the exposure levels of the general population in the US. Highly brominated congeners,such as BDE-207 and 209,are among the major PBDE congeners,and BDE-209 has the highest percentage(above 50%) for all occupational populations studied.Principal components analysis(PCA) demonstrates that the exposure of the general population in the US is closely related to penta-BDE while the human burden in China is not.The PBDE in indoor air(gas phase) in the US is highly correlated with the PBDE burden in the general population in the US,indicating a major exposure pathway.For the occupationally exposed populations in China,the congener profiles are closely related to the commercial deca-BDE products.Examination of exposure profiles for general and occupational populations in China suggests that it is essential to include more highly brominated congeners,such as BDE-207 and 209,in future human exposure studies,in order to assess the real burdens and profiles of PBDEs exposure in China.Strict pollution prevention and occupational protection procedures are in need in China to avoid the PBDE contamination problem that has occurred in the US.

  5. ASSESSING HUMAN EXPOSURE TO GRASS POLLEN IN DENMARK

    DEFF Research Database (Denmark)

    Peel, Robert George; Hertel, Ole; Herbert, Rob

    Objectives: Exposure to pollen is typically assessed using data collected at fixed roof-top monitoring stations, which give a general picture of airborne pollen concentrations over a wide region. Actual exposure levels can be obtained through personal exposure monitoring. This is typically done...... using a suction sampler worn on the chest or lapel that measures breathing zone concentration; a more useful exposure parameter for pollen allergy sufferers is the amount of pollen inhaled, i.e. the dose. The objective of this study was to investigate how well monitoring station data reflect actual...... exposure, something that is currently not well understood. Methods: Exposure samples were collected during the 2011 grass pollen season in an area of abundant unmaintained grass coverage close to the centre of Aarhus, Denmark. Sampling was performed at two-hourly intervals between 12:00 and 20:00 on 14...

  6. AGE-RELATED TOXICITY PATHWAY ANALYSIS IN BROWN NORWAY RAT BRAIN FOLLOWING ACUTE TOLUENE EXPOSURE

    Science.gov (United States)

    The influence of aging on susceptibility to environmental exposures is poorly understood. To investigate-the contribution of different life stages on response to toxicants, we examined the effects of an acute exposure to the volatile organic compound, toluene (0.0 or 1.0 g/kg), i...

  7. Human Rights Engagement and Exposure: New Scales to Challenge Social Work Education

    Science.gov (United States)

    McPherson, Jane; Abell, Neil

    2012-01-01

    Objectives: Advancing human rights is a core competency of U.S. social work education; yet, human rights attitudes and behaviors have never been measured in the social work literature. Thus, this article describes the development and initial validation of two scales, Human Rights Engagement in Social Work (HRESW) and Human Rights Exposure in…

  8. Human Rights Engagement and Exposure: New Scales to Challenge Social Work Education

    Science.gov (United States)

    McPherson, Jane; Abell, Neil

    2012-01-01

    Objectives: Advancing human rights is a core competency of U.S. social work education; yet, human rights attitudes and behaviors have never been measured in the social work literature. Thus, this article describes the development and initial validation of two scales, Human Rights Engagement in Social Work (HRESW) and Human Rights Exposure in…

  9. Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

    Directory of Open Access Journals (Sweden)

    Cui Zhi-Hua

    2012-03-01

    Full Text Available Abstract Background Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs and thromboxane A2 (TXA2. The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods A trimellitic anhydride (TMA sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2 after allergen challenge. Results Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187 induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells.

  10. A geographically-diverse collection of 418 human gut microbiome pathway genome databases

    KAUST Repository

    Hahn, Aria S.

    2017-04-11

    Advances in high-throughput sequencing are reshaping how we perceive microbial communities inhabiting the human body, with implications for therapeutic interventions. Several large-scale datasets derived from hundreds of human microbiome samples sourced from multiple studies are now publicly available. However, idiosyncratic data processing methods between studies introduce systematic differences that confound comparative analyses. To overcome these challenges, we developed GutCyc, a compendium of environmental pathway genome databases (ePGDBs) constructed from 418 assembled human microbiome datasets using MetaPathways, enabling reproducible functional metagenomic annotation. We also generated metabolic network reconstructions for each metagenome using the Pathway Tools software, empowering researchers and clinicians interested in visualizing and interpreting metabolic pathways encoded by the human gut microbiome. For the first time, GutCyc provides consistent annotations and metabolic pathway predictions, making possible comparative community analyses between health and disease states in inflammatory bowel disease, Crohn’s disease, and type 2 diabetes. GutCyc data products are searchable online, or may be downloaded and explored locally using MetaPathways and Pathway Tools.

  11. Human platelet lysate versus minoxidil stimulates hair growth by activating anagen promoting signaling pathways.

    Science.gov (United States)

    Dastan, Maryam; Najafzadeh, Nowruz; Abedelahi, Ali; Sarvi, Mohammadreza; Niapour, Ali

    2016-12-01

    Minoxidil and human platelet lysate (HPL) are commonly used to treat patients with hair loss. However, the roles of HPL versus minoxidil in hair follicle biology largely remain unknown. Here, we hypothesized that bulge and dermal papilla (DP) cells may express specific genes, including Kras, Erk, Akt, Shh and β-catenin after exposure to minoxidil or HPL. The mouse hair follicles were isolated on day 10 after depilation and bulge or DP regions were dissected. The bulge and DP cells were cultured for 14days in DMEM/F12 medium. Then, the cells were treated with 100μM minoxidil and 10% HPL for 10 days. Nuclear morphology was identified using DAPi staining. Reverse transcriptase and real-time polymerase chain reaction (PCR) analysis were also performed to examine the expression of Kras, Erk, Akt, Shh and β-catenin mRNA levels in the treated bulge and DP regions after organ culture. Here, we found that minoxidil influences bulge and DP cell survival (Pminoxidil treatment in both bulge and DP cells. HPL mediated Erk upregulation in both bulge and DP cells (Pminoxidil-treated bulge cells. In contrast, the expression of β-cateinin and Shh in the DP cells was not meaningfully increased after treatment with HPL. Our results suggest that minoxidil and HPL can promote hair growth by activating the main anagen inducing signaling pathways. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Role and mechanism of the AMPK pathway in waterborne Zn exposure influencing the hepatic energy metabolism of Synechogobius hasta

    Science.gov (United States)

    Wu, Kun; Huang, Chao; Shi, Xi; Chen, Feng; Xu, Yi-Huan; Pan, Ya-Xiong; Luo, Zhi; Liu, Xu

    2016-12-01

    Previous studies have investigated the physiological responses in the liver of Synechogobius hasta exposed to waterborne zinc (Zn). However, at present, very little is known about the underlying molecular mechanisms of these responses. In this study, RNA sequencing (RNA-seq) was performed to analyse the differences in the hepatic transcriptomes between control and Zn-exposed S. hasta. A total of 36,339 unigenes and 1,615 bp of unigene N50 were detected. These genes were further annotated to the Nonredundant protein (NR), Nonredundant nucleotide (Nt), Swiss-Prot, Kyoto Encyclopedia of Genes and Genomes (KEGG), Clusters of Orthologous Groups (COG) and Gene Ontology (GO) databases. After 60 days of Zn exposure, 708 and 237 genes were significantly up- and down-regulated, respectively. Many differentially expressed genes (DEGs) involved in energy metabolic pathways were identified, and their expression profiles suggested increased catabolic processes and reduced biosynthetic processes. These changes indicated that waterborne Zn exposure increased the energy production and requirement, which was related to the activation of the AMPK signalling pathway. Furthermore, using the primary hepatocytes of S. hasta, we identified the role of the AMPK signalling pathway in Zn-influenced energy metabolism.

  13. Physiological responses to exposure to carbon dioxide and human bioeffluents

    DEFF Research Database (Denmark)

    Zhang, Xiaojing; Wargocki, Pawel; Lian, Zhiwei

    2015-01-01

    Present paper describes physiological responses as a result of exposures to CO2 (between 500 ppm to 3,000 ppm) with and without bioeffluents. Twenty-five subjects participated. They were exposed in the climate chamber for 255 minutes in groups of five at a time. During exposure, they performed di...

  14. Limiting criteria for human exposure to low humidity indoors

    DEFF Research Database (Denmark)

    Wyon, David; Fang, Lei; Meyer, H.;

    2002-01-01

    % RH. The subjects performed simulated office work throughout each exposure. Building Related Symptom (BRS) intensity was reported on visual-analogue scales. Tests of eye, nose and skin function were applied. In these short exposures subjective discomfort, though significantly increased by low humidity...

  15. Carcinogenic effects of oil dispersants: A KEGG pathway-based RNA-seq study of human airway epithelial cells.

    Science.gov (United States)

    Liu, Yao-Zhong; Zhang, Lei; Roy-Engel, Astrid M; Saito, Shigeki; Lasky, Joseph A; Wang, Guangdi; Wang, He

    2017-02-20

    The health impacts of the BP oil spill are yet to be further revealed as the toxicological effects of oil products and dispersants on human respiratory system may be latent and complex, and hence difficult to study and follow up. Here we performed RNA-seq analyses of a system of human airway epithelial cells treated with the BP crude oil and/or dispersants Corexit 9500 and Corexit 9527 that were used to help break up the oil spill. Based on the RNA-seq data, we then systemically analyzed the transcriptomic perturbations of the cells at the KEGG pathway level using two pathway-based analysis tools, GAGE (generally applicable gene set enrichment) and GSNCA (Gene Sets Net Correlations Analysis). Our results suggested a pattern of change towards carcinogenesis for the treated cells marked by upregulation of ribosomal biosynthesis (hsa03008) (p=1.97E-13), protein processing (hsa04141) (p=4.09E-7), Wnt signaling (hsa04310) (p=6.76E-3), neurotrophin signaling (hsa04722) (p=7.73E-3) and insulin signaling (hsa04910) (p=1.16E-2) pathways under the dispersant Corexit 9527 treatment, as identified by GAGE analysis. Furthermore, through GSNCA analysis, we identified gene co-expression changes for several KEGG cancer pathways, including small cell lung cancer pathway (hsa05222, p=9.99E-5), under various treatments of oil/dispersant, especially the mixture of oil and Corexit 9527. Overall, our results suggested carcinogenic effects of dispersants (in particular Corexit 9527) and their mixtures with the BP crude oil, and provided further support for more stringent safety precautions and regulations for operations involving long-term respiratory exposure to oil and dispersants.

  16. Genetic Variation in Base Excision Repair Pathway Genes, Pesticide Exposure, and Prostate Cancer Risk

    National Research Council Canada - National Science Library

    Kathryn Hughes Barry; Stella Koutros; Sonja I. Berndt; Gabriella Andreotti; Jane A. Hoppin; Dale P. Sandler; Laurie A. Burdette; Meredith Yeager; Laura E. Beane Freeman; Jay H. Lubin; Xiaomei Ma; Tongzhang Zheng; Michael C. R. Alavanja

    2011-01-01

    .... OBJECTIVES: Because base excision repair (BER) is the predominant pathway involved in repairing oxidative damage, we evaluated interactions between 39 pesticides and 394 tag single-nucleotide polymorphisms (SNPs...

  17. Exposure to extremely low-frequency electromagnetic fields inhibits T-type calcium channels via AA/LTE4 signaling pathway.

    Science.gov (United States)

    Cui, Yujie; Liu, Xiaoyu; Yang, Tingting; Mei, Yan-Ai; Hu, Changlong

    2014-01-01

    Extremely low-frequency electromagnetic fields (ELF-EMF) causes various biological effects through altering intracellular calcium homeostasis. The role of high voltage-gated (HVA) calcium channels in ELF-EMF induced effects has been extensively studied. However, the effect of ELF-EMF on low-voltage-gated (LVA) T-type calcium channels has not been reported. In this study, we test the effect of ELF-EMF (50Hz) on human T-type calcium channels transfected in HEK293 cells. Conversely to its stimulant effects on HVA channels, ELF-EMF exposure inhibited all T-type (Cav3.1, Cav3.2 and Cav3.3) channels. Neither the protein expression nor the steady-state activation and inactivation kinetics of Cav3.2 channels were altered by ELF-EMF (50Hz, 0.2mT) exposure. Exposure to ELF-EMF increased both arachidonic acid (AA) and leukotriene E4 (LTE4) levels in HEK293 cells. CAY10502 and bestatin, which block the increase of AA and LTE4 respectively, abrogated the ELF-EMF inhibitory effect on Cav3.2 channels. Exogenous LTE4 mimicked the ELF-EMF inhibition of T-type calcium channels. ELF-EMF (50Hz) inhibits native T-type calcium channels in primary cultured mouse cortical neurons via LTE4. We conclude that 50Hz ELF-EMF inhibits T-type calcium channels through AA/LTE4 signaling pathway.

  18. Nonthermal Effects of Radar Exposure on Human: A Review Article

    Directory of Open Access Journals (Sweden)

    vida zaroushani

    2014-01-01

    Full Text Available ABSTRACT Microwave is part of the electromagnetic spectrum that has different application such as communications, military, air-traffic Control and etc... Previous studies showed that radar frequency could be a health hazard agent. This review article mentioned some of the studies that investigated non-thermal effects of radar frequencies. Reproductive effects, cancers, blood effects, genetic, adverse immune effects and mental effects are non-thermal effects that presented in this report. There are many unknown aspects of the biological effects and many of them did not determined very well such as oxidative stress and mental effects. Compliance with permissible exposure limits, reduction in exposure, and shielding are some of the controlling methods to protect workers from the exposure of microwave and among them, The use of shielding is a superior method for prevention of microwave exposure and among them, electromagnetic Nano composites shields is appropriate for protection of workers from radar exposure.

  19. Asymmetry of Radial and Symmetry of Tangential Neuronal Migration Pathways in Developing Human Fetal Brains.

    Science.gov (United States)

    Miyazaki, Yuta; Song, Jae W; Takahashi, Emi

    2016-01-01

    The radial and tangential neural migration pathways are two major neuronal migration streams in humans that are critical during corticogenesis. Corticogenesis is a complex process of neuronal proliferation that is followed by neuronal migration and the formation of axonal connections. Existing histological assessments of these two neuronal migration pathways have limitations inherent to microscopic studies and are confined to small anatomic regions of interest (ROIs). Thus, little evidence is available about their three-dimensional (3-D) fiber pathways and development throughout the entire brain. In this study, we imaged and analyzed radial and tangential migration pathways in the whole human brain using high-angular resolution diffusion MR imaging (HARDI) tractography. We imaged ten fixed, postmortem fetal (17 gestational weeks (GW), 18 GW, 19 GW, three 20 GW, three 21 GW and 22 GW) and eight in vivo newborn (two 30 GW, 34 GW, 35 GW and four 40 GW) brains with no neurological/pathological conditions. We statistically compared the volume of the left and right radial and tangential migration pathways, and the volume of the radial migration pathways of the anterior and posterior regions of the brain. In specimens 22 GW or younger, the volume of radial migration pathways of the left hemisphere was significantly larger than that of the right hemisphere. The volume of posterior radial migration pathways was also larger when compared to the anterior pathways in specimens 22 GW or younger. In contrast, no significant differences were observed in the radial migration pathways of brains older than 22 GW. Moreover, our study did not identify any significant differences in volumetric laterality in the tangential migration pathways. These results suggest that these two neuronal migration pathways develop and regress differently, and radial neuronal migration varies regionally based on hemispheric and anterior-posterior laterality, potentially explaining regional differences in

  20. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    NARCIS (Netherlands)

    Chin, L.; Meyerson, M.; Aldape, K.; Bigner, D.; Mikkelsen, T.; VandenBerg, S.; Kahn, A.; Penny, R.; Gerhard, D. S.; Getz, G.; Brennan, C.; Taylor, B. S.; Winckler, W.; Park, P.; Ladanyi, M.; Hoadley, K. A.; Verhaak, R. G. W.; Hayes, D. N.; Spellman, Paul T.; Absher, D.; Weir, B. A.; Ding, L.; Wheeler, D.; Lawrence, M. S.; Cibulskis, K.; Mardis, E.; Zhang, Jinghui; Wilson, R. K.; Donehower, L.; Wheeler, D. A.; Purdom, E.; Wallis, J.; Laird, P. W.; Herman, J. G.; Schuebel, K. E.; Weisenberger, D. J.; Baylin, S. B.; Schultz, N.; Yao, Jun; Wiedemeyer, R.; Weinstein, J.; Sander, C.; Gibbs, R. A.; Gray, J.; Kucherlapati, R.; Lander, E. S.; Myers, R. M.; Perou, C. M.; McLendon, Roger; Friedman, Allan; Van Meir, Erwin G; Brat, Daniel J; Mastrogianakis, Gena Marie; Olson, Jeffrey J; Lehman, Norman; Yung, W. K. Alfred; Bogler, Oliver; Berger, Mitchel; Prados, Michael; Muzny, Donna; Morgan, Margaret; Scherer, Steve; Sabo, Aniko; Nazareth, Lynn; Lewis, Lora; Hall, Otis; Zhu, Yiming; Ren, Yanru; Alvi, Omar; Yao, Jiqiang; Hawes, Alicia; Jhangiani, Shalini; Fowler, Gerald; San Lucas, Anthony; Kovar, Christie; Cree, Andrew; Dinh, Huyen; Santibanez, Jireh; Joshi, Vandita; Gonzalez-Garay, Manuel L.; Miller, Christopher A.; Milosavljevic, Aleksandar; Sougnez, Carrie; Fennell, Tim; Mahan, Scott; Wilkinson, Jane; Ziaugra, Liuda; Onofrio, Robert; Bloom, Toby; Nicol, Rob; Ardlie, Kristin; Baldwin, Jennifer; Gabriel, Stacey; Fulton, Robert S.; McLellan, Michael D.; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.; O'Kelly, Michael; Robinson, Jim; Alexe, Gabriele; Beroukhim, Rameen; Carter, Scott; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Garraway, Levi; Golub, Todd; Protopopov, Alexei; Perna, Ilana; Aronson, Sandy; Sathiamoorthy, Narayan; Ren, Georgia; Kim, Hyunsoo; Kong, Sek Won; Xiao, Yonghong; Kohane, Isaac S.; Seidman, Jon; Cope, Leslie; Pan, Fei; Van Den Berg, David; Van Neste, Leander; Yi, Joo Mi; Li, Jun Z.; Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin; Brooks, James D.; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Choi, Yoon Gi; Han, Ju; Ray, Amrita; Wang, Victoria; Durinck, Steffen; Robinson, Mark; Wang, Nicholas J.; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Fontenay, Gerald V.; Ngai, John; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.; Speed, Terence P.; Socci, Nicholas D.; Olshen, Adam; Lash, Alex; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wang, Wei Qing; Qin, Li-Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Topal, Michael D.; Qi, Yuan; Balu, Sai; Shi, Yan; Wu, George; Bittner, Michael; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin; Schaefer, Carl; Madhavan, Subha; Buetow, Ken; Barker, Anna; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth

    2008-01-01

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular

  1. Comprehensive genomic characterization defines human glioblastoma genes and core pathways

    NARCIS (Netherlands)

    Chin, L.; Meyerson, M.; Aldape, K.; Bigner, D.; Mikkelsen, T.; VandenBerg, S.; Kahn, A.; Penny, R.; Gerhard, D. S.; Getz, G.; Brennan, C.; Taylor, B. S.; Winckler, W.; Park, P.; Ladanyi, M.; Hoadley, K. A.; Verhaak, R. G. W.; Hayes, D. N.; Spellman, Paul T.; Absher, D.; Weir, B. A.; Ding, L.; Wheeler, D.; Lawrence, M. S.; Cibulskis, K.; Mardis, E.; Zhang, Jinghui; Wilson, R. K.; Donehower, L.; Wheeler, D. A.; Purdom, E.; Wallis, J.; Laird, P. W.; Herman, J. G.; Schuebel, K. E.; Weisenberger, D. J.; Baylin, S. B.; Schultz, N.; Yao, Jun; Wiedemeyer, R.; Weinstein, J.; Sander, C.; Gibbs, R. A.; Gray, J.; Kucherlapati, R.; Lander, E. S.; Myers, R. M.; Perou, C. M.; McLendon, Roger; Friedman, Allan; Van Meir, Erwin G; Brat, Daniel J; Mastrogianakis, Gena Marie; Olson, Jeffrey J; Lehman, Norman; Yung, W. K. Alfred; Bogler, Oliver; Berger, Mitchel; Prados, Michael; Muzny, Donna; Morgan, Margaret; Scherer, Steve; Sabo, Aniko; Nazareth, Lynn; Lewis, Lora; Hall, Otis; Zhu, Yiming; Ren, Yanru; Alvi, Omar; Yao, Jiqiang; Hawes, Alicia; Jhangiani, Shalini; Fowler, Gerald; San Lucas, Anthony; Kovar, Christie; Cree, Andrew; Dinh, Huyen; Santibanez, Jireh; Joshi, Vandita; Gonzalez-Garay, Manuel L.; Miller, Christopher A.; Milosavljevic, Aleksandar; Sougnez, Carrie; Fennell, Tim; Mahan, Scott; Wilkinson, Jane; Ziaugra, Liuda; Onofrio, Robert; Bloom, Toby; Nicol, Rob; Ardlie, Kristin; Baldwin, Jennifer; Gabriel, Stacey; Fulton, Robert S.; McLellan, Michael D.; Larson, David E.; Shi, Xiaoqi; Abbott, Rachel; Fulton, Lucinda; Chen, Ken; Koboldt, Daniel C.; Wendl, Michael C.; Meyer, Rick; Tang, Yuzhu; Lin, Ling; Osborne, John R.; Dunford-Shore, Brian H.; Miner, Tracie L.; Delehaunty, Kim; Markovic, Chris; Swift, Gary; Courtney, William; Pohl, Craig; Abbott, Scott; Hawkins, Amy; Leong, Shin; Haipek, Carrie; Schmidt, Heather; Wiechert, Maddy; Vickery, Tammi; Scott, Sacha; Dooling, David J.; Chinwalla, Asif; Weinstock, George M.; O'Kelly, Michael; Robinson, Jim; Alexe, Gabriele; Beroukhim, Rameen; Carter, Scott; Chiang, Derek; Gould, Josh; Gupta, Supriya; Korn, Josh; Mermel, Craig; Mesirov, Jill; Monti, Stefano; Nguyen, Huy; Parkin, Melissa; Reich, Michael; Stransky, Nicolas; Garraway, Levi; Golub, Todd; Protopopov, Alexei; Perna, Ilana; Aronson, Sandy; Sathiamoorthy, Narayan; Ren, Georgia; Kim, Hyunsoo; Kong, Sek Won; Xiao, Yonghong; Kohane, Isaac S.; Seidman, Jon; Cope, Leslie; Pan, Fei; Van Den Berg, David; Van Neste, Leander; Yi, Joo Mi; Li, Jun Z.; Southwick, Audrey; Brady, Shannon; Aggarwal, Amita; Chung, Tisha; Sherlock, Gavin; Brooks, James D.; Jakkula, Lakshmi R.; Lapuk, Anna V.; Marr, Henry; Dorton, Shannon; Choi, Yoon Gi; Han, Ju; Ray, Amrita; Wang, Victoria; Durinck, Steffen; Robinson, Mark; Wang, Nicholas J.; Vranizan, Karen; Peng, Vivian; Van Name, Eric; Fontenay, Gerald V.; Ngai, John; Conboy, John G.; Parvin, Bahram; Feiler, Heidi S.; Speed, Terence P.; Socci, Nicholas D.; Olshen, Adam; Lash, Alex; Reva, Boris; Antipin, Yevgeniy; Stukalov, Alexey; Gross, Benjamin; Cerami, Ethan; Wang, Wei Qing; Qin, Li-Xuan; Seshan, Venkatraman E.; Villafania, Liliana; Cavatore, Magali; Borsu, Laetitia; Viale, Agnes; Gerald, William; Topal, Michael D.; Qi, Yuan; Balu, Sai; Shi, Yan; Wu, George; Bittner, Michael; Shelton, Troy; Lenkiewicz, Elizabeth; Morris, Scott; Beasley, Debbie; Sanders, Sheri; Sfeir, Robert; Chen, Jessica; Nassau, David; Feng, Larry; Hickey, Erin; Schaefer, Carl; Madhavan, Subha; Buetow, Ken; Barker, Anna; Vockley, Joseph; Compton, Carolyn; Vaught, Jim; Fielding, Peter; Collins, Francis; Good, Peter; Guyer, Mark; Ozenberger, Brad; Peterson, Jane; Thomson, Elizabeth

    2008-01-01

    Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular char

  2. Special issue of Atmospheric Environment for Particulate Matter: Atmospheric Sciences, Exposure, and the Fourth Colloquium on PM and Human Health

    Science.gov (United States)

    Middlebrook, Ann; Turner, Jay; Solomon, Paul A.

    2004-10-01

    In response to epidemiological studies published over 20 years ago, at least three research communities have been intensively studying airborne particulate matter (PM). These efforts have been coordinated by approaching the source-atmospheric accumulation/receptor-exposure-dose-health effects paradigm (adopted from NRC, 2001) from different perspectives or along different parts of the paradigm. The atmospheric sciences communities consider the emissions of particles and precursors from sources, their transport and transformation in air to receptor locations, and finally removal from the atmosphere. The exposure communities' interest is to examine the pathways by which pollution or PM, in this case, approaches and enters the body, typically by trying to relate PM concentrations at a central location(s) to exposure and perhaps dose. Both the atmospheric sciences and exposure communities approach the paradigm from left to right. In contrast, the health effects communities have studied health outcomes, including hospital admissions, school absences, disease rates and deaths in human populations, and potential mechanisms of biological actions in laboratory settings. In general, the health effects communities' approach the paradigm from right to left attempting to correlate an observed adverse health effect with dose or exposure measures. For the most part, research results are reported in scientific publications and conferences for each community respectively. Over the years, there has been little effort to integrate information from these diverse groups in a substantive way. While a major attempt took place in 1998 at the Chapel Hill workshop (Albritton and Greenbaum, 1998), little has occurred since.

  3. Metabolite profiling identifies pathways associated with metabolic risk in humans.

    Science.gov (United States)

    Cheng, Susan; Rhee, Eugene P; Larson, Martin G; Lewis, Gregory D; McCabe, Elizabeth L; Shen, Dongxiao; Palma, Melinda J; Roberts, Lee D; Dejam, Andre; Souza, Amanda L; Deik, Amy A; Magnusson, Martin; Fox, Caroline S; O'Donnell, Christopher J; Vasan, Ramachandran S; Melander, Olle; Clish, Clary B; Gerszten, Robert E; Wang, Thomas J

    2012-05-08

    Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmö Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, -0.04 to -0.22 per 1-SD change in log-glutamine; Prisk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and decreased blood pressure (Pprofiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice.

  4. Human exposure to acrolein: Time-dependence and individual variation in eye irritation.

    Science.gov (United States)

    Claeson, Anna-Sara; Lind, Nina

    2016-07-01

    The aim of the study was to examine the time dependence on sensory irritation detection following exposure to threshold levels of acrolein, in humans. The exposures occurred in an exposure chamber and the subjects were breathing fresh air through a mask that covered the nose and mouth. All participants participated in four exposure conditions, of which three consisted of a mixture of acrolein and heptane and one of only heptane. Exposure to acrolein at a concentration half of the TLV-C lead to sensory irritation. The perceived sensory irritation resulted in both increased detectability and sensory irritation after about 6.8min of exposure in 58% of the participants. The study confirm the previously suggested LOAEL of about 0.34mg/m(3) for eye irritation due to acrolein exposure. The sensory irritation was still significant 10min after exposure. These results have implications for risk assessment and limit setting in occupational hygiene.

  5. Activation of VEGF/Flk-1-ERK Pathway Induced Blood-Brain Barrier Injury After Microwave Exposure.

    Science.gov (United States)

    Wang, Li-Feng; Li, Xiang; Gao, Ya-Bing; Wang, Shui-Ming; Zhao, Li; Dong, Ji; Yao, Bin-Wei; Xu, Xin-Ping; Chang, Gong-Min; Zhou, Hong-Mei; Hu, Xiang-Jun; Peng, Rui-Yun

    2015-08-01

    Microwaves have been suggested to induce neuronal injury and increase permeability of the blood-brain barrier (BBB), but the mechanism remains unknown. The role of the vascular endothelial growth factor (VEGF)/Flk-1-Raf/MAPK kinase (MEK)/extracellular-regulated protein kinase (ERK) pathway in structural and functional injury of the blood-brain barrier (BBB) following microwave exposure was examined. An in vitro BBB model composed of the ECV304 cell line and primary rat cerebral astrocytes was exposed to microwave radiation (50 mW/cm(2), 5 min). The structure was observed by scanning electron microscopy (SEM) and the permeability was assessed by measuring transendothelial electrical resistance (TEER) and horseradish peroxidase (HRP) transmission. Activity and expression of VEGF/Flk-1-ERK pathway components and occludin also were examined. Our results showed that microwave radiation caused intercellular tight junctions to broaden and fracture with decreased TEER values and increased HRP permeability. After microwave exposure, activation of the VEGF/Flk-1-ERK pathway and Tyr phosphorylation of occludin were observed, along with down-regulated expression and interaction of occludin with zonula occludens-1 (ZO-1). After Flk-1 (SU5416) and MEK1/2 (U0126) inhibitors were used, the structure and function of the BBB were recovered. The increase in expression of ERK signal transduction molecules was muted, while the expression and the activity of occludin were accelerated, as well as the interactions of occludin with p-ERK and ZO-1 following microwave radiation. Thus, microwave radiation may induce BBB damage by activating the VEGF/Flk-1-ERK pathway, enhancing Tyr phosphorylation of occludin, while partially inhibiting expression and interaction of occludin with ZO-1.

  6. Human exposure risk to heavy metals through groundwater used for drinking in an intensively irrigated river delta

    Science.gov (United States)

    Vetrimurugan, E.; Brindha, K.; Elango, L.; Ndwandwe, Osman Muzi

    2016-09-01

    Drinking water containing heavy metals above the maximum permissible limits cause potential risk to human health. The aim of this study was to determine the groundwater suitability for drinking use based on heavy metal concentration and the associated human exposure risk in an intensively irrigated part of the Cauvery river basin, Tamil Nadu, India. Sixteen heavy metals analysed were in the order of dominance of chromium water quality, and silver, lead and nickel were above limits in all the groundwater samples. In less than 50 % of the groundwater samples, aluminium, boron, cadmium, copper, iron and manganese exceeded their individual permissible limits. Heavy metal pollution index based on 11 heavy metals indicated that groundwater quality of this area is poor-to-unsuitable. Non-carcinogenic risk for humans due to ingestion of groundwater through drinking water pathway was very high for infants, children and adults. Silver, lead, nickel, cadmium and manganese largely contributed to the health hazard. Sources of heavy metals were identified to be geological and from human activities, i.e., application of fertilizers in agricultural fields, seawater intrusion due to intensive pumping for agriculture and wastewater from industries. Groundwater and surface water in this area pose large threat due to high levels of heavy metals, and it is necessary to avoid this water for drinking due to potential risk of health hazard. This study also demonstrated the application of HPI and human exposure hazard index to study the groundwater quality based on heavy metals' concentration.

  7. Tumor promotion by exposure to radiofrequency electromagnetic fields below exposure limits for humans.

    Science.gov (United States)

    Lerchl, Alexander; Klose, Melanie; Grote, Karen; Wilhelm, Adalbert F X; Spathmann, Oliver; Fiedler, Thomas; Streckert, Joachim; Hansen, Volkert; Clemens, Markus

    2015-04-17

    The vast majority of in vitro and in vivo studies did not find cancerogenic effects of exposure to electromagnetic fields (RF-EMF), i.e. emitted by mobile phones and base stations. Previously published results from a pilot study with carcinogen-treated mice, however, suggested tumor-promoting effects of RF-EMF (Tillmann et al., 2010). We have performed a replication study using higher numbers of animals per group and including two additional exposure levels (0 (sham), 0.04, 0.4 and 2 W/kg SAR). We could confirm and extend the originally reported findings. Numbers of tumors of the lungs and livers in exposed animals were significantly higher than in sham-exposed controls. In addition, lymphomas were also found to be significantly elevated by exposure. A clear dose-response effect is absent. We hypothesize that these tumor-promoting effects may be caused by metabolic changes due to exposure. Since many of the tumor-promoting effects in our study were seen at low to moderate exposure levels (0.04 and 0.4 W/kg SAR), thus well below exposure limits for the users of mobile phones, further studies are warranted to investigate the underlying mechanisms. Our findings may help to understand the repeatedly reported increased incidences of brain tumors in heavy users of mobile phones.

  8. Campylobacter fetus infections in humans : exposure and disease

    NARCIS (Netherlands)

    Wagenaar, Jaap A; van Bergen, Marcel A P; Blaser, Martin J; Tauxe, Robert V; Newell, Diane G; van Putten, Jos P M

    2014-01-01

    Campylobacter fetus can cause intestinal illness and, occasionally, severe systemic infections. Infections mainly affect persons at higher risk, including elderly and immunocompromised individuals and those with occupational exposure to infected animals. Outbreaks are infrequent but have provided in

  9. Physiological responses to exposure to carbon dioxide and human bioeffluents

    DEFF Research Database (Denmark)

    Zhang, Xiaojing; Wargocki, Pawel; Lian, Zhiwei

    2015-01-01

    different cognitive tasks and assessed their comfort and acute health symptoms. Besides, the following were determined: heart rate, blood pressure, oxygen saturation of blood, respiration rate, minute ventilation rate, nasal peak flow, forced expiratory volume, and the end-tidal CO2 pressure (ETCO2). Saliva...... with bioeffluents, the performance of Tsai-Partington test was reduced, and diastolic blood pressure and alpha-amylase increased after exposure compared with their levels before exposure, which may suggest higher arousal/stress. During exposure to CO2 without bioeffluents, the performance of Tsai-Partington test...... also was lower, which may suggest higher stress/arousal, too. However, no effects on blood pressure and alpha-amylase were seen for this exposure....

  10. Climate change impacts on human exposures to air pollution

    Science.gov (United States)

    This is an abstract for a presentations at the Annual Conference of the International Society on Exposure Science and Environmental Epidemiology. This presentation will serve as an introduction to the symposium.

  11. Integrating Human Indoor Air Pollutant Exposure within Life Cycle Impact Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Hellweg, Stefanie; Demou, Evangelia; Bruzzi, Raffaella; Meijer, Arjen; Rosenbaum, Ralph K.; Huijbregts, Mark A.J.; McKone, Thomas E.

    2008-12-21

    Neglecting health effects from indoor pollutant emissions and exposure, as currently done in Life Cycle Assessment (LCA), may result in product or process optimizations at the expense of workers? or consumers? health. To close this gap, methods for considering indoor exposure to chemicals are needed to complement the methods for outdoor human exposure assessment already in use. This paper summarizes the work of an international expert group on the integration of human indoor and outdoor exposure in LCA, within the UNEP/SETAC Life Cycle Initiative. A new methodological framework is proposed for a general procedure to include human-health effects from indoor exposure in LCA. Exposure models from occupational hygiene and household indoor air quality studies and practices are critically reviewed and recommendations are provided on the appropriateness of various model alternatives in the context of LCA. A single-compartment box model is recommended for use as a default in LCA, enabling one to screen occupational and household exposures consistent with the existing models to assess outdoor emission in a multimedia environment. An initial set of model parameter values was collected. The comparison between indoor and outdoor human exposure per unit of emission shows that for many pollutants, intake per unit of indoor emission may be several orders of magnitude higher than for outdoor emissions. It is concluded that indoor exposure should be routinely addressed within LCA.

  12. Pesticide Flow Analysis to Assess Human Exposure in Greenhouse Flower Production in Colombia

    Directory of Open Access Journals (Sweden)

    Claudia R. Binder

    2013-03-01

    Full Text Available Human exposure assessment tools represent a means for understanding human exposure to pesticides in agricultural activities and managing possible health risks. This paper presents a pesticide flow analysis modeling approach developed to assess human exposure to pesticide use in greenhouse flower crops in Colombia, focusing on dermal and inhalation exposure. This approach is based on the material flow analysis methodology. The transfer coefficients were obtained using the whole body dosimetry method for dermal exposure and the button personal inhalable aerosol sampler for inhalation exposure, using the tracer uranine as a pesticide surrogate. The case study was a greenhouse rose farm in the Bogota Plateau in Colombia. The approach was applied to estimate the exposure to pesticides such as mancozeb, carbendazim, propamocarb hydrochloride, fosetyl, carboxin, thiram, dimethomorph and mandipropamide. We found dermal absorption estimations close to the AOEL reference values for the pesticides carbendazim, mancozeb, thiram and mandipropamide during the study period. In addition, high values of dermal exposure were found on the forearms, hands, chest and legs of study participants, indicating weaknesses in the overlapping areas of the personal protective equipment parts. These results show how the material flow analysis methodology can be applied in the field of human exposure for early recognition of the dispersion of pesticides and support the development of measures to improve operational safety during pesticide management. Furthermore, the model makes it possible to identify the status quo of the health risk faced by workers in the study area.

  13. Human exposure to pulsed fields in the frequency range from 6 to 100 GHz

    Science.gov (United States)

    Laakso, Ilkka; Morimoto, Ryota; Heinonen, Juhani; Jokela, Kari; Hirata, Akimasa

    2017-09-01

    Restrictions on human exposure to electromagnetic waves at frequencies higher than 3-10 GHz are defined in terms of the incident power density to prevent excessive temperature rise in superficial tissue. However, international standards and guidelines differ in their definitions of how the power density is interpreted for brief exposures. This study investigated how the temperature rise was affected by exposure duration at frequencies higher than 6 GHz. Far-field exposure of the human face to pulses shorter than 10 s at frequencies from 6 to 100 GHz was modelled using the finite-difference time-domain method. The bioheat transfer equation was used for thermal modelling. We investigated the effects of frequency, polarization, exposure duration, and depth below the skin surface on the temperature rise. The results indicated limitations in the current human exposure guidelines and showed that radiant exposure, i.e. energy absorption per unit area, can be used to limit temperature rise for pulsed exposure. The data are useful for the development of human exposure guidelines at frequencies higher than 6 GHz.

  14. Pesticide flow analysis to assess human exposure in greenhouse flower production in Colombia.

    Science.gov (United States)

    Lesmes-Fabian, Camilo; Binder, Claudia R

    2013-03-25

    Human exposure assessment tools represent a means for understanding human exposure to pesticides in agricultural activities and managing possible health risks. This paper presents a pesticide flow analysis modeling approach developed to assess human exposure to pesticide use in greenhouse flower crops in Colombia, focusing on dermal and inhalation exposure. This approach is based on the material flow analysis methodology. The transfer coefficients were obtained using the whole body dosimetry method for dermal exposure and the button personal inhalable aerosol sampler for inhalation exposure, using the tracer uranine as a pesticide surrogate. The case study was a greenhouse rose farm in the Bogota Plateau in Colombia. The approach was applied to estimate the exposure to pesticides such as mancozeb, carbendazim, propamocarb hydrochloride, fosetyl, carboxin, thiram, dimethomorph and mandipropamide. We found dermal absorption estimations close to the AOEL reference values for the pesticides carbendazim, mancozeb, thiram and mandipropamide during the study period. In addition, high values of dermal exposure were found on the forearms, hands, chest and legs of study participants, indicating weaknesses in the overlapping areas of the personal protective equipment parts. These results show how the material flow analysis methodology can be applied in the field of human exposure for early recognition of the dispersion of pesticides and support the development of measures to improve operational safety during pesticide management. Furthermore, the model makes it possible to identify the status quo of the health risk faced by workers in the study area.

  15. Multiple Drug Transport Pathways through Human P-Glycoprotein.

    Science.gov (United States)

    McCormick, James W; Vogel, Pia D; Wise, John G

    2015-07-21

    P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented.

  16. Multiple successional pathways in human-modified tropical landscapes

    NARCIS (Netherlands)

    Arroyo-Rodríguez, Víctor; Melo, Felipe P.L.; Martínez-Ramos, Miguel; Bongers, Frans; Chazdon, Robin L.; Meave, Jorge A.; Norden, Natalia; Santos, Bráulio A.; Leal, Inara R.; Tabarelli, Marcelo

    2017-01-01

    Old-growth tropical forests are being extensively deforested and fragmented worldwide. Yet forest recovery through succession has led to an expansion of secondary forests in human-modified tropical landscapes (HMTLs). Secondary forests thus emerge as a potential repository for tropical biodiversi

  17. Human Infection with MERS Coronavirus after Exposure to Infected Camels, Saudi Arabia, 2013

    OpenAIRE

    Memish, Ziad A.; Cotten, Matthew; Meyer, Benjamin; Simon J Watson; Alsahafi, Abdullah J.; Al Rabeeah, Abdullah A.; Corman, Victor Max; Sieberg, Andrea; Makhdoom, Hatem Q.; Assiri, Abdullah; Al Masri, Malaki; Aldabbagh, Souhaib; Bosch, Berend-Jan; Beer, Martin; Müller, Marcel A.

    2014-01-01

    We investigated a case of human infection with Middle East respiratory syndrome coronavirus (MERS-CoV) after exposure to infected camels. Analysis of the whole human-derived virus and 15% of the camel-derived virus sequence yielded nucleotide polymorphism signatures suggestive of cross-species transmission. Camels may act as a direct source of human MERS-CoV infection.

  18. TCDD induces the hypoxia-inducible factor (HIF)-1α regulatory pathway in human trophoblastic JAR cells.

    Science.gov (United States)

    Liao, Tien-Ling; Chen, Su-Chee; Tzeng, Chii-Reuy; Kao, Shu-Huei

    2014-09-30

    The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α) stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS) and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K) inhibitor) or N-acetylcysteine (a ROS scavenger). The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development.

  19. Role of IL-17 Pathways in Immune Privilege: A RNA Deep Sequencing Analysis of the Mice Testis Exposure to Fluoride

    Science.gov (United States)

    Huo, Meijun; Han, Haijun; Sun, Zilong; Lu, Zhaojing; Yao, Xinglei; Wang, Shaolin; Wang, Jundong

    2016-01-01

    We sequenced RNA transcripts from the testicles of healthy male mice, divided into a control group with distilled water and two experimental groups with 50 and 100 mg/l NaF in drinking water for 56 days. Bowtie/Tophat were used to align 50-bp paired-end reads into transcripts, Cufflinks to measure the relative abundance of each transcript and IPA to analyze RNA-Sequencing data. In the 100 mg/l NaF-treated group, four pathways related to IL-17, TGF-β and other cellular growth factor pathways were overexpressed. The mRNA expression of IL-17RA, IL-17RC, MAP2K1, MAP2K2, MAP2K3 and MAPKAPK2, monitored by qRT-PCR, increased remarkably in the 100 mg/L NaF group and coincided with the result of RNA-Sequencing. Fluoride exposure could disrupt spermatogenesis and testicles in male mice by influencing many signaling pathways and genes, which work on the immune signal transduction and cellular metabolism. The high expression of the IL-17 signal pathway was a response to the invasion of the testicular immune system due to extracellular fluoride. The PI3-kinase/AKT, MAPKs and the cytokines in TGF-β family were contributed to control the IL-17 pathway activation and maintain the immune privilege and spermatogenesis. All the findings provided new ideas for further molecular researches of fluorosis on the reproduction and immune response mechanism. PMID:27572304

  20. TOXICITY PATHWAY ANALYSIS IN AGING BROWN NORWAY RAT BRAIN FOLLOWING ACUTE TOLUENE EXPOSURE

    Science.gov (United States)

    The influence of aging on susceptibility to environmental stressors is poorly understood. To investigate the contribution of different life stages on response to toxicants, we examined the effects of acute exposure by oral gavage of the volatile organic solvent toluene (0.00, 0.3...

  1. TOXICITY PATHWAY ANALYSIS IN AGING BROWN NORWAY RAT BRAIN FOLLOWING ACUTE TOLUENE EXPOSURE

    Science.gov (United States)

    The influence of aging on susceptibility to environmental stressors is poorly understood. To investigate the contribution of different life stages on response to toxicants, we examined the effects of acute exposure by oral gavage of the volatile organic solvent toluene (0.00, 0.3...

  2. 40 CFR 26.1203 - Prohibition of research involving intentional exposure of any human subject who is a pregnant...

    Science.gov (United States)

    2010-07-01

    ... intentional exposure of any human subject who is a pregnant woman (and therefore her fetus), a nursing woman... Exposure of Human Subjects who are Children or Pregnant or Nursing Women § 26.1203 Prohibition of research involving intentional exposure of any human subject who is a pregnant woman (and therefore her fetus),...

  3. Identification of molecular markers related to human alveolar bone cells and pathway analysis in diabetic patients.

    Science.gov (United States)

    Sun, X; Ren, Q H; Bai, L; Feng, Q

    2015-10-28

    Alveolar bone osteoblasts are widely used in dental and related research. They are easily affected by systemic diseases such as diabetes. However, the mechanism of diabetes-induced alveolar bone absorption remains unclear. This study systematically explored the changes in human alveolar bone cell-related gene expression and biological pathways, which may facilitate the investigation of its mechanism. Alveolar bone osteoblasts isolated from 5 male diabetics and 5 male healthy adults were cultured. Total RNA was extracted from these cells and subjected to gene microarray analysis. Differentially expressed genes were screened, and a gene interaction network was constructed. An enrichment pathway analysis was simultaneously performed on differentially expressed genes to identify the biological pathways associated with changes in the alveolar bone cells of diabetic humans. In total, we identified 147 mRNAs that were differentially expressed in diabetic alveolar bone cells (than in the normal cells; 91 upregulated and 36 downregulated mRNAs). The constructed co-expression network showed 3 pairs of significantly-expressed genes. High-enrichment pathway analysis identified 8 pathways that were affected by changes in gene expression; three of the significant pathways were related to metabolism (inositol phosphate metabolism, propanoate metabolism, and pyruvate metabolism). Here, we identified a few potential genes and biological pathways for the diagnosis and treatment of alveolar bone cells in diabetic patients.

  4. HExpoChem: a systems biology resource to explore human exposure to chemicals

    DEFF Research Database (Denmark)

    Taboureau, Olivier; Jacobsen, Ulrik Plesner; Kalhauge, Christian Gram

    2013-01-01

    of computational biology approaches are needed to assess the health risks of chemical exposure. Here we present HExpoChem, a tool based on environmental chemicals and their bioactivities on human proteins with the objective of aiding the qualitative exploration of human exposure to chemicals. The chemical......Summary: Humans are exposed to diverse hazardous chemicals daily. Although an exposure to these chemicals is suspected to have adverse effects on human health, mechanistic insights into how they interact with the human body are still limited. Therefore, acquisition of curated data and development......–protein interactions have been enriched with a quality-scored human protein–protein interaction network, a protein–protein association network and a chemical–chemical interaction network, thus allowing the study of environmental chemicals through formation of protein complexes and phenotypic outcomes enrichment...

  5. Developing a Salivary Antibody Multiplex Immunoassay to Measure Human Exposure to Environmental Pathogens

    Science.gov (United States)

    The etiology and impacts of human exposure to environmental pathogens are of major concern worldwide and, thus, the ability to assess exposure and infections using cost effective, high-throughput approaches would be indispensable. The principal objective of this work is to devel...

  6. Probabilistic estimation of residential air exchange rates for population-based human exposure modeling

    Science.gov (United States)

    Residential air exchange rates (AERs) are a key determinant in the infiltration of ambient air pollution indoors. Population-based human exposure models using probabilistic approaches to estimate personal exposure to air pollutants have relied on input distributions from AER meas...

  7. 3'-5' RNA degradation pathways in human cells

    DEFF Research Database (Denmark)

    Lubas, Michal Szymon

    RNA synthesis and degradation are key steps in the regulation of gene expression in all living organisms. During the course of his PhD studies, Michal Lubas centred his research on the nuclear and cytoplasmic RNA turnover of both noncoding and coding RNAs in human cells. His proteomic studies...... of the cytoplasmic 3'-5' exoribonuclease hDIS3L2. Using low throughout and high throughput techniques, both in vivo and in vitro, he characterised the nuclease and disclosed the role of hDIS3L2 in cytoplasmic mRNA metabolism....

  8. MODELING ENERGY EXPENDITURE AND OXYGEN CONSUMPTION IN HUMAN EXPOSURE MODELS: ACCOUNTING FOR FATIGUE AND EPOC

    Science.gov (United States)

    Human exposure and dose models often require a quantification of oxygen consumption for a simulated individual. Oxygen consumption is dependent on the modeled Individual's physical activity level as described in an activity diary. Activity level is quantified via standardized val...

  9. Exposure to perfluorinated compounds and human semen quality in arctic and European populations

    DEFF Research Database (Denmark)

    Toft, Gunnar; Jönsson, B A G; Lindh, C H

    2012-01-01

    Perfluorinated compounds (PFCs) have been suspected to adversely affect human reproductive health. The aim of this study was to investigate the associations between PFC exposure and male semen quality....

  10. In vivo plasma concentration for lindane after 6 hour exposure in human skin

    Data.gov (United States)

    U.S. Environmental Protection Agency — Dataset is a time course description of lindane disappearance in blood plasma after dermal exposure in human volunteers. This dataset is associated with the...

  11. MODELING ENERGY EXPENDITURE AND OXYGEN CONSUMPTION IN HUMAN EXPOSURE MODELS: ACCOUNTING FOR FATIGUE AND EPOC

    Science.gov (United States)

    Human exposure and dose models often require a quantification of oxygen consumption for a simulated individual. Oxygen consumption is dependent on the modeled Individual's physical activity level as described in an activity diary. Activity level is quantified via standardized val...

  12. A SIMPLE COLORIMETRIC METHOD TO DETECT BIOLOGICAL EVIDENCE OF HUMAN EXPOSURE TO MICROCYSTINS

    Science.gov (United States)

    Toxic cyanobacteria are contaminants of surface waters worldwide. Microcystins are some of the most commonly detected toxins. Biological evidence of human exposure may be difficult to obtain due to limitations associated with cost, laboratory capacity, analytic support, and exp...

  13. Human Health Effects Associated with Exposure to Cyanobacteria and Cyanotoxins: What Do We Know?

    Science.gov (United States)

    The study of environmental health typically focuses on human populations. However, companion animals, livestock and wildlife also experience adverse health effects from environmental pollutants. Animals may experience direct exposure to pollutants unlike people in most ambient ex...

  14. Pigmentation, pleiotropy, and genetic pathways in humans and mice

    Energy Technology Data Exchange (ETDEWEB)

    Barsh, G.S. [Stanford Univ., CA (United States)

    1995-10-01

    Some of the most striking polymorphisms in human populations affect the color of our eyes, hair, or skin. Despite some simple lessons from high school biology (blue eyes are recessive; brown are dominant), the genetic basis of such phenotypic variability has, for the most part, eluded Mendelian description. A logical place to search for the keys to understanding common variation in human pigmentation are genes in which defects cause uncommon conditions such as albinism or piebaldism. The area under this lamppost has recently gotten larger, with two articles, one in this issue of the Journal, that describe the map position for Hermansky-Pudlak syndrome (HPS) and with the recent cloning of a gene that causes X-linked ocular albinism (OA1). In addition, a series of three recent articles in Cell demonstrate (1) that defects in the gene encoding the endothelin B (ET{sub B}) receptor cause hypopigmentation and Hirschsprung disease in a Mennonite population and the mouse mutation piebald(s) and (2) that a defect in the edn3 gene, which encodes one of the ligands for the ET{sub B} receptor, causes the lethal spotting (ls) mouse mutation. 47 refs., 1 fig.

  15. Dose-Dependent Response to 3-Nitrobenzanthrone Exposure in Human Urothelial Cancer Cells.

    Science.gov (United States)

    Pink, Mario; Verma, Nisha; Zerries, Anna; Schmitz-Spanke, Simone

    2017-09-28

    A product of incomplete combustion of diesel fuel, 3-nitrobenzanthrone (3-NBA), has been classified as a cancer-causing substance. It first gained attention as a potential urinary bladder carcinogen due to the presence of its metabolite in urine and formation of DNA adducts. The aim of the present study was to characterize the dose-response relationship of 3-NBA in human urothelial cancer cell line (RT4) exposed to concentrations ranging from 0.0003 μM (environmentally relevant) to 80 μM by utilizing toxicological and metabolomic approaches. We observed that the RT4 cells were capable of bioactivation of 3-NBA within 30 min of exposure. Activity measurements of various enzymes involved in the conversion of 3-NBA in RT4 cells demonstrated NAD(P)H:quinone oxidoreductase (NQO1) as the main contributor for its bioactivation. Moreover, cytotoxicity assessment exhibited an initiation of adaptive mechanisms at low dosages, which diminished at higher doses, indicating that the capacity of these mechanisms no longer suffices, resulting in increased levels of intracellular reactive oxygen species, reduced proliferation, and hyperpolarisation of the mitochondrial membrane. To characterize the underlying mechanisms of this cellular response, the metabolism of 3-NBA and metabolomic changes in the cells were analyzed. The metabolomic analysis of the cells (0.0003, 0.01, 0.08, 10, and 80 μM 3-NBA) showed elevated levels of various antioxidants at low concentrations of 3-NBA. However, at higher exposure concentrations, it appeared that the cells reprogrammed their metabolism to maintain the cell homeostasis via activation of pentose phosphate pathway (PPP).

  16. Pathways Regulating Spheroid Formation of Human Follicular Thyroid Cancer Cells under Simulated Microgravity Conditions: A Genetic Approach

    Directory of Open Access Journals (Sweden)

    Stefan Riwaldt

    2016-04-01

    Full Text Available Microgravity induces three-dimensional (3D growth in numerous cell types. Despite substantial efforts to clarify the underlying mechanisms for spheroid formation, the precise molecular pathways are still not known. The principal aim of this paper is to compare static 1g-control cells with spheroid forming (MCS and spheroid non-forming (AD thyroid cancer cells cultured in the same flask under simulated microgravity conditions. We investigated the morphology and gene expression patterns in human follicular thyroid cancer cells (UCLA RO82-W-1 cell line after a 24 h-exposure on the Random Positioning Machine (RPM and focused on 3D growth signaling processes. After 24 h, spheroid formation was observed in RPM-cultures together with alterations in the F-actin cytoskeleton. qPCR indicated more changes in gene expression in MCS than in AD cells. Of the 24 genes analyzed VEGFA, VEGFD, MSN, and MMP3 were upregulated in MCS compared to 1g-controls, whereas ACTB, ACTA2, KRT8, TUBB, EZR, RDX, PRKCA, CAV1, MMP9, PAI1, CTGF, MCP1 were downregulated. A pathway analysis revealed that the upregulated genes code for proteins, which promote 3D growth (angiogenesis and prevent excessive accumulation of extracellular proteins, while genes coding for structural proteins are downregulated. Pathways regulating the strength/rigidity of cytoskeletal proteins, the amount of extracellular proteins, and 3D growth may be involved in MCS formation.

  17. Maternal Disononyl Phthalate Exposure Activates Allergic Airway Inflammation via Stimulatingthe Phosphoinositide 3-kinase/Akt Pathway in Rat Pups

    Institute of Scientific and Technical Information of China (English)

    CHEN Li; CHEN Jiao; XIE ChangMing; ZHAO Yan; WANG Xiu; andZHANG YunHui

    2015-01-01

    ObjectiveTo evaluate the effectof diisononyl phthalate (DINP) exposure during gestation and lacta-tion on allergic response in pups and to explore the role of phosphoinositide 3-kinase/Akt pathway on it. MethodsFemale Wistar rats were treated with DINP at different dosages (0, 5, 50,and 500 mg/kg of body weight per day). The pups were sensitized and challenged by ovalbumin (OVA). The airway response was assessed; the airway histological studies were performed by hematoxylin and eosin (HE) staining; and the relative cytokines in phosphoinositide 3-kinase (PI3K)/Akt pathway were measured by enzyme-linked immunosorbent assay (ELISA) and western blot analysis. ResultsThere was no significant difference in DINP’s effect on airway hyperresponsiveness (AHR) between male pups and female pups. In the 50 mg/(kg·d) DINP-treated group, airway response to OVA significantly increased and pups showed dramatically enhanced pulmonary resistance (RI) compared with those from controls (P<0.05). Enhanced Akt phosphorylation and NF-κB translocation, and Th2 cytokines expression were observed in pups of 50 mg/(kg·d) DINP-treated group. However, in the 5 and 500 mg/(kg·d) DINP-treated pups, no significant effects were observed. ConclusionTherewas an adjuvant effect of DINP on allergic airway inflammation in pups. Maternal DINP exposure could promote OVA-induced allergic airway response in pups in part by upregulation of PI3K/Akt pathway.

  18. Toxicogenomic outcomes predictive of forestomach carcinogenesis following exposure to benzo(a)pyrene: Relevance to human cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Labib, Sarah, E-mail: Sarah.Labib@hc-sc.gc.ca; Guo, Charles H., E-mail: Charles.Guo@hc-sc.gc.ca; Williams, Andrew, E-mail: Andrew.Williams@hc-sc.gc.ca; Yauk, Carole L., E-mail: Carole.Yauk@hc-sc.gc.ca; White, Paul A., E-mail: Paul.White@hc-sc.gc.ca; Halappanavar, Sabina, E-mail: Sabina.Halappanavar@hc-sc.gc.ca

    2013-12-01

    Forestomach tumors are observed in mice exposed to environmental carcinogens. However, the relevance of this data to humans is controversial because humans lack a forestomach. We hypothesize that an understanding of early molecular changes after exposure to a carcinogen in the forestomach will provide mode-of-action information to evaluate the applicability of forestomach cancers to human cancer risk assessment. In the present study we exposed mice to benzo(a)pyrene (BaP), an environmental carcinogen commonly associated with tumors of the rodent forestomach. Toxicogenomic tools were used to profile gene expression response in the forestomach. Adult Muta™Mouse males were orally exposed to 25, 50, and 75 mg BaP/kg-body-weight/day for 28 consecutive days. The forestomach was collected three days post-exposure. DNA microarrays, real-time RT-qPCR arrays, and protein analyses were employed to characterize responses in the forestomach. Microarray results showed altered expression of 414 genes across all treatment groups (± 1.5 fold; false discovery rate adjusted P ≤ 0.05). Significant downregulation of genes associated with phase II xenobiotic metabolism and increased expression of genes implicated in antigen processing and presentation, immune response, chemotaxis, and keratinocyte differentiation were observed in treated groups in a dose-dependent manner. A systematic comparison of the differentially expressed genes in the forestomach from the present study to differentially expressed genes identified in human diseases including human gastrointestinal tract cancers using the NextBio Human Disease Atlas showed significant commonalities between the two models. Our results provide molecular evidence supporting the use of the mouse forestomach model to evaluate chemically-induced gastrointestinal carcinogenesis in humans. - Highlights: • Benzo(a)pyrene-mediated transcriptomic response in the forestomach was examined. • The immunoproteosome subunits and MHC class I

  19. PathCards: multi-source consolidation of human biological pathways

    Science.gov (United States)

    Belinky, Frida; Nativ, Noam; Stelzer, Gil; Zimmerman, Shahar; Iny Stein, Tsippi; Safran, Marilyn; Lancet, Doron

    2015-01-01

    The study of biological pathways is key to a large number of systems analyses. However, many relevant tools consider a limited number of pathway sources, missing out on many genes and gene-to-gene connections. Simply pooling several pathways sources would result in redundancy and the lack of systematic pathway interrelations. To address this, we exercised a combination of hierarchical clustering and nearest neighbor graph representation, with judiciously selected cutoff values, thereby consolidating 3215 human pathways from 12 sources into a set of 1073 SuperPaths. Our unification algorithm finds a balance between reducing redundancy and optimizing the level of pathway-related informativeness for individual genes. We show a substantial enhancement of the SuperPaths’ capacity to infer gene-to-gene relationships when compared with individual pathway sources, separately or taken together. Further, we demonstrate that the chosen 12 sources entail nearly exhaustive gene coverage. The computed SuperPaths are presented in a new online database, PathCards, showing each SuperPath, its constituent network of pathways, and its contained genes. This provides researchers with a rich, searchable systems analysis resource.Database URL: http://pathcards.genecards.org/ PMID:25725062

  20. Florida red tide and human health: a pilot beach conditions reporting system to minimize human exposure.

    Science.gov (United States)

    Kirkpatrick, Barbara; Currier, Robert; Nierenberg, Kate; Reich, Andrew; Backer, Lorraine C; Stumpf, Richard; Fleming, Lora; Kirkpatrick, Gary

    2008-08-25

    With over 50% of the US population living in coastal counties, the ocean and coastal environments have substantial impacts on coastal communities. While many of the impacts are positive, such as tourism and recreation opportunities, there are also negative impacts, such as exposure to harmful algal blooms (HABs) and water borne pathogens. Recent advances in environmental monitoring and weather prediction may allow us to forecast these potential adverse effects and thus mitigate the negative impact from coastal environmental threats. One example of the need to mitigate adverse environmental impacts occurs on Florida's west coast, which experiences annual blooms, or periods of exuberant growth, of the toxic dinoflagellate, Karenia brevis. K. brevis produces a suite of potent neurotoxins called brevetoxins. Wind and wave action can break up the cells, releasing toxin that can then become part of the marine aerosol or sea spray. Brevetoxins in the aerosol cause respiratory irritation in people who inhale it. In addition, asthmatics who inhale the toxins report increase upper and lower airway symptoms and experience measurable changes in pulmonary function. Real-time reporting of the presence or absence of these toxic aerosols will allow asthmatics and local coastal residents to make informed decisions about their personal exposures, thus adding to their quality of life. A system to protect public health that combines information collected by an Integrated Ocean Observing System (IOOS) has been designed and implemented in Sarasota and Manatee Counties, Florida. This system is based on real-time reports from lifeguards at the eight public beaches. The lifeguards provide periodic subjective reports of the amount of dead fish on the beach, apparent level of respiratory irritation among beach-goers, water color, wind direction, surf condition, and the beach warning flag they are flying. A key component in the design of the observing system was an easy reporting pathway for

  1. The human placenta--an alternative for studying foetal exposure

    DEFF Research Database (Denmark)

    Myren, Maja; Mose, Tina; Mathiesen, Line;

    2007-01-01

    , and though its main task is to act as a barrier and transport nutrients and oxygen to the foetus, many foreign compounds are transported across the placenta to some degree and may therefore influence the unborn child. Foetal exposures to environmental and medicinal products may have impact on the growth...

  2. 18. Adduct detection in human monitoring for carcinogen exposure

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Determination of the covalently bound products (adducts) of carcinogens with DNA or proteins may be used for the monitoring of exposure to these compounds. Protein adducts are generally stable and are not enzymatically repaired, and the use of these for cxposure monitoring is normally carried out with globin or albumin, because

  3. Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human tumorigenesis

    DEFF Research Database (Denmark)

    Tort, F.; Bartkova, J.; Sehested, M.

    2006-01-01

    activation. Here, we show that, in a series of human colorectal adenomas, those with deregulation of cyclin D1 and/or p16(Ink4a) showed little evidence of constitutive DNA damage response (DDR), contrary to cyclin E-overexpressing higher-grade cases. These observations were consistent with diverse cell...... culture models with differential defects of retinoblastoma pathway components, as overexpression of cyclin D1 or lack of p16(Ink4a), either alone or combined, did not elicit detectable DDR. In contrast, inactivation of pRb, the key component of the pathway, activated the DDR in cultured human or mouse...

  4. The role of multimedia, multi-pathway exposure assessments in risk-based regulations at California hazardous wastes sites

    Energy Technology Data Exchange (ETDEWEB)

    McKone, T.E. [Lawrence Livermore National Lab., CA (United States); Butler, E.G.; Wong, J.J. [California Dept., of Toxic Substances Control, Sacrameto, CA (United States). Office of Scientific Affairs

    1993-10-01

    The Department of Toxic Substances Control (DTSC), within the California Environmental Protection Agency, has the responsibility for managing the State`s hazardous-waste program to protect public health and the environment. The Office of Scientific Affairs (OSA) within the DTSC provides scientific assistance in the areas of toxicology, risk and environmental assessment, training, and guidance to the regional offices within DTSC. Part of this assistance and guidance is the preparation of regulations, scientific standards, guidance documents, and recommended procedures for use by regional staff, local governmental agencies, or responsible parties and their contractors in the characterization and mitigation of hazardous-waste-substances-release sites. CalTOX has been developed as a spreadsheet model to assist in health-risk assessments that address contaminated soils and the contamination of adjacent air, surface water, sediments, and ground water. The model system includes a multimedia transport and transformation model, exposure scenario models, and efforts to quantify and reduce uncertainty in multimedia, multiple-pathway exposure models. This paper lists the objectives of a multimedia, total exposure model; provides an overview of the CalTOX model components; and describes the philosophy under which the model was developed.

  5. Children, computer exposure and musculoskeletal outcomes: the development of pathway models for school and home computer-related musculoskeletal outcomes.

    Science.gov (United States)

    Harris, Courtenay; Straker, Leon; Pollock, Clare; Smith, Anne

    2015-01-01

    Children's computer use is rapidly growing, together with reports of related musculoskeletal outcomes. Models and theories of adult-related risk factors demonstrate multivariate risk factors associated with computer use. Children's use of computers is different from adult's computer use at work. This study developed and tested a child-specific model demonstrating multivariate relationships between musculoskeletal outcomes, computer exposure and child factors. Using pathway modelling, factors such as gender, age, television exposure, computer anxiety, sustained attention (flow), socio-economic status and somatic complaints (headache and stomach pain) were found to have effects on children's reports of musculoskeletal symptoms. The potential for children's computer exposure to follow a dose-response relationship was also evident. Developing a child-related model can assist in understanding risk factors for children's computer use and support the development of recommendations to encourage children to use this valuable resource in educational, recreational and communication environments in a safe and productive manner. Computer use is an important part of children's school and home life. Application of this developed model, that encapsulates related risk factors, enables practitioners, researchers, teachers and parents to develop strategies that assist young people to use information technology for school, home and leisure in a safe and productive manner.

  6. Relationship between Human Aging Muscle and Oxidative System Pathway

    Directory of Open Access Journals (Sweden)

    Enrico Doria

    2012-01-01

    Full Text Available Ageing is a complex process that in muscle is usually associated with a decrease in mass, strength, and velocity of contraction. One of the most striking effects of ageing on muscle is known as sarcopenia. This inevitable biological process is characterized by a general decline in the physiological and biochemical functions of the major systems. At the cellular level, aging is caused by a progressive decline in mitochondrial function that results in the accumulation of reactive oxygen species (ROS generated by the addition of a single electron to the oxygen molecule. The aging process is characterized by an imbalance between an increase in the production of reactive oxygen species in the organism and the antioxidant defences as a whole. The goal of this review is to examine the results of existing studies on oxidative stress in aging human skeletal muscles, taking into account different physiological factors (sex, fibre composition, muscle type, and function.

  7. Human health risk assessment of lead from mining activities at semi-arid locations in the context of total lead exposure.

    Science.gov (United States)

    Zheng, Jiajia; Huynh, Trang; Gasparon, Massimo; Ng, Jack; Noller, Barry

    2013-12-01

    Lead from historical mining and mineral processing activities may pose potential human health risks if materials with high concentrations of bioavailable lead minerals are released to the environment. Since the Joint Expert Committee on Food Additives of Food and Agriculture Organization/World Health Organization withdrew the Provisional Tolerable Weekly Intake of lead in 2011, an alternative method was required for lead exposure assessment. This study evaluated the potential lead hazard to young children (0-7 years) from a historical mining location at a semi-arid area using the U.S. EPA Integrated Exposure Uptake Biokinetic (IEUBK) Model, with selected site-specific input data. This study assessed lead exposure via the inhalation pathway for children living in a location affected by lead mining activities and with specific reference to semi-arid conditions and made comparison with the ingestion pathway by using the physiologically based extraction test for gastro-intestinal simulation. Sensitivity analysis for major IEUBK input parameters was conducted. Three groups of input parameters were classified according to the results of predicted blood concentrations. The modelled lead absorption attributed to the inhalation route was lower than 2 % (mean ± SE, 0.9 % ± 0.1 %) of all lead intake routes and was demonstrated as a less significant exposure pathway to children's blood, compared with ingestion. Whilst dermal exposure was negligible, diet and ingestion of soil and dust were the dominant parameters in terms of children's blood lead prediction. The exposure assessment identified the changing role of dietary intake when house lead loadings varied. Recommendations were also made to conduct comprehensive site-specific human health risk assessment in future studies of lead exposure under a semi-arid climate.

  8. In vitro ozone exposure increases release of arachidonic acid products from a human bronchial epithelial cell line

    Energy Technology Data Exchange (ETDEWEB)

    McKinnon, K.P.; Madden, M.C.; Noah, T.L.; Devlin, R.B. (TRC Environmental Corporation, Chapel Hill, NC (United States))

    1993-02-01

    Eicosanoids released after ozone exposure of a human bronchial epithelial cell line, BEAS-S6, were analyzed by high-pressure liquid chromatography (HPLC) of supernatants from exposed cells prelabeled with [3H]arachidonic acid. BEAS cells released thromboxane B2 (TxB2), prostaglandin E2 (PGE2), leukotriene C4 (LTC4), LTD4, LTE4, and 12-hydroxyheptadecatrienoic acid (HHT) after exposure to ozone at concentrations of 0.1, 0.25, 0.5, and 1.0 ppm. The eicosanoids were identified by coelution with authentic standards. The largest product from ozone-exposed BEAS cells was the most polar peak, designated Peak 1. Release of cyclooxygenase products such as TxB2, PGE2, and HHT was inhibited by acetylsalicylic acid. Peaks that migrated with authentic standards for LTB4, LTC4, and LTD4 were inhibited by the lipoxygenase inhibitor nordihydroguaiaretic acid. The leukotrienes LTB4 and LTC4/D4 could also be detected by immunoassay of concentrated peak fractions. Thus BEAS cells released eicosanoids from cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism following exposure to ozone. Airway epithelial cells may be an important source of eicosanoids following ozone stimulation in humans.

  9. Altered calcium handling and increased contraction force in human embryonic stem cell derived cardiomyocytes following short term dexamethasone exposure.

    Science.gov (United States)

    Kosmidis, Georgios; Bellin, Milena; Ribeiro, Marcelo C; van Meer, Berend; Ward-van Oostwaard, Dorien; Passier, Robert; Tertoolen, Leon G J; Mummery, Christine L; Casini, Simona

    2015-11-27

    One limitation in using human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) for disease modeling and cardiac safety pharmacology is their immature functional phenotype compared with adult cardiomyocytes. Here, we report that treatment of human embryonic stem cell derived cardiomyocytes (hESC-CMs) with dexamethasone, a synthetic glucocorticoid, activated glucocorticoid signaling which in turn improved their calcium handling properties and contractility. L-type calcium current and action potential properties were not affected by dexamethasone but significantly faster calcium decay, increased forces of contraction and sarcomeric lengths, were observed in hESC-CMs after dexamethasone exposure. Activating the glucocorticoid pathway can thus contribute to mediating hPSC-CMs maturation.

  10. A systematic review of the human body burden of e-waste exposure in China.

    Science.gov (United States)

    Song, Qingbin; Li, Jinhui

    2014-07-01

    As China is one of the countries facing the most serious pollution and human exposure effects of e-waste in the world, much of the population there is exposed to potentially hazardous substances due to informal e-waste recycling processes. This report reviews recent studies on human exposure to e-waste in China, with particular focus on exposure routes (e.g. dietary intake, inhalation, and soil/dust ingestion) and human body burden markers (e.g. placenta, umbilical cord blood, breast milk, blood, hair, and urine) and assesses the evidence for the association between such e-waste exposure and the human body burden in China. The results suggest that residents in the e-waste exposure areas, located mainly in the three traditional e-waste recycling sites (Taizhou, Guiyu, and Qingyuan), are faced with a potential higher daily intake of these pollutants than residents in the control areas, especially via food ingestion. Moreover, pollutants (PBBs, PBDEs, PCBs, PCDD/Fs, and heavy metals) from the e-waste recycling processes were all detectable in the tissue samples at high levels, showing that they had entered residents' bodies through the environment and dietary exposure. Children and neonates are the groups most sensitive to the human body effects of e-waste exposure. We also recorded plausible outcomes associated with exposure to e-waste, including 7 types of human body burden. Although the data suggest that exposure to e-waste is harmful to health, better designed epidemiological investigations in vulnerable populations, especially neonates and children, are needed to confirm these associations. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Genetic control of the alternative pathway of complement in humans and age-related macular degeneration.

    Science.gov (United States)

    Hecker, Laura A; Edwards, Albert O; Ryu, Euijung; Tosakulwong, Nirubol; Baratz, Keith H; Brown, William L; Charbel Issa, Peter; Scholl, Hendrik P; Pollok-Kopp, Beatrix; Schmid-Kubista, Katharina E; Bailey, Kent R; Oppermann, Martin

    2010-01-01

    Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues.

  12. Repeated PM2.5 exposure inhibits BEAS-2B cell P53 expression through ROS-Akt-DNMT3B pathway-mediated promoter hypermethylation.

    Science.gov (United States)

    Zhou, Wei; Tian, Dongdong; He, Jun; Wang, Yimei; Zhang, Lijun; Cui, Lan; Jia, Li; Zhang, Li; Li, Lizhong; Shu, Yulei; Yu, Shouzhong; Zhao, Jun; Yuan, Xiaoyan; Peng, Shuangqing

    2016-04-12

    Long-term exposure to fine particulate matter (PM2.5) has been reported to be closely associated with the increased lung cancer risk in populations, but the mechanisms underlying PM-associated carcinogenesis are not yet clear. Previous studies have indicated that aberrant epigenetic alterations, such as genome-wide DNA hypomethylation and gene-specific DNA hypermethylation contribute to lung carcinogenesis. And silence or mutation of P53 tumor suppressor gene is the most prevalent oncogenic driver in lung cancer development. To explore the effects of PM2.5 on global and P53 promoter methylation changes and the mechanisms involved, we exposed human bronchial epithelial cells (BEAS-2B) to low concentrations of PM2.5 for 10 days. Our results indicated that PM2.5-induced global DNA hypomethylation was accompanied by reduced DNMT1 expression. PM2.5 also induced hypermethylation of P53 promoter and inhibited its expression by increasing DNMT3B protein level. Furthermore, ROS-induced activation of Akt was involved in PM2.5-induced increase in DNMT3B. In conclusion, our results strongly suggest that repeated exposure to PM2.5 induces epigenetic silencing of P53 through ROS-Akt-DNMT3B pathway-mediated promoter hypermethylation, which not only provides a possible explanation for PM-induced lung cancer, but also may help to identify specific interventions to prevent PM-induced lung carcinogenesis.

  13. Health risk assessment of various metal(loid)s via multiple exposure pathways on children living near a typical lead-acid battery plant, China.

    Science.gov (United States)

    Cao, Suzhen; Duan, Xiaoli; Zhao, Xiuge; Wang, Beibei; Ma, Jin; Fan, Delong; Sun, Chengye; He, Bin; Wei, Fusheng; Jiang, Guibin

    2015-05-01

    Manufacture of lead-acid batteries is of widespread interest because of its emissions of heavy metals and metalloids into environment, harming environmental quality and consequently causing detrimental effects on human health. In this study, exposure pathways and health risks of children to heavy metal(loid)s (Pb, Cd, As, etc) were investigated based on field sampling and questionnaire. Pb was one of the most abundant elements in children's blood, with an elevated blood lead level of 12.45 μg dL(-1). Soil/dust and food were heavily polluted by targeted metal(loid)s. Food ingestion accounted for more than 80% of the total exposure for most metal(loid)s. The non-cancer risks to children were 3-10 times higher than the acceptable level of 1, while the cancer risks were 5-200 times higher than the maximum acceptable level of 1.0 × 10(-4). The study emphasized the significance of effective environmental management, particularly to ensure food security near battery facilities. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Additional human exposure information for gasoline substance risk assessment (period 2002-2007)

    Energy Technology Data Exchange (ETDEWEB)

    Bomer, R.; Carter, M.; Dmytrasz, B.; Mulari, M.; Pizzella, G.; Roth, S.; Van de Sandt, P.

    2009-06-15

    This report provides an update on human exposure information for gasoline-related activities for which previous assessments had suggested that exposure was either elevated or highly variable or available data were considered out-of-date. In addition data are presented for several activities for which no information had been available previously. The occupational exposures activities described in this report include railcar loading, refinery maintenance, laboratory operations, aviation gasoline refuelling, gasoline pump maintenance and repair, gasoline pump calibration, and the operation of gasoline-powered gardening equipment. In addition, general public exposure levels are described, particularly relating to residency near service stations.

  15. Impairment of object recognition memory by maternal bisphenol A exposure is associated with inhibition of Akt and ERK/CREB/BDNF pathway in the male offspring hippocampus.

    Science.gov (United States)

    Wang, Chong; Li, Zhihui; Han, Haijun; Luo, Guangying; Zhou, Bingrui; Wang, Shaolin; Wang, Jundong

    2016-02-03

    Bisphenol A (BPA) is a commonly used endocrine-disrupting chemical used as a component of polycarbonates plastics that has potential adverse effects on human health. Exposure to BPA during development has been implicated in memory deficits, but the mechanism of action underlying the effect is not fully understood. In this study, we investigated the effect of maternal exposure to BPA on object recognition memory and the expressions of proteins important for memory, especially focusing on the ERK/CREB/BDNF pathway. Pregnant Sprague-Dawley female rats were orally treated with either vehicle or BPA (0.05, 0.5, 5 or 50 mg/kg BW/day) during days 9-20 of gestation. Male offspring were tested on postnatal day 21 with the object recognition task. Recognition memory was assessed using the object recognition index (index=the time spent exploring the novel object/(the time spent exploring the novel object+the time spent exploring the familiar object)). In the test session performed 90 min after the training session, BPA-exposed male offspring not only spent more time in exploring the familiar object at the highest dose than the control, but also displayed a significantly decreased the object recognition index at the doses of 0.5, 5 and 50 mg/kg BW/day. During the test session performed 24h after the training session, BPA-treated males did not change the time spent exploring the familiar object, but had a decreased object recognition index at 5 and 50 mg/kg BW/day, when compared to control group. These findings indicate that object recognition memory was susceptible to maternal BPA exposure. Western blot analysis of hippocampi from BPA-treated male offspring revealed a decrease in Akt, phospho-Akt, p44/42 MAPK and phospho-p44/42 MAPK protein levels, compared to controls. In addition, BPA significantly inhibited the levels of phosphorylation of CREB and BDNF in the hippocampus. Our results show that maternal BPA exposure may full impair object recognition memory, and that

  16. Axon guidance pathways served as common targets for human speech/language evolution and related disorders.

    Science.gov (United States)

    Lei, Huimeng; Yan, Zhangming; Sun, Xiaohong; Zhang, Yue; Wang, Jianhong; Ma, Caihong; Xu, Qunyuan; Wang, Rui; Jarvis, Erich D; Sun, Zhirong

    2017-07-07

    Human and several nonhuman species share the rare ability of modifying acoustic and/or syntactic features of sounds produced, i.e. vocal learning, which is the important neurobiological and behavioral substrate of human speech/language. This convergent trait was suggested to be associated with significant genomic convergence and best manifested at the ROBO-SLIT axon guidance pathway. Here we verified the significance of such genomic convergence and assessed its functional relevance to human speech/language using human genetic variation data. In normal human populations, we found the affected amino acid sites were well fixed and accompanied with significantly more associated protein-coding SNPs in the same genes than the rest genes. Diseased individuals with speech/language disorders have significant more low frequency protein coding SNPs but they preferentially occurred outside the affected genes. Such patients' SNPs were enriched in several functional categories including two axon guidance pathways (mediated by netrin and semaphorin) that interact with ROBO-SLITs. Four of the six patients have homozygous missense SNPs on PRAME gene family, one youngest gene family in human lineage, which possibly acts upon retinoic acid receptor signaling, similarly as FOXP2, to modulate axon guidance. Taken together, we suggest the axon guidance pathways (e.g. ROBO-SLIT, PRAME gene family) served as common targets for human speech/language evolution and related disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Diesel exhaust particles increase IL-1β-induced human β-defensin expression via NF-κB-mediated pathway in human lung epithelial cells

    Directory of Open Access Journals (Sweden)

    Lee Chun

    2006-05-01

    Full Text Available Abstract Background Human β-defensin (hBD-2, antimicrobial peptide primarily induced in epithelial cells, is a key factor in the innate immune response of the respiratory tract. Several studies showed increased defensin levels in both inflammatory lung diseases, such as cystic fibrosis, diffuse panbronchiolitis, idiopathic pulmonary fibrosis and acute respiratory distress syndrome, and infectious diseases. Recently, epidemiologic studies have demonstrated acute and serious adverse effects of particulate air pollution on respiratory health, especially in people with pre-existing inflammatory lung disease. To elucidate the effect of diesel exhaust particles (DEP on pulmonary innate immune response, we investigated the hBD-2 and interleukin-8 (IL-8 expression to DEP exposure in interleukin-1 beta (IL-1β-stimulated A549 cells. Results IL-1β markedly up-regulated the hBD-2 promoter activity, and the subsequent DEP exposure increased dose-dependently the expression of hBD-2 and inflammatory cytokine IL-8 at the transcriptional level. In addition, DEP further induced the NF-κB activation in IL-1β-stimulated A549 cells more rapidly than in unstimulated control cells, which was showed by nuclear translocation of p65 NF-κB and degradation of IκB-α. The experiment using two NF-κB inhibitors, PDTC and MG132, confirmed that this increase of hBD-2 expression following DEP exposure was regulated through NF-κB-mediated pathway. Conclusion These results demonstrated that DEP exposure increases the expression of antimicrobial peptide and inflammatory cytokine at the transcriptional level in IL-1β-primed A549 epithelial cells and suggested that the increase is mediated at least partially through NF-κB activation. Therefore, DEP exposure may contribute to enhance the airway-responsiveness especially on the patients suffering from chronic respiratory disease.

  18. Acute Activation of Oxidative Pentose Phosphate Pathway as First-Line Response to Oxidative Stress in Human Skin Cells.

    Science.gov (United States)

    Kuehne, Andreas; Emmert, Hila; Soehle, Joern; Winnefeld, Marc; Fischer, Frank; Wenck, Horst; Gallinat, Stefan; Terstegen, Lara; Lucius, Ralph; Hildebrand, Janosch; Zamboni, Nicola

    2015-08-01

    Integrity of human skin is endangered by exposure to UV irradiation and chemical stressors, which can provoke a toxic production of reactive oxygen species (ROS) and oxidative damage. Since oxidation of proteins and metabolites occurs virtually instantaneously, immediate cellular countermeasures are pivotal to mitigate the negative implications of acute oxidative stress. We investigated the short-term metabolic response in human skin fibroblasts and keratinocytes to H2O2 and UV exposure. In time-resolved metabolomics experiments, we observed that within seconds after stress induction, glucose catabolism is routed to the oxidative pentose phosphate pathway (PPP) and nucleotide synthesis independent of previously postulated blocks in glycolysis (i.e., of GAPDH or PKM2). Through ultra-short (13)C labeling experiments, we provide evidence for multiple cycling of carbon backbones in the oxidative PPP, potentially maximizing NADPH reduction. The identified metabolic rerouting in oxidative and non-oxidative PPP has important physiological roles in stabilization of the redox balance and ROS clearance.

  19. Assessment of human exposure to fumonisin B1

    NARCIS (Netherlands)

    Nijs, M. de; Egmond, H.P. van; Nauta, M.; Rombouts, F.M.; Notermans, S.H.W.

    1998-01-01

    Fumonisin B1 is currently regarded as the most significant mycotoxin produced by Fusarium spp. It has carcinogenic properties and may play a role in the etiology of human esophageal cancer. The human population is exposed to fumonisin B1 primarily by intake of fumonisin B1-contaminated maize. Maize

  20. Genetic evidence for common pathways in human age-related diseases.

    Science.gov (United States)

    Johnson, Simon C; Dong, Xiao; Vijg, Jan; Suh, Yousin

    2015-10-01

    Aging is the single largest risk factor for chronic disease. Studies in model organisms have identified conserved pathways that modulate aging rate and the onset and progression of multiple age-related diseases, suggesting that common pathways of aging may influence age-related diseases in humans as well. To determine whether there is genetic evidence supporting the notion of common pathways underlying age-related diseases, we analyzed the genes and pathways found to be associated with five major categories of age-related disease using a total of 410 genomewide association studies (GWAS). While only a small number of genes are shared among all five disease categories, those found in at least three of the five major age-related disease categories are highly enriched for apoliprotein metabolism genes. We found that a more substantial number of gene ontology (GO) terms are shared among the 5 age-related disease categories and shared GO terms include canonical aging pathways identified in model organisms, such as nutrient-sensing signaling, translation, proteostasis, stress responses, and genome maintenance. Taking advantage of the vast amount of genetic data from the GWAS, our findings provide the first direct evidence that conserved pathways of aging simultaneously influence multiple age-related diseases in humans as has been demonstrated in model organisms. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  1. Gene Expression Profiles from Disease Discordant Twins Suggest Shared Antiviral Pathways and Viral Exposures among Multiple Systemic Autoimmune Diseases.

    Science.gov (United States)

    Gan, Lu; O'Hanlon, Terrance P; Lai, Zhennan; Fannin, Rick; Weller, Melodie L; Rider, Lisa G; Chiorini, John A; Miller, Frederick W

    2015-01-01

    Viral agents are of interest as possible autoimmune triggers due to prior reported associations and widely studied molecular mechanisms of antiviral immune responses in autoimmunity. Here we examined new viral candidates for the initiation and/or promotion of systemic autoimmune diseases (SAID), as well as possible related signaling pathways shared in the pathogenesis of those disorders. RNA isolated from peripheral blood samples from 33 twins discordant for SAID and 33 matched, unrelated healthy controls was analyzed using a custom viral-human gene microarray. Paired comparisons were made among three study groups-probands with SAID, their unaffected twins, and matched, unrelated healthy controls-using statistical and molecular pathway analyses. Probands and unaffected twins differed significantly in the expression of 537 human genes, and 107 of those were associated with viral infections. These 537 differentially expressed human genes participate in overlapping networks of several canonical, biologic pathways relating to antiviral responses and inflammation. Moreover, certain viral genes were expressed at higher levels in probands compared to either unaffected twins or unrelated, healthy controls. Interestingly, viral gene expression levels in unaffected twins appeared intermediate between those of probands and the matched, unrelated healthy controls. Of the viruses with overexpressed viral genes, herpes simplex virus-2 (HSV-2) was the only human viral pathogen identified using four distinct oligonucleotide probes corresponding to three HSV-2 genes associated with different stages of viral infection. Although the effects from immunosuppressive therapy on viral gene expression remain unclear, this exploratory study suggests a new approach to evaluate shared viral agents and antiviral immune responses that may be involved in the development of SAID.

  2. Human Exposure to Herpesvirus B–Seropositive Macaques, Bali, Indonesia

    Science.gov (United States)

    Engel, Gregory A.; Schillaci, Michael A.; Suaryana, Komang Gde; Putra, Artha; Fuentes, Agustin; Henkel, Richard

    2002-01-01

    Herpesvirus B (Cercopithecine herpesvirus 1) has been implicated as the cause of approximately 40 cases of meningoencephalitis affecting persons in direct or indirect contact with laboratory macaques. However, the threat of herpesvirus B in nonlaboratory settings worldwide remains to be addressed. We investigated the potential for exposure to herpesvirus B in workers at a “monkey forest” (a temple that has become a tourist attraction because of its monkeys) in Bali, Indonesia. In July 2000, 105 workers at the Sangeh Monkey Forest in Central Bali were surveyed about contact with macaques (Macaca fascicularis). Nearly half of those interviewed had either been bitten or scratched by a macaque. Prevalence of injury was higher in those who fed macaques. Serum from 31 of 38 Sangeh macaques contained antibodies to herpesvirus B. We conclude that workers coming into contact with macaques at the Sangeh Monkey Forest are at risk for exposure to herpesvirus B. PMID:12141963

  3. Human exposure to herpesvirus B-seropositive macaques, Bali, Indonesia.

    Science.gov (United States)

    Engel, Gregory A; Jones-Engel, Lisa; Schillaci, Michael A; Suaryana, Komang Gde; Putra, Artha; Fuentes, Agustin; Henkel, Richard

    2002-08-01

    Herpesvirus B (Cercopithecine herpesvirus 1) has been implicated as the cause of approximately 40 cases of meningoencephalitis affecting persons in direct or indirect contact with laboratory macaques. However, the threat of herpesvirus B in nonlaboratory settings worldwide remains to be addressed. We investigated the potential for exposure to herpesvirus B in workers at a "monkey forest" (a temple that has become a tourist attraction because of its monkeys) in Bali, Indonesia. In July 2000, 105 workers at the Sangeh Monkey Forest in Central Bali were surveyed about contact with macaques (Macaca fascicularis). Nearly half of those interviewed had either been bitten or scratched by a macaque. Prevalence of injury was higher in those who fed macaques. Serum from 31 of 38 Sangeh macaques contained antibodies to herpesvirus B. We conclude that workers coming into contact with macaques at the Sangeh Monkey Forest are at risk for exposure to herpesvirus B.

  4. Critical elements for human health risk assessment of less than lifetime exposures.

    Science.gov (United States)

    Geraets, Liesbeth; Nijkamp, Monique M; Ter Burg, Wouter

    2016-11-01

    Less than lifetime exposure has confronted risk assessors as to how to interpret the risks for human health in case a chronic health-based limit is exceeded. Intermittent, fluctuating and peak exposures do not match with the basis of the chronic limit values possibly leading to conservative outcomes. This paper presents guidance on how to deal with human risk assessment of less than lifetime exposure. Important steps to be considered are characterization of the human exposure situation, evaluation whether the human less than lifetime exposure scenario corresponds to a non-chronic internal exposure: toxicokinetic and toxicodynamic considerations, and, finally, re-evaluation of the risk assessment. Critical elements for these steps are the mode of action, Haber's rule, and toxicokinetics (ADME) amongst others. Previous work for the endpoints non-genotoxic carcinogenicity and developmental toxicity is included in the guidance. The guidance provides a way to consider the critical elements, without setting default factors to correct for the less than lifetime exposure in risk assessment.

  5. Lead Exposure Induces Telomere Instability in Human Cells.

    Directory of Open Access Journals (Sweden)

    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.

  6. Novel Human Radiation Exposure Biomarker Panel Applicable for Population Triage

    Energy Technology Data Exchange (ETDEWEB)

    Bazan, Jose G. [Department of Radiation Oncology, Stanford University, Stanford, California (United States); Chang, Polly; Balog, Robert; D' Andrea, Annalisa; Shaler, Thomas; Lin, Hua; Lee, Shirley; Harrison, Travis [SRI International, Menlo Park, California (United States); Shura, Lei; Schoen, Lucy; Knox, Susan J. [Department of Radiation Oncology, Stanford University, Stanford, California (United States); Cooper, David E., E-mail: david.cooper@sri.com [SRI International, Menlo Park, California (United States)

    2014-11-01

    Purpose: To identify a panel of radiation-responsive plasma proteins that could be used in a point-of-care biologic dosimeter to detect clinically significant levels of ionizing radiation exposure. Methods and Materials: Patients undergoing preparation for hematopoietic cell transplantation using radiation therapy (RT) with either total lymphoid irradiation or fractionated total body irradiation were eligible. Plasma was examined from patients with potentially confounding conditions and from normal individuals. Each plasma sample was analyzed for a panel of 17 proteins before RT was begun and at several time points after RT exposure. Paired and unpaired t tests between the dose and control groups were performed. Conditional inference trees were constructed based on panels of proteins to compare the non-RT group with the RT group. Results: A total of 151 patients (62 RT, 41 infection, 48 trauma) were enrolled on the study, and the plasma from an additional 24 healthy control individuals was analyzed. In comparison with to control individuals, tenascin-C was upregulated and clusterin was downregulated in patients receiving RT. Salivary amylase was strongly radiation responsive, with upregulation in total body irradiation patients and slight downregulation in total lymphoid irradiation patients compared with control individuals. A panel consisting of these 3 proteins accurately distinguished between irradiated patients and healthy control individuals within 3 days after exposure: 97% accuracy, 0.5% false negative rate, 2% false positive rate. The accuracy was diminished when patients with trauma, infection, or both were included (accuracy, 74%-84%; false positive rate, 14%-33%, false negative rate: 8%-40%). Conclusions: A panel of 3 proteins accurately distinguishes unirradiated healthy donors from those exposed to RT (0.8-9.6 Gy) within 3 days of exposure. These findings have significant implications in terms of triaging individuals in the case of nuclear or other

  7. Activation of Neutrophils via IP3 Pathway Following Exposure to Demodex-Associated Bacterial Proteins.

    Science.gov (United States)

    McMahon, Fred; Banville, Nessa; Bergin, David A; Smedman, Christian; Paulie, Staffan; Reeves, Emer; Kavanagh, Kevin

    2016-02-01

    Rosacea is a chronic inflammatory condition that predominantly affects the skin of the face. Sera from rosacea patients display elevated reactivity to proteins from a bacterium (Bacillus oleronius) originally isolated from a Demodex mite from a rosacea patient suggesting a possible role for bacteria in the induction and persistence of this condition. This work investigated the ability of B. oleronius proteins to activate neutrophils and demonstrated activation via the IP3 pathway. Activated neutrophils displayed increased levels of IP1 production, F-actin formation, chemotaxis, and production of the pro-inflammatory cytokines IL-1β and IL-6 following stimulation by pure and crude B. oleronius protein preparations (2 μg/ml), respectively. In addition, neutrophils exposed to pure and crude B. oleronius proteins (2 μg/ml) demonstrated increased release of internally stored calcium (Ca(2+)), a hallmark of the IP3 pathway of neutrophil activation. Neutrophils play a significant role in the inflammation associated with rosacea, and this work demonstrates how B. oleronius proteins can induce neutrophil recruitment and activation.

  8. Early suppression of NFkappaB and IL-8 in bronchial epithelium after ozone exposure in healthy human subjects.

    Science.gov (United States)

    Bosson, Jenny; Blomberg, Anders; Pourazar, Jamshid; Mudway, Ian S; Frew, Anthony J; Kelly, Frank J; Sandström, Thomas

    2009-09-01

    Exposure to elevated concentrations of ozone, a common air pollutant, has been associated with numerous adverse health effects. We have previously reported the time-course of ozone-induced airway inflammation, demonstrating an early up-regulation of vascular endothelial adhesion molecules in bronchial mucosa at 1.5 hours, followed by a neutrophilic infiltration 6 hours after exposure to 0.2 ppm ozone. We hypothesized that the neutrophilic infiltration in the bronchial mucosa would reflect an early increase in bronchial epithelial expression of redox-sensitive transcription factors and kinases regulating neutrophil chemoattractant expression. To test this hypothesis, endobronchial biopsies were obtained from healthy human subjects (n = 11) 1.5 hours after 0.2 ppm of ozone and filtered air exposures (lasting for 2 hours) and stained for mitogen-activated protein kinases (MAPKs), transcription factors, and neutrophil chemoattractants. Total epithelial staining was quantified, as well as the extent of nuclear translocation. Contrary to expectation, ozone significantly suppressed total and nuclear expression of nuclear factor kappaB (NFkappaB) in bronchial epithelial cells (p = 0.02 and p = 0.003 respectively). Similarly, the total staining for phosphorylated C-jun was suppressed (p = 0.021). Expression of interleukin 8 (IL-8) in the bronchial epithelium was likewise decreased after ozone (p = 0.018), while GRO-alpha, ENA-78, C-fos, p-p38, p-JNK, and p-ERK stainings were unchanged. These data suggest that the redox-sensitive NFkappaB and activator protein 1 (AP-1) pathways within the human bronchial epithelium do not seem to be involved in the early inflammatory cell recruitment pathways in healthy subjects exposed to ozone.

  9. Evaluation of exposure pathways to man from disposal of radioactive materials into sanitary sewer systems

    Energy Technology Data Exchange (ETDEWEB)

    Kennedy, W.E. Jr.; Parkhurst, M.A.; Aaberg, R.L.; Rhoads, K.C.; Hill, R.L.; Martin, J.B. [Pacific Northwest Lab., Richland, WA (United States)

    1992-05-01

    In accordance with 10 CFR 20, the US Nuclear Regulatory Commission (NRC) regulates licensees` discharges of small quantities of radioactive materials into sanitary sewer systems. This generic study was initiated to examine the potential radiological hazard to the public resulting from exposure to radionuclides in sewage sludge during its treatment and disposal. Eleven scenarios were developed to characterize potential exposures to radioactive materials during sewer system operations and sewage sludge treatment and disposal activities and during the extended time frame following sewage sludge disposal. Two sets of deterministic dose calculations were performed; one to evaluate potential doses based on the radionuclides and quantities associated with documented case histories of sewer system contamination and a second, somewhat more conservative set, based on theoretical discharges at the maximum allowable levels for a more comprehensive list of 63 radionuclides. The results of the stochastic uncertainty and sensitivity analysis were also used to develop a collective dose estimate. The collective doses for the various radionuclides and scenarios range from 0.4 person-rem for {sup 137}Cs in Scenario No. 5 (sludge incinerator effluent) to 420 person-rem for {sup 137}Cs in Scenario No. 3 (sewage treatment plant liquid effluent). None of the 22 scenario/radionuclide combinations considered have collective doses greater than 1000 person-rem/yr. However, the total collective dose from these 22 combinations was found to be about 2100 person-rem.

  10. [Exposure pathways to pesticides in schoolchildren in the Province of Talca, Chile].

    Science.gov (United States)

    Muñoz-Quezada, María Teresa; Lucero, Boris; Iglesias, Verónica; Muñoz, María Pía

    2014-01-01

    To describe pesticide concentrations in distinct environmental matrices at two time points (low and high seasons in local agricultural production) and to estimate the association between the presence of pesticide residues in matrices and the use of pesticides in the home with the sociodemographic variables of schoolchildren in the Province of Talca, Chile. A cross-sectional study was conducted in 190 schoolchildren. Families were surveyed about their children's vegetable consumption in school and at home, the use of pesticides in the home, and other sociodemographic variables. Additionally, we measured pesticide residues in vegetables and water consumed by the schoolchildren and in the soil of 14 schools. At both time points, the vegetable matrix had the highest pesticide concentration, both in urban and rural schoolchildren. The most common pesticide residues in vegetables were chlorpyrifos, diphenylamine, pyrimethanil, and thiabendazole. In the home, pyrethroid and organophosphate pesticides were mainly used in summer. Dangerous pesticide residues such as azinphos methyl and dimethoate were found in vegetables consumed by the children in schools and households, and organochlorines were found in the soil in some schools. Pesticide exposure should be limited and the health effects related to pesticide exposure should be assessed in the school population. Copyright © 2013 SESPAS. Published by Elsevier Espana. All rights reserved.

  11. Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human tumorigenesis

    DEFF Research Database (Denmark)

    Tort, F.; Bartkova, J.; Sehested, M.

    2006-01-01

    Loss of G(1)-S control and aberrations of the p16(Ink4a)-cyclin D1/cyclin-dependent kinase (CDK) 4(6)-pRb-E2F-cyclin E/CDK2 pathway are common in human cancer. Previous studies showed that oncogene-induced aberrant proliferation, such as on cyclin E overexpression, causes DNA damage and checkpoint...... culture models with differential defects of retinoblastoma pathway components, as overexpression of cyclin D1 or lack of p16(Ink4a), either alone or combined, did not elicit detectable DDR. In contrast, inactivation of pRb, the key component of the pathway, activated the DDR in cultured human or mouse...... cells, analogous to elevated cyclin E. These results highlight differential effect of diverse oncogenic events on driving the 'cancer cell cycles' and their ability to deregulate the replication-driving CDK2 kinase and to alarm the DDR as a potential anticancer barrier in accordance...

  12. De novo purine biosynthesis by two pathways in Burkitt lymphoma cells and in human spleen.

    Science.gov (United States)

    Reem, G H

    1972-05-01

    This study was designed to answer the question whether human lymphocytes and spleen cells were capable of de novo purine biosynthesis. Experiments were carried out in cell-free extracts prepared from human spleen, and from a cell line established from Burkitt lymphoma. Burkitt lymphoma cells and human spleen cells could synthesize the first and second intermediates of the purine biosynthetic pathway. Cell-free extracts of all cell lines studied contained the enzyme systems which catalyze the synthesis of phosphoribosyl-1-amine, the first intermediate unique to the purine biosynthetic pathway and of phosphoribosyl glycinamide, the second intermediate of this pathway. Phosphoribosyl-1-amine could be synthesized in cell-free extracts from alpha-5-phosphoribosyl-1-pyrophosphate (PRPP) and glutamine, from PRPP and ammonia, and by an alternative pathway, directly from ribose-5-phosphate and ammonia. These findings suggest that extrahepatic tissues may be an important source for the de novo synthesis of purine ribonucleotide in man. They also indicate that ammonia may play an important role in purine biosynthesis. The alternative pathway for the synthesis of phosphoribosyl-1-amine from ribose-5-phosphate and ammonia was found to be subject to inhibition by the end products of the purine synthetic pathway, particularly by adenylic acid and to a lesser degree by guanylic acid. The alternative pathway for phosphoribosyl-1-amine synthesis from ribose-5-phosphate and ammonia may contribute significantly towards the regulation of the rate of de novo purine biosynthesis in the normal state, in metabolic disorders in which purines are excessively produced and in myeloproliferative diseases.

  13. Comparative Proteomic Analysis of Human Liver Tissue and Isolated Hepatocytes with a Focus on Proteins Determining Drug Exposure.

    Science.gov (United States)

    Vildhede, Anna; Wiśniewski, Jacek R; Norén, Agneta; Karlgren, Maria; Artursson, Per

    2015-08-07

    Freshly isolated human hepatocytes are considered the gold standard for in vitro studies of liver functions, including drug transport, metabolism, and toxicity. For accurate predictions of the in vivo outcome, the isolated hepatocytes should reflect the phenotype of their in vivo counterpart, i.e., hepatocytes in human liver tissue. Here, we quantified and compared the membrane proteomes of freshly isolated hepatocytes and human liver tissue using a label-free shotgun proteomics approach. A total of 5144 unique proteins were identified, spanning over 6 orders of magnitude in abundance. There was a good global correlation in protein abundance. However, the expression of many plasma membrane proteins was lower in the isolated hepatocytes than in the liver tissue. This included transport proteins that determine hepatocyte exposure to many drugs and endogenous compounds. Pathway analysis of the differentially expressed proteins confirmed that hepatocytes are exposed to oxidative stress during isolation and suggested that plasma membrane proteins were degraded via the protein ubiquitination pathway. Finally, using pitavastatin as an example, we show how protein quantifications can improve in vitro predictions of in vivo liver clearance. We tentatively conclude that our data set will be a useful resource for improved hepatocyte predictions of the in vivo outcome.

  14. Mimicking human neuronal pathways in silico: an emergent model on the effective connectivity.

    Science.gov (United States)

    Gürcan, Önder; Türker, Kemal S; Mano, Jean-Pierre; Bernon, Carole; Dikenelli, Oğuz; Glize, Pierre

    2014-04-01

    We present a novel computational model that detects temporal configurations of a given human neuronal pathway and constructs its artificial replication. This poses a great challenge since direct recordings from individual neurons are impossible in the human central nervous system and therefore the underlying neuronal pathway has to be considered as a black box. For tackling this challenge, we used a branch of complex systems modeling called artificial self-organization in which large sets of software entities interacting locally give rise to bottom-up collective behaviors. The result is an emergent model where each software entity represents an integrate-and-fire neuron. We then applied the model to the reflex responses of single motor units obtained from conscious human subjects. Experimental results show that the model recovers functionality of real human neuronal pathways by comparing it to appropriate surrogate data. What makes the model promising is the fact that, to the best of our knowledge, it is the first realistic model to self-wire an artificial neuronal network by efficiently combining neuroscience with artificial self-organization. Although there is no evidence yet of the model's connectivity mapping onto the human connectivity, we anticipate this model will help neuroscientists to learn much more about human neuronal networks, and could also be used for predicting hypotheses to lead future experiments.

  15. HPIminer: A text mining system for building and visualizing human protein interaction networks and pathways.

    Science.gov (United States)

    Subramani, Suresh; Kalpana, Raja; Monickaraj, Pankaj Moses; Natarajan, Jeyakumar

    2015-04-01

    The knowledge on protein-protein interactions (PPI) and their related pathways are equally important to understand the biological functions of the living cell. Such information on human proteins is highly desirable to understand the mechanism of several diseases such as cancer, diabetes, and Alzheimer's disease. Because much of that information is buried in biomedical literature, an automated text mining system for visualizing human PPI and pathways is highly desirable. In this paper, we present HPIminer, a text mining system for visualizing human protein interactions and pathways from biomedical literature. HPIminer extracts human PPI information and PPI pairs from biomedical literature, and visualize their associated interactions, networks and pathways using two curated databases HPRD and KEGG. To our knowledge, HPIminer is the first system to build interaction networks from literature as well as curated databases. Further, the new interactions mined only from literature and not reported earlier in databases are highlighted as new. A comparative study with other similar tools shows that the resultant network is more informative and provides additional information on interacting proteins and their associated networks. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Linking Social Change and Developmental Change: Shifting Pathways of Human Development

    Science.gov (United States)

    Greenfield, Patricia M.

    2009-01-01

    P. M. Greenfield's new theory of social change and human development aims to show how changing sociodemographic ecologies alter cultural values and learning environments and thereby shift developmental pathways. Worldwide sociodemographic trends include movement from rural residence, informal education at home, subsistence economy, and…

  17. The Use of Signal-Transduction and Metabolic 1 Pathways to Predict Human Disease Targets from Electric and Magnetic Fields using Literature-Based In Vitro Microarray Data from 2002 to 2011

    Directory of Open Access Journals (Sweden)

    Fred Parham

    2016-09-01

    Full Text Available Using in-vitro data in human cell lines, several research groups have investigated changes in gene expression in cellular systems following exposure to extremely low frequency (ELF and radiofrequency (RF electromagnetic fields (EMF. For ELF EMF, we obtained 5 studies with complete microarray data and 3 studies with only lists of significantly altered genes. Likewise, for RF EMF we obtained 13 complete microarray data sets and 5 limited datasets. Plausible linkages between exposure to ELF and RF EMF and human diseases were identified using a three-step process: a linking genes associated with classes of human diseases to molecular pathways; b linking pathways to ELF and RF EMF microarray data; and c identifying associations between human disease and EMF exposures where the pathways are significantly similar. A total of 60 pathways were associated with human diseases, mostly focused on basic cellular functions like JAK-STAT signaling or metabolic functions like xenobiotic metabolism by cytochrome P450 enzymes. ELF EMF datasets were sporadically linked to human diseases but no clear pattern emerged. Individual data sets showed some linkage to cancer, chemical dependency, metabolic disorders and neurological disorders. RF EMF datasets were not strongly linked to any disorders. Based on these analyses, the most promising area for further research would be to focus on EMF and neurological function and disorders.

  18. Continual exposure to cigarette smoke extracts induces tumor-like transformation of human nontumor bronchial epithelial cells in a microfluidic chip.

    Science.gov (United States)

    Li, Encheng; Xu, Zhiyun; Liu, Fen; Wang, Huiling; Wen, Jiabin; Shao, Shujuan; Zhang, Lichuan; Wang, Lei; Liu, Chong; Lu, Jianxin; Wang, Wenxin; Gao, Zhancheng; Wang, Qi

    2014-08-01

    Heavy cigarette smoking-related chronic obstructive pulmonary disease is an independent risk factor for lung squamous carcinoma. However, the mechanisms underlying the malignant transformation of bronchial epithelial cells are unclear. In our study, human tumor-adjacent bronchial epithelial cells were obtained from 10 cases with smoking-related chronic obstructive pulmonary disease and lung squamous carcinoma and cultured in an established microfluidic chip for continual exposure to cigarette smoke extracts (CSE) to investigate the potential tumor-like transformation and mechanisms. The integrated microfluidic chip included upstream concentration gradient generator and downstream cell culture chambers supplied by flowing medium containing different concentrations of CSE. Our results showed that continual exposure to low doses of CSE promoted cell proliferation whereas to high doses of CSE triggered cell apoptosis. Continual exposure to CSE promoted reactive oxygen species production in human epithelial cells in a dose-dependent manner. More importantly, continual exposure to low dose of CSE promoted the epithelial-to-mesenchymal transition process and anchorage-independent growth, and increased chromosome instability in bronchial epithelial cells, accompanied by activating the GRP78, NF-κB, and PI3K pathways. The established microfluidic chip is suitable for primary culture of human tumor-adjacent bronchial epithelial cells to investigate the malignant transformation. Continual exposure to low doses of CSE promoted tumor-like transformation of human nontumor bronchial epithelial cells by inducing reactive oxygen species production and activating the relevant signaling.

  19. Human Parotid Gland Alpha-Amylase Secretion as a Function of Chronic Hyperbaric Exposure

    Science.gov (United States)

    1979-01-01

    parotid ...Pullman, WA 99163 Gilman, S. C, G. J. Fischer, R. J. Biersner, R. D. Thornton, and D. A. Miller. 1979. Human parotid gland alpha-amylase secretion...as a function of chronic hyperbaric exposure. Undersea Biomed. Res. 6(3):303-307.—Secretion of a-amylase by the human parotid gland increased

  20. Human Infection with MERS coronavirus after exposure to infected camels, Saudi Arabia, 2013

    NARCIS (Netherlands)

    Memish, Ziad A.; Cotten, Matthew; Meyer, Benjamin; Watson, Simon J.; Alsahafi, Abdullah J.; Al Rabeeah, Abdullah A.; Corman, Victor Max; Sieberg, Andrea; Makhdoom, Hatem Q.; Assiri, Abdullah; Al Masri, Malaki; Aldabbagh, Souhaib; Bosch, Berend Jan; Beer, Martin; Müller, Marcel A.; Kellam, Paul; Drosten, Christian

    2014-01-01

    We investigated a case of human infection with Middle East respiratory syndrome coronavirus (MERS-CoV) after exposure to infected camels. Analysis of the whole human-derived virus and 15% of the camel-derived virus sequence yielded nucleotide polymorphism signatures suggestive of cross-species trans

  1. A Chain Modeling Approach To Estimate the Impact of Soil Cadmium Pollution on Human Dietary Exposure

    NARCIS (Netherlands)

    Franz, E.; Romkens, P.F.A.M.; Raamsdonk, van L.W.D.; Fels-Klerx, van der H.J.

    2008-01-01

    Cadmium in soil poses a risk for human health, due to its accumulation in food and feed crops. The extent of accumulation depends strongly on soil type and the degree of pollution. The objective of the present study was to develop a predictive model to estimate human dietary cadmium exposure from so

  2. Ochratoxin A in Portugal: A Review to Assess Human Exposure

    Directory of Open Access Journals (Sweden)

    Sofia C. Duarte

    2010-06-01

    Full Text Available In Portugal, the climate, dietary habits, and food contamination levels present the characteristics for higher population susceptibility to ochratoxin A (OTA, one of the known mycotoxins with the greatest public health and agro-economic importance. In this review, following a brief historical insight on OTA research, a summary of the available data on OTA occurrence in food (cereals, bread, wine, meat and biological fluids (blood, urine is made. With this data, an estimation of intake is made to ascertain and update the risk exposure estimation of the Portuguese population, in comparison to previous studies and other populations.

  3. Exposure measurement of aflatoxins and aflatoxin metabolites in human body fluids. A short review.

    Science.gov (United States)

    Leong, Yin-Hui; Latiff, Aishah A; Ahmad, Nurul Izzah; Rosma, Ahmad

    2012-05-01

    Aflatoxins are highly toxic secondary fungal metabolites mainly produced by Aspergillus flavus and A. parasiticus. Human exposure to aflatoxins may result directly from ingestion of contaminated foods, or indirectly from consumption of foods from animals previously exposed to aflatoxins in feeds. This paper focuses on exposure measurement of aflatoxins and aflatoxin metabolites in various human body fluids. Research on different metabolites present in blood, urine, breast milk, and other human fluids or tissues including their detection techniques is reviewed. The association between dietary intake of aflatoxins and biomarker measurement is also highlighted. Finally, aspects related to the differences between aflatoxin determination in food versus the biomarker approach are discussed.

  4. Mixtures of endocrine disrupting contaminants modelled on human high end exposures

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Kortenkamp, A.; Petersen, Marta Axelstad

    2012-01-01

    in vivo endocrine disrupting effects and information about human exposures was available, including phthalates, pesticides, UV‐filters, bisphenol A, parabens and the drug paracetamol. The mixture ratio was chosen to reflect high end human intakes. To make decisions about the dose levels for studies...... though each individual chemical is present at low, ineffective doses, but the effects of mixtures modelled based on human intakes have not previously been investigated. To address this issue for the first time, we selected 13 chemicals for a developmental mixture toxicity study in rats where data about...... in the rat, we employed the point of departure index (PODI) approach, which sums up ratios between estimated exposure levels and no‐observed‐adverse‐effect‐level (NOAEL) values of individual substances. For high end human exposures to the 13 selected chemicals, we calculated a PODI of 0.016. As only a PODI...

  5. Assessing hazardous risks of human exposure to temple airborne polycyclic aromatic hydrocarbons.

    Science.gov (United States)

    Chiang, Kuo-Chih; Chio, Chia-Pin; Chiang, Yu-Hui; Liao, Chung-Min

    2009-07-30

    We proposed an integrated probabilistic risk assessment framework based on reported data to quantify human health risks of temple goers/workers to airborne polycyclic aromatic hydrocarbons (PAHs) from incense burning in typical Taiwanese temples. The framework probabilistically integrates exposure, human respiratory tract, and incremental lifetime cancer risk (ILCR) models to quantitatively estimate size-dependent PAHs exposure in human lung regions and cancer risks for temple goers (moderate and high exposures) and temple workers (extreme exposure). Our results show that the ILCRs are greater than the acceptable level of 10(-6) for extreme and high exposure groups through inhalation route. The result also indicates that the higher ILCRs (10(-6) to 10(-4)) are found in ingestion and dermal contact routes for temple goers/workers. For personal extreme exposure to carcinogenic PAH in the temple, 95% probability total ILCR (TILCR) (9.87 x 10(-4) to 1.13 x 10(-3)) is much greater than the range of 10(-6) to 10(-4), indicating high potential health risk to temple workers. For temple goers with high and moderate exposure groups, however, the 95% probability TILCRs were estimated from 6.44 x 10(-5) to 7.50 x 10(-5) and 5.75 x 10(-6) to 6.99 x 10(-6), respectively. This study successfully offers a scientific basis for risk analysis due to incense burning to enhance broad risk management strategies for temple indoor air quality.

  6. Effects of exposure to oil spills on human health: Updated review.

    Science.gov (United States)

    Laffon, Blanca; Pásaro, Eduardo; Valdiglesias, Vanessa

    2016-01-01

    Oil spills may involve health risks for people participating in the cleanup operations and coastal inhabitants, given the toxicological properties of the oil components. In spite of this, only after a few major oil spills (crude oil or fuel oil no. 6) have studies on effects of exposure to diverse aspects of human health been performed. Previously, Aguilera et al. (2010) examined all documents published to that date dealing with any type of human health outcome in populations exposed to oil spills. The aim of the present review was to compile all new information available and determine whether evidence reported supports the existence of an association between exposure and adverse human health risks. Studies were classified in three groups according to type of health outcome addressed: (i) effects on mental health, (ii) physical/physiological effects, and (iii) genotoxic, immunotoxic, and endocrine toxicity. New studies published on oil-spill-exposed populations-coastal residents in the vicinity of the spills or participants in cleanup operations-provide additional support to previous evidence on adverse health effects related to exposure regarding different parameters in all three categories considered. Some of the observed effects even indicated that several symptoms may persist for some years after exposure. Hence, (1) health protection in these individuals should be a matter of concern; and (2) health risk assessment needs to be carried out not only at the time of exposure but also for prolong periods following exposure, to enable early detection of any potential exposure-related harmful effects.

  7. In vitro exposure of human chondrocytes to pulsed electromagnetic fields

    Directory of Open Access Journals (Sweden)

    V Nicolin

    2009-08-01

    Full Text Available The effect of pulsed electromagnetic fields (PEMFs on the proliferation and survival of matrix-induced autologous chondrocyte implantation (MACI®-derived cells was studied to ascertain the healing potential of PEMFs. MACI-derived cells were taken from cartilage biopsies 6 months after surgery and cultured. No dedifferentiation towards the fibroblastic phenotype occurred, indicating the success of the surgical implantation. The MACI-derived cultured chondrocytes were exposed to 12 h/day (short term or 4 h/day (long term PEMFs exposure (magnetic field intensity, 2 mT; frequency, 75 Hz and proliferation rate determined by flow cytometric analysis. The PEMFs exposure elicited a significant increase of cell number in the SG2M cell cycle phase. Moreover, cells isolated from MACI® scaffolds showed the presence of collagen type II, a typical marker of chondrocyte functionality. The results show that MACI® membranes represent an optimal bioengineering device to support chondrocyte growth and proliferation in surgical implants. The surgical implant of MACI® combined with physiotherapy is suggested as a promising approach for a faster and safer treatment of cartilage traumatic lesions.

  8. Novel biomarkers of prenatal methamphetamine exposure in human meconium

    Science.gov (United States)

    Gray, Teresa R.; Kelly, Tamsin; LaGasse, Linda L.; Smith, Lynne M.; Derauf, Chris; Haning, William; Grant, Penny; Shah, Rizwan; Arria, Amelia; Strauss, Arthur; Lester, Barry M.; Huestis, Marilyn A.

    2008-01-01

    Meconium analysis can detect fetal exposure to drugs taken by the mother during pregnancy. Methamphetamine and amphetamine have previously been observed in meconium of methamphetamine-exposed neonates; the presence of other metabolites has not been investigated. Detection of such analytes may lead to more sensitive identification and, thus improved medical treatment of affected infants. Methods and Materials Forty-three methamphetamine-positive meconium specimens were analyzed for newly identified methamphetamine biomarkers, p-hydroxymethamphetamine, p-hydroxyamphetamine, and norephedrine. Due to methamphetamine adulteration in illicit ecstasy and to simultaneously monitor 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine prenatal exposure, MDMA, its metabolites and related sympathomimetic amines were assayed. Results Methamphetamine, amphetamine and unconjugated p-hydroxymethamphetamine were the most prevalent and abundant analytes present in meconium; however, unconjugated p-hydroxyamphetamine and norephedrine also were identified. Discussion It is possible that one of these additional analytes could be important for predicting toxicity or maternal or neonatal outcome measures in fetuses exposed to methamphetamine at specific gestational ages or with different metabolic capabilities. Although these new biomarkers were present in lower concentrations than methamphetamine and amphetamine in the meconium of previously confirmed specimens, additional research will determine if inclusion of these analytes can increase identification of methamphetamine-exposed neonates. Conclusion Novel methamphetamine biomarker concentrations were characterized in meconium of infants exposed in utero to methamphetamine. PMID:19125148

  9. Gene expression signatures that predict radiation exposure in mice and humans.

    Directory of Open Access Journals (Sweden)

    Holly K Dressman

    2007-04-01

    Full Text Available BACKGROUND: The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation. METHODS AND FINDINGS: We have made use of gene expression analysis of peripheral blood (PB mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans. CONCLUSIONS: We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.

  10. Effects of ozone exposure on lipid metabolism in human alveolar macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Friedman, M.; Madden, M.C.; Samet, J.M.; Koren, H.S.

    1991-01-01

    Alveolar macrophages (AM) store arachidonic acid (AA) which is esterified in cellular phospholipids until liberated by phospholipase A2 or C after exposure to inflammatory stimuli. Following release, there can be subsequent metabolism of AA into various potent, biological active mediators including prostaglandins and platelet activating factor (PAF). To examine the possibility that these mediators may account for some of the pathophysiologic alterations seen in the lung following O3 exposure, human AM were collected by bronchoalveolar lavage of normal subjects, plated into tissue culture dishes, and the adherent cells were incubated with 3H-AA or 3H-lysoPAF. Human AM exposed 1.0 ppm O3 for 2 hr released 65 + or - 12% more tritium, derived from 3H-AA, than paired air-exposed controls into media supernatants. In other studies using a similar O3 exposure protocol, there was also a significant increase in human AM PGE2 production (2.0 + or - 0.5 fold-increase above air-exposure values, p<0.01, n=17). In additional studies, using a similar O3 exposure protocol (1.0 ppm for 1 hr), there was also a significant increase in human AM PAF content (1.7 + or - 0.2 fold-increase above air-exposure values, p<0.02, n=5).

  11. Pathways to human experimentation, 1933-1945: Germany, Japan, and the United States.

    Science.gov (United States)

    Baader, Gerhard; Lederer, Susan E; Low, Morris; Schmaltz, Florian; Schwerin, Alexander V

    2005-01-01

    The history of human experimentation in the twelve years between Hitler's rise to power and the end of the Second World War is notorious in the annals of the twentieth century. The horrific experiments conducted at Dachau, Auschwitz, Ravensbrueck, Birkenau, and other National Socialist concentration camps reflected an extreme indifference to human life and human suffering. Unfortunately, they do not reflect the extent and complexity of the human experiments undertaken in the years between 1933 and 1945. Following the prosecution of twenty-three high-ranking National Socialist physicians and medical administrators for war crimes and crimes against humanity in the Nuremberg Medical Trial (United States v. Karl Brandt et al.), scholars have rightly focused attention on the nightmarish researches conducted by a small group of investigators on concentration camp inmates. Less well known are alternative pathways that brought investigators to undertake human experimentation in other laboratories, settings, and nations.

  12. Source-to-receptor pathways of anthropogenic PM 2.5 in Detroit, Michigan: Comparison of two inhalation exposure studies

    Science.gov (United States)

    Morishita, Masako; Keeler, Gerald J.; McDonald, Jacob D.; Wagner, James G.; Young, Li-Hao; Utsunomiya, Satoshi; Ewing, Rodney C.; Harkema, Jack R.

    Recent studies have attributed toxic effects of ambient fine particulate matter (aerodynamic diameter ≤ 2.5 μm; PM 2.5) to physical and/or chemical properties rather than total mass. However, identifying specific components or sources of a complex mixture of ambient PM 2.5 that are responsible for adverse health effects is still challenging. In order to improve our understanding of source-to-receptor pathways for ambient PM 2.5 (links between sources of ambient PM 2.5 and measures of biologically relevant dose), integrated inhalation toxicology studies using animal models and concentrated air particles (CAPs) were completed in southwest Detroit, a community where the pediatric asthma rate is more than twice the national average. Ambient PM 2.5 was concentrated with a Harvard fine particle concentrator housed in AirCARE1, a mobile air research laboratory which facilitates inhalation exposure studies in real-world settings. Detailed characterizations of ambient PM 2.5 and CAPs, identification of major emission sources of PM 2.5, and quantification of trace elements in the lung tissues of laboratory rats that were exposed to CAPs for two distinct 3-day exposure periods were completed. This paper describes the physical/chemical properties and sources of PM 2.5, pulmonary metal concentrations and meteorology from two different 3-day exposure periods—both conducted at the southwest Detroit location in July 2003—which resulted in disparate biological effects. More specifically, during one of the exposure periods, ambient PM 2.5-derived trace metals were recovered from lung tissues of CAPs-exposed animals, and these metals were linked to local combustion point sources in southwest Detroit via receptor modeling and meteorology; whereas in the other exposure period, no such trace metals were observed. By comparing these two disparate results, this investigation was able to define possible links between PM 2.5 emitted from refineries and incinerators and biologically

  13. Numb/Notch signaling pathway modulation enhances human pancreatic cancer cell radiosensitivity.

    Science.gov (United States)

    Bi, Yi-Liang; Min, Min; Shen, Wei; Liu, Yan

    2016-11-01

    The present study aims to evaluate whether repression of the Numb/Notch signaling pathway affects the radiosensitivity of human pancreatic cancer cell lines. Different doses of X-rays (0, 2, 3, 4, and 5 Gy) were applied to the PANC-1, SW1990, and MIA PaCa-2 human pancreatic cancer cell lines, and the Numb/Notch pathway inhibitor DAPT was added at different doses (0, 1, 3, and 5 μmol/l). MTT assay, colony formation assay, flow cytometry, scratch assay, and Transwell experiments were performed, and qRT-PCR and Western blot were conducted for the detection of Numb expression. Tumorigenicity assay in nude mice was carried out to verify the influence of blocker of the Numb/Notch signaling pathway on the radiosensitivity of xenograft tumors. The MTT assay, colony formation assay and flow cytometry experiments revealed that proliferation decreased as radiation dose increased. The viability of PANC-1 cells at 5 Gy, SW 1990 cells at 4 Gy and 5 Gy, and MIA PaCa-2 cells at 2-5 Gy was significantly lower than that of non-irradiated cells (all P cancer cells is associated with X-ray radiation and that inhibition of the Numb/Notch signaling pathway can enhance radiosensitivity, suggesting that inhibition of the Numb/Notch signaling pathway may serve as a potential target for clinical improvement of the radiosensitivity of pancreatic cancer.

  14. A Direct Cortico-Nigral Pathway as Revealed by Constrained Spherical Deconvolution Tractography in Humans

    Directory of Open Access Journals (Sweden)

    Alberto Cacciola

    2016-07-01

    Full Text Available Substantia nigra is an important neuronal structure, located in the ventral midbrain, that exerts a regulatory function within the basal ganglia circuitry through the nigro-striatal pathway. Although its subcortical connections are relatively well known in human brain, very little is known about its cortical connections. The existence of a direct cortico-nigral pathway has been demonstrated in rodents and primates but only hypothesized in humans. In this study, we aimed at evaluating cortical connections of substantia nigra in vivo in human brain, by using probabilistic constrained spherical deconvolution tractography on magnetic resonance diffusion weighted imaging data. We found that substantia nigra is connected with cerebral cortex as a whole, with the most representative connections involving prefrontal cortex, precentral and postcentral gyri and superior parietal lobule. These results may be relevant for the comprehension of the pathophysiology of several neurological disorders involving substantia nigra, such as parkinson’s disease, schizophrenia and pathological addictions.

  15. Human arsenic exposure and risk assessment at the landscape level: a review.

    Science.gov (United States)

    Khan, Nasreen Islam; Owens, Gary; Bruce, David; Naidu, Ravi

    2009-04-01

    Groundwater contaminated with arsenic (As), when extensively used for irrigation, causes potentially long term detrimental effects to the landscape. Such contamination can also directly affect human health when irrigated crops are primarily used for human consumption. Therefore, a large number of humans are potentially at risk worldwide due to daily As exposure. Numerous previous studies have been severely limited by small sample sizes which are not reliably extrapolated to large populations or landscapes. Human As exposure and risk assessment are no longer simple assessments limited to a few food samples from a small area. The focus of more recent studies has been to perform risk assessment at the landscape level involving the use of biomarkers to identify and quantify appropriate health problems and large surveys of human dietary patterns, supported by analytical testing of food, to quantify exposure. This approach generates large amounts of data from a wide variety of sources and geographic information system (GIS) techniques have been used widely to integrate the various spatial, demographic, social, field, and laboratory measured datasets. With the current worldwide shift in emphasis from qualitative to quantitative risk assessment, it is likely that future research efforts will be directed towards the integration of GIS, statistics, chemistry, and other dynamic models within a common platform to quantify human health risk at the landscape level. In this paper we review the present and likely future trends of human As exposure and GIS application in risk assessment at the landscape level.

  16. A Smarter Pathway for Delivering Cue Exposure Therapy? The Design and Development of a Smartphone App Targeting Alcohol Use Disorder.

    Science.gov (United States)

    Mellentin, Angelina Isabella; Stenager, Elsebeth; Nielsen, Bent; Nielsen, Anette Søgaard; Yu, Fei

    2017-01-30

    Although the number of alcohol-related treatments in app stores is proliferating, none of them are based on a psychological framework and supported by empirical evidence. Cue exposure treatment (CET) with urge-specific coping skills (USCS) is often used in Danish treatment settings. It is an evidence-based psychological approach that focuses on promoting "confrontation with alcohol cues" as a means of reducing urges and the likelihood of relapse. The objective of this study was to describe the design and development of a CET-based smartphone app; an innovative delivery pathway for treating alcohol use disorder (AUD). The treatment is based on Monty and coworkers' manual for CET with USCS (2002). It was created by a multidisciplinary team of psychiatrists, psychologists, programmers, and graphic designers as well as patients with AUD. A database was developed for the purpose of registering and monitoring training activities. A final version of the CET app and database was developed after several user tests. The final version of the CET app includes an introduction, 4 sessions featuring USCS, 8 alcohol exposure videos promoting the use of one of the USCS, and a results component providing an overview of training activities and potential progress. Real-time urges are measured before, during, and after exposure to alcohol cues and are registered in the app together with other training activity variables. Data packages are continuously sent in encrypted form to an external database and will be merged with other data (in an internal database) in the future. The CET smartphone app is currently being tested at a large-scale, randomized controlled trial with the aim of clarifying whether it can be classified as an evidence-based treatment solution. The app has the potential to augment the reach of psychological treatment for AUD.

  17. Human volunteer study with PGME: Eye irritation during vapour exposure

    NARCIS (Netherlands)

    Emmen, H.H.; Muijser, H.; Arts, J.H.E.; Prinsen, M.K.

    2003-01-01

    The objective of this study was to establish the possible occurrence of eye irritation and subjective symptoms in human volunteers exposed to propylene glycol monomethyl ether (PGME) vapour at concentrations of 0, 100 and 150 ppm. Testing was conducted in 12 healthy male volunteers using a repeated

  18. Human volunteer study with PGME: Eye irritation during vapour exposure

    NARCIS (Netherlands)

    Emmen, H.H.; Muijser, H.; Arts, J.H.E.; Prinsen, M.K.

    2003-01-01

    The objective of this study was to establish the possible occurrence of eye irritation and subjective symptoms in human volunteers exposed to propylene glycol monomethyl ether (PGME) vapour at concentrations of 0, 100 and 150 ppm. Testing was conducted in 12 healthy male volunteers using a repeated

  19. Human Resource Challenges to Integrating HIV Pre-Exposure ...

    African Journals Online (AJOL)

    AJRH Managing Editor

    We documented consultation discussions through note taking. Human resource .... coordinators, and nursing officer in-charges. Interviews were ... shifting as playing an important role in PrEP .... counseling, and to high patient volume and longer wait times on the ... about the safety and efficacy of PrEP, which may influence ...

  20. Assessment of dietary exposure and effect in humans

    NARCIS (Netherlands)

    Duynhoven, Van John P.M.; Jacobs, Doris M.

    2016-01-01

    In human nutritional science progress has always depended strongly on analytical measurements for establishing relationships between diet and health. This field has undergone significant changes as a result of the development of NMR and mass spectrometry methods for large scale detection, identif

  1. Developing and evaluating distributions for probabilistic human exposure assessments

    Energy Technology Data Exchange (ETDEWEB)

    Maddalena, Randy L.; McKone, Thomas E.

    2002-08-01

    This report describes research carried out at the Lawrence Berkeley National Laboratory (LBNL) to assist the U. S. Environmental Protection Agency (EPA) in developing a consistent yet flexible approach for evaluating the inputs to probabilistic risk assessments. The U.S. EPA Office of Emergency and Remedial Response (OERR) recently released Volume 3 Part A of Risk Assessment Guidance for Superfund (RAGS), as an update to the existing two-volume set of RAGS. The update provides policy and technical guidance on performing probabilistic risk assessment (PRA). Consequently, EPA risk managers and decision-makers need to review and evaluate the adequacy of PRAs for supporting regulatory decisions. A critical part of evaluating a PRA is the problem of evaluating or judging the adequacy of input distributions PRA. Although the overarching theme of this report is the need to improve the ease and consistency of the regulatory review process, the specific objectives are presented in two parts. The objective of Part 1 is to develop a consistent yet flexible process for evaluating distributions in a PRA by identifying the critical attributes of an exposure factor distribution and discussing how these attributes relate to the task-specific adequacy of the input. This objective is carried out with emphasis on the perspective of a risk manager or decision-maker. The proposed evaluation procedure provides consistency to the review process without a loss of flexibility. As a result, the approach described in Part 1 provides an opportunity to apply a single review framework for all EPA regions and yet provide the regional risk manager with the flexibility to deal with site- and case-specific issues in the PRA process. However, as the number of inputs to a PRA increases, so does the complexity of the process for calculating, communicating and managing risk. As a result, there is increasing effort required of both the risk professionals performing the analysis and the risk manager

  2. The potential utility of animal poisoning data to identify human exposure to environmental toxins.

    Science.gov (United States)

    Hungerford, L L; Trammel, H L; Clark, J M

    1995-04-01

    The database of the National Animal Poison Control Center (NAPCC) was evaluated as a source for animal poison data indicating human health hazards in indoor and outdoor environments. From 14,150 calls in the 1985 database, 259 cases were identified with histories suggesting human exposure. A subgroup of 25 cases with known human exposure was found. Dogs were the most common sentinel animal, but bird cases represented the highest proportional selection from the total 1985 call list. Indoor exposures represented 43.2% of cases; the most common toxicants were insecticides, lead and toxic fumes. Exposures associated with lawns were mainly due to insecticides and herbicides and constituted 25.5% of cases. Other outdoor exposures composed the remaining 31.7% of cases, with insecticides, herbicides and unidentified toxins the leading categories. Many of the specific agents identified, such as organophosphate insecticides, lead, gas and fume toxins, and phenoxy herbicides are also risk factors in human diseases. This study indicates that databases such as NAPCC could serve as sources of sentinel animal intoxications for followup studies to evaluate known and potential human health hazards.

  3. Mutagenic potential assessment associated with human exposure to natural radioactivity.

    Science.gov (United States)

    Marcon, Alexandre Endres; Navoni, Julio Alejandro; de Oliveira Galvão, Marcos Felipe; Garcia, Anuska Conde Fagundes Soares; do Amaral, Viviane Souza; Petta, Reinaldo Antônio; Campos, Thomas Ferreira da Costa; Panosso, Renata; Quinelato, Antônio Luiz; de Medeiros, Sílvia Regina Batistuzzo

    2017-01-01

    Lucrécia city, known to harbor a high cancer rate, is located in a semiarid region characterized by the presence of mineral reservoirs, facing a high exposure to metal and natural radioactivity. The present study aimed to assess the environmental scenario at a semiarid region located in Northeastern Brazil. Metal concentration, alpha and beta radiation, and cyanobacteria content in tap water along with indoor radon and gamma emitters (U, K and Th) concentrations were measured. In addition, mutagenic and nuclear instability effects were assessed using buccal micronucleus cytome assay. The study included five samplings corresponding to a period between 2007 and 2009. Drinking water from Lucrécia city presented levels of Mn, Ni and Cr along with cyanobacteria in concentrations one to four times higher than regulatory guidelines considered. Furthermore, high levels of all the tested radionuclides were found. A high percentage of the houses included in this study presented indoor radon concentrations over 100 Bq m(-3). The mean annual effective dose from Lucrécia houses was six times higher than observed in a control region. The levels of exposure in most of the Lucrécia houses were classified as middle to high. A significant mutagenic effect, represented as an increase of micronuclei (MN) frequency and nuclear abnormalities as nuclear buds (NB), binucleated cells (BN), and pyknotic cells (PYC) were found. The results obtained highlight the role of high background radioactivity on the observed mutagenic effect and could help to explain the exacerbated cancer rate reported in this locality.

  4. Relationship between vapor intrusion and human exposure to trichloroethylene.

    Science.gov (United States)

    Archer, Natalie P; Bradford, Carrie M; Villanacci, John F; Crain, Neil E; Corsi, Richard L; Chambers, David M; Burk, Tonia; Blount, Benjamin C

    2015-01-01

    Trichloroethylene (TCE) in groundwater has the potential to volatilize through soil into indoor air where it can be inhaled. The purpose of this study was to determine whether individuals living above TCE-contaminated groundwater are exposed to TCE through vapor intrusion. We examined associations between TCE concentrations in various environmental media and TCE concentrations in residents. For this assessment, indoor air, outdoor air, soil gas, and tap water samples were collected in and around 36 randomly selected homes; blood samples were collected from 63 residents of these homes. Additionally, a completed exposure survey was collected from each participant. Environmental and blood samples were analyzed for TCE. Mixed model multiple linear regression analyses were performed to determine associations between TCE in residents' blood and TCE in indoor air, outdoor air, and soil gas. Blood TCE concentrations were above the limit of quantitation (LOQ; ≥ 0.012 µg L(-1)) in 17.5% of the blood samples. Of the 36 homes, 54.3%, 47.2%, and >84% had detectable concentrations of TCE in indoor air, outdoor air, and soil gas, respectively. Both indoor air and soil gas concentrations were statistically significantly positively associated with participants' blood concentrations (P = 0.0002 and P = 0.04, respectively). Geometric mean blood concentrations of residents from homes with indoor air concentrations of >1.6 µg m(-3) were approximately 50 times higher than geometric mean blood TCE concentrations in participants from homes with no detectable TCE in indoor air (P < .0001; 95% CI 10.4-236.4). This study confirms the occurrence of vapor intrusion and demonstrates the magnitude of exposure from vapor intrusion of TCE in a residential setting.

  5. Prenatal substance exposure and child self-regulation: Pathways to risk and protection.

    Science.gov (United States)

    Eiden, Rina D; Godleski, Stephanie; Schuetze, Pamela; Colder, Craig R

    2015-09-01

    A conceptual model of the association between prenatal cocaine exposure (PCE) and child self-regulation via maternal harshness and language development was examined. Specifically, the model tested whether PCE was associated with self-regulation either directly or indirectly via high maternal harshness and poor language development. The role of child sex, autonomic reactivity, and cumulative environmental risk as potential moderators was also explored. The sample was 216 mother-child dyads recruited at birth and assessed at 2, 7, 13, 24, 36, and 48 months of child ages. Participating mothers were primarily African American (72%). Results indicated a significant indirect association between PCE and child effortful control at 36 months via higher maternal harshness. Autonomic reactivity moderated the association between maternal harshness and self-regulation such that among children with poor autonomic reactivity, high maternal harshness was associated with lower conscience at 3 years. Child sex and environmental risk did not moderate the association between PCE and self-regulation. Thus, the quality of caregiving experience played a significant role in the development of self-regulation among PCE children, especially those at higher autonomic risk. In particular, PCE children who also exhibit poor autonomic reactivity may be particularly susceptible to environmental influences such as parenting. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Use of chromosome translocations for measuring prior environment exposures in humans

    Energy Technology Data Exchange (ETDEWEB)

    Tucker, J. D.

    1997-05-01

    Recent advances in cytogenetic methodology are beginning to have a major impact upon our ability to provide assessments of environmental exposure in humans. The advent of fluorescent-based techniques for `painting` whole chromosomes has made the analysis of chromosome translocations rapid, specific, sensitive and routine. Chromosome painting has been used to address a wide variety of scientific questions, resulting in an increased understanding of the biological consequences of adverse environmental exposure. This paper describes the use of chromosome translocations as a biological marker of exposure and effect in humans. The relevance of translocations is discussed, as are the advantages and disadvantages of painting compared to classical cytogenetic methods for translocation evaluation. The factors to consider in the use of translocations as a retrospective indicator of exposure are then described. Several theoretical parameters that are important to the use of translocations are provided, and the paper concludes with a vision for the future of cytogenetic methodology.

  7. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model

    DEFF Research Database (Denmark)

    van den Driesche, Sander; Macdonald, Joni; Anderson, Richard A

    2015-01-01

    Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons......, but effects on fetal testosterone production have not been demonstrated. We used a validated xenograft model to expose human fetal testes to clinically relevant doses and regimens of acetaminophen. Exposure to a therapeutic dose of acetaminophen for 7 days significantly reduced plasma testosterone (45......% reduction; P = 0.025) and seminal vesicle weight (a biomarker of androgen exposure; 18% reduction; P = 0.005) in castrate host mice bearing human fetal testis xenografts, whereas acetaminophen exposure for just 1 day did not alter either parameter. Plasma acetaminophen concentrations (at 1 hour after...

  8. Scope and limitations of yeast as a model organism for studying human tissue-specific pathways.

    Science.gov (United States)

    Mohammadi, Shahin; Saberidokht, Baharak; Subramaniam, Shankar; Grama, Ananth

    2015-12-29

    Budding yeast, S. cerevisiae, has been used extensively as a model organism for studying cellular processes in evolutionarily distant species, including humans. However, different human tissues, while inheriting a similar genetic code, exhibit distinct anatomical and physiological properties. Specific biochemical processes and associated biomolecules that differentiate various tissues are not completely understood, neither is the extent to which a unicellular organism, such as yeast, can be used to model these processes within each tissue. We present a novel framework to systematically quantify the suitability of yeast as a model organism for different human tissues. To this end, we develop a computational method for dissecting the global human interactome into tissue-specific cellular networks. By individually aligning these networks with the yeast interactome, we simultaneously partition the functional space of human genes, and their corresponding pathways, based on their conservation both across species and among different tissues. Finally, we couple our framework with a novel statistical model to assess the conservation of tissue-specific pathways and infer the overall similarity of each tissue with yeast. We further study each of these subspaces in detail, and shed light on their unique biological roles in the human tissues. Our framework provides a novel tool that can be used to assess the suitability of the yeast model for studying tissue-specific physiology and pathophysiology in humans. Many complex disorders are driven by a coupling of housekeeping (universally expressed in all tissues) and tissue-selective (expressed only in specific tissues) dysregulated pathways. While tissue-selective genes are significantly associated with the onset and development of a number of tissue-specific pathologies, we show that the human-specific subset has even higher association. Consequently, they provide excellent candidates as drug targets for therapeutic interventions.

  9. Development of human white matter fiber pathways: From newborn to adult ages.

    Science.gov (United States)

    Cohen, Andrew H; Wang, Rongpin; Wilkinson, Molly; MacDonald, Patrick; Lim, Ashley R; Takahashi, Emi

    2016-05-01

    Major long-range white matter pathways (cingulum, fornix, uncinate fasciculus [UF], inferior fronto-occipital fasciculus [IFOF], inferior longitudinal fasciculus [ILF], thalamocortical [TC], and corpus callosal [CC] pathways) were identified in eighty-three healthy humans ranging from newborn to adult ages. We tracked developmental changes using high-angular resolution diffusion MR tractography. Fractional anisotropy (FA), apparent diffusion coefficient, number, length, and volume were measured in pathways in each subject. Newborns had fewer, and more sparse, pathways than those of the older subjects. FA, number, length, and volume of pathways gradually increased with age and reached a plateau between 3 and 5 years of age. Data were further analyzed by normalizing with mean adult values as well as with each subject's whole brain values. Comparing subjects of 3 years old and under to those over 3 years old, the studied pathways showed differential growth patterns. The CC, bilateral cingulum, bilateral TC, and the left IFOF pathways showed significant growth both in volume and length, while the bilateral fornix, bilateral ILF and bilateral UF showed significant growth only in volume. The TC and CC took similar growth patterns with the whole brain. FA values of the cingulum and IFOF, and the length of ILF showed leftward asymmetry. The fornix, ILF and UF occupied decreased space compared to the whole brain during development with higher FA values, likely corresponding to extensive maturation of the pathways compared to the mean whole brain maturation. We believe that the outcome of this study will provide an important database for future reference.

  10. Human exposure to high natural background radiation: what can it teach us about radiation risks?

    OpenAIRE

    Jolyon H Hendry; Simon, Steven L.; Wojcik, Andrzej; Sohrabi, Mehdi; Burkart, Werner; Cardis, Elisabeth; Laurier, Dominique; Tirmarche, Margot; Hayata, Isamu

    2009-01-01

    Natural radiation is the major source of human exposure to ionising radiation, and its largest contributing component to effective dose arises from inhalation of 222Rn and its radioactive progeny. However, despite extensive knowledge of radiation risks gained through epidemiologic investigations and mechanistic considerations, the health effects of chronic low-level radiation exposure are still poorly understood. The present paper reviews the possible contribution of studies of populations li...

  11. Human urinary mutagenicity after wood smoke exposure during traditional temazcal use

    OpenAIRE

    Long, Alexandra S.; Lemieux, Christine L.; Yousefi, Paul; Ruiz-Mercado, Ilse; Lam, Nicholas L.; Orellana, Carolina Romero; White, Paul A.; Smith, Kirk R.; Holland, Nina

    2014-01-01

    In Central America, the traditional temazcales or wood-fired steam baths, commonly used by many Native American populations, are often heated by wood fires with little ventilation, and this use results in high wood smoke exposure. Urinary mutagenicity has been previously employed as a non-invasive biomarker of human exposure to combustion emissions. This study examined the urinary mutagenicity in 19 indigenous Mayan families from the highlands of Guatemala who regularly use temazcales (N = 32...

  12. Immunomodulation of human monocytes following exposure to Lutzomyia intermedia saliva

    Directory of Open Access Journals (Sweden)

    Barral Aldina

    2008-04-01

    Full Text Available Abstract Background Sand fly saliva contains potent and complex pharmacologic molecules that are able to modulate the host's hemostatic, inflammatory, and immune systems. In this study, we evaluated the effects of salivary gland sonicate (SGS of Lutzomyia intermedia, the natural vector of Leishmania braziliensis, on monocytes obtained from the peripheral blood mononuclear cells (PBMC of healthy volunteers. We investigated the effects of sand fly saliva on cytokine production and surface molecule expression of LPS-stimulated human monocytes uninfected or infected with L. braziliensis. Results Pre-treatment of non-infected human monocytes with L. intermedia SGS followed by LPS-stimulation led to a significant decrease in IL-10 production accompanied by a significant increase in CD86, CD80, and HLA-DR expression. Pre-treatment with SGS followed by LPS stimulation and L. braziliensis infection led to a significant increase in TNF-α, IL-6, and IL-8 production without significant alterations in co-stimulatory molecule expression. However, pre-treatment with L. intermedia SGS did not result in significant changes in the infection rate of human monocytes. Conclusion Our data indicate that L. intermedia saliva is able to modulate monocyte response, and, although this modulation is dissociated from enhanced infection with L. braziliensis, it may be associated with successful parasitism.

  13. Xanthohumol induces apoptosis in human malignant glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways.

    Science.gov (United States)

    Festa, Michela; Capasso, Anna; D'Acunto, Cosimo W; Masullo, Milena; Rossi, Adriano G; Pizza, Cosimo; Piacente, Sonia

    2011-12-27

    The effect of the biologically active prenylated chalcone and potential anticancer agent xanthohumol (1) has been investigated on apoptosis of the T98G human malignant glioblastoma cell line. Compound 1 decreased the viability of T98G cells by induction of apoptosis in a time- and concentration-dependent manner. Apoptosis induced by 1 was associated with activation of caspase-3, caspase-9, and PARP cleavage and was mediated by the mitochondrial pathway, as exemplified by mitochondrial depolarization, cytochrome c release, and downregulation of the antiapoptotic Bcl-2 protein. Xanthohumol induced intracellular reactive oxygen species (ROS), an effect that was reduced by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC). Intracellular ROS production appeared essential for the activation of the mitochondrial pathway and induction of apoptosis after exposure to 1. Oxidative stress due to treatment with 1 was associated with MAPK activation, as determined by ERK1/2 and p38 phosphorylation. Phosphorylation of ERK1/2 and p38 was attenuated using NAC to inhibit ROS production. After treatment with 1, ROS provided a specific environment that resulted in MAPK-induced cell death, with this effect reduced by the ERK1/2 specific inhibitor PD98059 and partially inhibited by the p38 inhibitor SB203580. These findings suggest that xanthohumol (1) is a potential chemotherapeutic agent for the treatment of glioblastoma multiforme.

  14. Disruption of apoptosis pathways involved in zebrafish gonad differentiation by 17α-ethinylestradiol and fadrozole exposures

    Energy Technology Data Exchange (ETDEWEB)

    Luzio, Ana, E-mail: aluzio@utad.pt [Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Departamento de Biologia e Ambiente (DeBA), University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Matos, Manuela [University of Lisbon, Faculty of Sciences, BioISI– Biosystems & Integrative Sciences Institute, Campo Grande, 1749-016 Lisbon (Portugal); Department of Genetics and Biotechnology, Life Sciences and Environment School (ECVA), University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Santos, Dércia [Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Fontaínhas-Fernandes, António A.; Monteiro, Sandra M. [Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Departamento de Biologia e Ambiente (DeBA), University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); and others

    2016-08-15

    Highlights: • Apoptosis in females is avoided by anti-apoptotic pathways and in males is essential to the “juvenile ovary” failure. • BIRC5 is central to the regulation of zebrafish spermatogenesis. • EE2 did not change sex ratios, but Fadrozole induced masculinization with a significant increase in male proportion. • The few females identified after exposure to Fadrozole may have avoided sex reversal by increasing anti-apoptotic proteins. • EE2 increased the pro-apoptotic genes/proteins in males, promoting gonad differentiation. - Abstract: Zebrafish (Danio rerio) sex determination seems to involve genetic factors (GSD) but also environmental factors (ESD), such as endocrine disrupting chemicals (EDCs) that are known to mimic endogenous hormones and disrupt gonad differentiation. Apoptosis has also been proposed to play a crucial role in zebrafish gonad differentiation. Nevertheless, the interactions between EDCs and apoptosis have received little attention. Thus, this study aimed to assess if and which apoptotic pathways are involved in zebrafish gonad differentiation and how EDCs may interfere with this process. With these purposes, zebrafish were exposed to 17α-ethinylestradiol (EE{sub 2}, 4 ng/L) and fadrozole (Fad, 50 μg/L) from 2 h to 35 days post-fertilization (dpf). Afterwards, a gene expression analysis by qRT-PCR and a stereological analysis, based on systematic sampling and protein immunohistochemistry, were performed. The death receptors (FAS; TRADD), anti-apoptotic (BCL-2; MDM2), pro-apoptotic (CASP-2 and −6) and cell proliferation (BIRC5/survivin; JUN) genes and proteins were evaluated. In general, apoptosis was inhibited in females through the involvement of anti-apoptotic pathways, while in males apoptosis seemed to be crucial to the failure of the “juvenile ovary” development and the induction of testes transformation. The JUN protein was shown to be necessary in juvenile ovaries, while the BIRC5 protein seemed to be involved

  15. Sensory and Physiological Effects on Humans of Combined Exposures to Air Temperatures and Volatile Organic Compounds

    DEFF Research Database (Denmark)

    Mølhave, Lars; Liu, Zunyong; Jørgensen, Anne Hempel

    1993-01-01

    Ten healthy humans were exposed to combinations of volatile organic compounds (VOCs) and air temperature (0 mg/m3 and 10 mg/m3 of a mixture of 22 volatile organic compounds and 18, 22 and 26° C). Previously demonstrated effects of VOCs and thermal exposures were replicated. For the first time nasal...... cross-sectional areas and nasal volumes, as measured by acoustic rhinometry, were shown to decrease with decreasing temperature and increasing VOC exposure. Temperature and pollutant exposures affected air quality, the need for more ventilation, skin humidity on the forehead, sweating, acute sensory...

  16. Preimplantation Exposure to Bisphenol A and Triclosan May Lead to Implantation Failure in Humans

    Directory of Open Access Journals (Sweden)

    Mu Yuan

    2015-01-01

    Full Text Available Endocrine disrupting chemicals (EDCs are chemicals that have the capacity to interfere with normal endocrine systems. Two EDCs, bisphenol A (BPA and triclosan (TCS, are mass-produced and widespread. They both have estrogenic properties and similar chemical structures and pharmacokinetic features and have been detected in human fluids and tissues. Clinical evidence has suggested a positive association between BPA exposure and implantation failure in IVF patients. Studies in mouse models have suggested that preimplantation exposure to BPA and TCS can lead to implantation failure. This paper reviews the relationship between preimplantation exposure to BPA and TCS and implantation failure and discusses the remaining problems and possible solutions.

  17. Quantitative assessment of human and pet exposure to Salmonella associated with dry pet foods.

    Science.gov (United States)

    Lambertini, Elisabetta; Buchanan, Robert L; Narrod, Clare; Ford, Randall M; Baker, Robert C; Pradhan, Abani K

    2016-01-04

    Recent Salmonella outbreaks associated with dry pet foods and treats highlight the importance of these foods as previously overlooked exposure vehicles for both pets and humans. In the last decade efforts have been made to raise the safety of this class of products, for instance by upgrading production equipment, cleaning protocols, and finished product testing. However, no comprehensive or quantitative risk profile is available for pet foods, thus limiting the ability to establish safety standards and assess the effectiveness of current and proposed Salmonella control measures. This study sought to develop an ingredients-to-consumer quantitative microbial exposure assessment model to: 1) estimate pet and human exposure to Salmonella via dry pet food, and 2) assess the impact of industry and household-level mitigation strategies on exposure. Data on prevalence and concentration of Salmonella in pet food ingredients, production process parameters, bacterial ecology, and contact transfer in the household were obtained through literature review, industry data, and targeted research. A probabilistic Monte Carlo modeling framework was developed to simulate the production process and basic household exposure routes. Under the range of assumptions adopted in this model, human exposure due to handling pet food is null to minimal if contamination occurs exclusively before extrusion. Exposure increases considerably if recontamination occurs post-extrusion during coating with fat, although mean ingested doses remain modest even at high fat contamination levels, due to the low percent of fat in the finished product. Exposure is highly variable, with the distribution of doses ingested by adult pet owners spanning 3Log CFU per exposure event. Child exposure due to ingestion of 1g of pet food leads to significantly higher doses than adult doses associated with handling the food. Recontamination after extrusion and coating, e.g., via dust or equipment surfaces, may also lead to

  18. An agent-based model of exposure to human toxocariasis: a multi-country validation.

    Science.gov (United States)

    Kanobana, K; Devleesschauwer, B; Polman, K; Speybroeck, N

    2013-07-01

    Seroprevalence data illustrate that human exposure to Toxocara is frequent. Environmental contamination with Toxocara spp. eggs is assumed to be the best indicator of human exposure, but increased risk of exposure has also been associated with many other factors. Reported associations are inconsistent, however, and there is still ambiguity regarding the factors driving the onset of Toxocara antibody positivity. The objective of this work was to assess the validity of our current conceptual understanding of the key processes driving human exposure to Toxocara. We constructed an agent-based model predicting Toxocara antibody positivity (as a measure of exposure) in children. Exposure was assumed to depend on the joint probability of 3 parameters: (1) environmental contamination with Toxocara spp. eggs, (2) larvation of these eggs and (3) the age-related contact with these eggs. This joint probability was linked to processes of acquired humoral immunity, influencing the rate of antibody seroreversion. The results of the simulation were validated against published data from 5 different geographical settings. Using simple rules and a stochastic approach with parameter estimates derived from the respective contexts, plausible serological patterns emerged from the model in nearly all settings. Our approach leads to novel insights in the transmission dynamics of Toxocara.

  19. Human health risk assessment from exposure to trihalomethanes in Canadian cities.

    Science.gov (United States)

    Chowdhury, Shakhawat; Hall, Kevin

    2010-07-01

    Lifetime exposure to trihalomethanes (THMs) through ingestion, inhalation and dermal contacts may pose risks to human health. Current approaches may under predict THMs exposure by using THMs in cold water during showering and bathing. Warming of chlorinated water during showering may increase THMs formation through reactions between organics and residual chlorine, which can increase human health risks. In this study, THMs concentrations in shower water were estimated using THMs rate increase model. Using cold water THMs, exposure through ingestion was estimated, while THMs exposure during showering was estimated using THMs in warm water. Human health cancer risks and additional expenses for 20 most populated Canadian cities from exposure to THMs were estimated. Inhalation and dermal contact during showering contributed 30% to 50% of total cancer risks, while risks from inhalation and dermal contacts were comparable for all cities. Overall cancer risks were estimated between 7.2 x 10(-6) and 6.4 x 10(-5) for these cities. Cancer incidents were estimated highest for Montreal (94/year) followed by Toronto (53/year), which may require additional medical expenses of 18.8 and 10.7 million dollars/year for Montreal and Toronto respectively. Cancer risks from exposure to THMs can be controlled by reducing THMs in water supply and varying shower stall volume, shower duration and air exchange rate in shower stall. Copyright 2010 Elsevier Ltd. All rights reserved.

  20. Local Adaptation of Sun-Exposure-Dependent Gene Expression Regulation in Human Skin

    Science.gov (United States)

    Kita, Ryosuke; Fraser, Hunter B.

    2016-01-01

    Sun-exposure is a key environmental variable in the study of human evolution. Several skin-pigmentation genes serve as classical examples of positive selection, suggesting that sun-exposure has significantly shaped worldwide genomic variation. Here we investigate the interaction between genetic variation and sun-exposure, and how this impacts gene expression regulation. Using RNA-Seq data from 607 human skin samples, we identified thousands of transcripts that are differentially expressed between sun-exposed skin and non-sun-exposed skin. We then tested whether genetic variants may influence each individual’s gene expression response to sun-exposure. Our analysis revealed 10 sun-exposure-dependent gene expression quantitative trait loci (se-eQTLs), including genes involved in skin pigmentation (SLC45A2) and epidermal differentiation (RASSF9). The allele frequencies of the RASSF9 se-eQTL across diverse populations correlate with the magnitude of solar radiation experienced by these populations, suggesting local adaptation to varying levels of sunlight. These results provide the first examples of sun-exposure-dependent regulatory variation and suggest that this variation has contributed to recent human adaptation. PMID:27760139

  1. Risk of human exposure to polycyclic aromatic hydrocarbons: A case study in Beijing, China.

    Science.gov (United States)

    Yu, Yanxin; Li, Qi; Wang, Hui; Wang, Bin; Wang, Xilong; Ren, Aiguo; Tao, Shu

    2015-10-01

    Polycyclic aromatic hydrocarbons (PAHs) can cause adverse effects on human health. The relative contributions of their two major intake routes (diet and inhalation) to population PAH exposure are still unclear. We modeled the contributions of diet and inhalation to the overall PAH exposure of the population of Beijing in China, and assessed their human incremental lifetime cancer risks (ILCR) using a Mont Carlo simulation approach. The results showed that diet accounted for about 85% of low-molecular-weight PAH (L-PAH) exposure, while inhalation accounted for approximately 57% of high-molecular-weight PAH (H-PAH) exposure of the Beijing population. Meat and cereals were the main contributors to dietary PAH exposure. Both gaseous- and particulate-phase PAHs contributed to L-PAH exposure through inhalation, whereas exposure to H-PAHs was mostly from the particulate-phase. To reduce the cancer incidence of the Beijing population, more attention should be given to inhaled particulate-phase PAHs with considerable carcinogenic potential.

  2. Understanding specificity in metabolic pathways--structural biology of human nucleotide metabolism.

    Science.gov (United States)

    Welin, Martin; Nordlund, Pär

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  3. Understanding specificity in metabolic pathways-Structural biology of human nucleotide metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Welin, Martin [Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm (Sweden); Nordlund, Paer, E-mail: Par.Nordlund@ki.se [Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm (Sweden); Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm (Sweden)

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  4. Insights into the pyrimidine biosynthetic pathway of human malaria parasite Plasmodium falciparum as chemotherapeutic target.

    Science.gov (United States)

    Krungkrai, Sudaratana R; Krungkrai, Jerapan

    2016-06-01

    Malaria is a major cause of morbidity and mortality in humans. Artemisinins remain as the first-line treatment for Plasmodium falciparum (P. falciparum) malaria although drug resistance has already emerged and spread in Southeast Asia. Thus, to fight this disease, there is an urgent need to develop new antimalarial drugs for malaria chemotherapy. Unlike human host cells, P. falciparum cannot salvage preformed pyrimidine bases or nucleosides from the extracellular environment and relies solely on nucleotides synthesized through the de novo biosynthetic pathway. This review presents significant progress on understanding the de novo pyrimidine pathway and the functional enzymes in the human parasite P. falciparum. Current knowledge in genomics and metabolomics are described, particularly focusing on the parasite purine and pyrimidine nucleotide metabolism. These include gene annotation, characterization and molecular mechanism of the enzymes that are different from the human host pathway. Recent elucidation of the three-dimensional crystal structures and the catalytic reactions of three enzymes: dihydroorotate dehydrogenase, orotate phosphoribosyltransferase, and orotidine 5'-monophosphate decarboxylase, as well as their inhibitors are reviewed in the context of their therapeutic potential against malaria.

  5. Overview on relative importance of house dust ingestion in human exposure to polybrominated diphenyl ethers (PBDEs): International comparison and Korea as a case.

    Science.gov (United States)

    Kim, Seung-Kyu; Kim, Kyoung-Soo; Sang, Hee Hong

    2016-11-15

    Human exposure studies to polybrominated diphenyl ethers (PBDEs) have reached different results about the relative importance of diet intake and house dust ingestion. In the present study, concentrations of PBDEs in Korean house dust (n=15) from geographically different cities were measured, which were in agreement with a previous result, and compared with those for 22 countries of five continents collected from the most recent scientific literature. Compared with other exposure pathways, diet intake was the most important contributor to total PBDEs exposure of Korean adults (i.e., 71% of overall intake). On global comparison, total PBDE levels in house dust differed by two to three orders of magnitude among the countries investigated, with a significant relationship with gross domestic product (GDP). Whereas, dietary daily intakes exhibited a narrow difference within one order of magnitude worldwide and no relationship with GDP. Consequently, the relative importance of major two pathways depended on the contamination extent of PBDEs in house dust, which may be associated with the amount of PBDE products in use. In most countries except for UK and USA, the contribution of house dust ingestion was less important than diet intake in the current and are expected to much more mitigate in the future. However, how fast the effect of regulation will be reflected to house dust and human exposure is necessary to be monitored steadily.

  6. Dioxin exposure of human CD34+ hemopoietic cells induces gene expression modulation that recapitulates its in vivo clinical and biological effects.

    Science.gov (United States)

    Fracchiolla, Nicola Stefano; Todoerti, Katia; Bertazzi, Pier Alberto; Servida, Federica; Corradini, Paolo; Carniti, Cristiana; Colombi, Antonio; Cecilia Pesatori, Angela; Neri, Antonino; Deliliers, Giorgio Lambertenghi

    2011-04-28

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has a large number of biological effects, including skin, cardiovascular, neurologic diseases, diabetes, infertility, cancers and immunotoxicity. We analysed the in vitro TCDD effects on human CD34+ cells and tested the gene expression modulation by means of microarray analyses before and after TCDD exposure. We identified 257 differentially modulated probe sets, identifying 221 well characterized genes. A large part of these resulted associated to cell adhesion and/or angiogenesis and to transcription regulation. Synaptic transmission and visual perception functions, with the particular involvement of the GABAergic pathway were also significantly modulated. Numerous transcripts involved in cell cycle or cell proliferation, immune response, signal transduction, ion channel activity or calcium ion binding, tissue development and differentiation, female or male fertility or in several metabolic pathways were also affected after dioxin exposure. The transcriptional profile induced by TCDD treatment on human CD34+ cells strikingly reproduces the clinical and biological effects observed in individuals exposed to dioxin and in biological experimental systems. Our data support a role of dioxin in the neoplastic transformation of hemopoietic stem cells and in immune modulation processes after in vivo exposure, as indicated by the epidemiologic data in dioxin accidentally exposed populations, providing a molecular basis for it. In addition, TCDD alters genes associated to glucidic and lipidic metabolisms, to GABAergic transmission or involved in male and female fertility, thus providing a possible explanation of the diabetogenic, dyslipidemic, neurologic and fertility effects induced by TCDD in vivo exposure.

  7. Oxytocin Pathway Genes: Evolutionary Ancient System Impacting on Human Affiliation, Sociality, and Psychopathology.

    Science.gov (United States)

    Feldman, Ruth; Monakhov, Mikhail; Pratt, Maayan; Ebstein, Richard P

    2016-02-01

    Oxytocin (OT), a nonapeptide signaling molecule originating from an ancestral peptide, appears in different variants across all vertebrate and several invertebrate species. Throughout animal evolution, neuropeptidergic signaling has been adapted by organisms for regulating response to rapidly changing environments. The family of OT-like molecules affects both peripheral tissues implicated in reproduction, homeostasis, and energy balance, as well as neuromodulation of social behavior, stress regulation, and associative learning in species ranging from nematodes to humans. After describing the OT-signaling pathway, we review research on the three genes most extensively studied in humans: the OT receptor (OXTR), the structural gene for OT (OXT/neurophysin-I), and CD38. Consistent with the notion that sociality should be studied from the perspective of social life at the species level, we address human social functions in relation to OT-pathway genes, including parenting, empathy, and using social relationships to manage stress. We then describe associations between OT-pathway genes with psychopathologies involving social dysfunctions such as autism, depression, or schizophrenia. Human research particularly underscored the involvement of two OXTR single nucleotide polymorphisms (rs53576, rs2254298) with fewer studies focusing on other OXTR (rs7632287, rs1042778, rs2268494, rs2268490), OXT (rs2740210, rs4813627, rs4813625), and CD38 (rs3796863, rs6449197) single nucleotide polymorphisms. Overall, studies provide evidence for the involvement of OT-pathway genes in human social functions but also suggest that factors such as gender, culture, and early environment often confound attempts to replicate first findings. We conclude by discussing epigenetics, conceptual implications within an evolutionary perspective, and future directions, especially the need to refine phenotypes, carefully characterize early environments, and integrate observations of social behavior across

  8. TCDD Induces the Hypoxia-Inducible Factor (HIF-1α Regulatory Pathway in Human Trophoblastic JAR Cells

    Directory of Open Access Journals (Sweden)

    Tien-Ling Liao

    2014-09-01

    Full Text Available The exposure to dioxin can compromise pregnancy outcomes and increase the risk of preterm births. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD has been demonstrated to induce placental hypoxia at the end of pregnancy in a rat model, and hypoxia has been suggested to be the cause of abnormal trophoblast differentiation and placental insufficiency syndromes. In this study, we demonstrate that the non-hypoxic stimulation of human trophoblastic cells by TCDD strongly increased hypoxia inducible factor-1 alpha (HIF-1α stabilization. TCDD exposure induced the generation of reactive oxygen species (ROS and nitric oxide. TCDD-induced HIF-1α stabilization and Akt phosphorylation was inhibited by pretreatment with wortmannin (a phosphatidylinositol 3-kinase (PI3K inhibitor or N-acetylcysteine (a ROS scavenger. The augmented HIF-1α stabilization by TCDD occurred via the ROS-dependent activation of the PI3K/Akt pathway. Additionally, a significant increase in invasion and metallomatrix protease-9 activity was found in TCDD-treated cells. The gene expression of vascular endothelial growth factor and placental growth factor was induced upon TCDD stimulation, whereas the protein levels of peroxisome proliferator-activated receptor γ (PPARγ, PPARγ coactivator-1α, mitochondrial transcription factor, and uncoupling protein 2 were decreased. Our results indicate that an activated HIF-1α pathway, elicited oxidative stress, and induced metabolic stress contribute to TCDD-induced trophoblastic toxicity. These findings may provide molecular insight into the TCDD-induced impairment of trophoblast function and placental development.

  9. Inflammatory and repair pathways induced in human bronchoalveolar lavage cells with ozone inhalation.

    Directory of Open Access Journals (Sweden)

    Pascale Leroy

    Full Text Available Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury.To examine the responses of airway cells to ozone-induced oxidative injury, 19 subjects (7 with asthma were exposed to clean air (0ppb, medium (100ppb, and high (200ppb ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG in epithelial injury was evaluated in an in vitro model of injury [16HBE14o- cell line scratch assay].Ozone exposure caused a dose-dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up-regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an α9β1 integrin-dependent manner.Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury.

  10. Quercetin induces human colon cancer cells apoptosis by inhibiting the nuclear factor-kappa B Pathway.

    Science.gov (United States)

    Zhang, Xiang-An; Zhang, Shuangxi; Yin, Qing; Zhang, Jing

    2015-01-01

    Quercetin can inhibit the growth of cancer cells with the ability to act as chemopreventers. Its cancer-preventive effect has been attributed to various mechanisms, including the induction of cell-cycle arrest and/or apoptosis as well as the antioxidant functions. Nuclear factor kappa-B (NF-κB) is a signaling pathway that controls transcriptional activation of genes important for tight regulation of many cellular processes and is aberrantly expressed in many types of cancer. Inhibitors of NF-κB pathway have shown potential anti-tumor activities. However, it is not fully elucidated in colon cancer. In this study, we demonstrate that quercetin induces apoptosis in human colon cancer CACO-2 and SW-620 cells through inhibiting NF-κB pathway, as well as down-regulation of B-cell lymphoma 2 and up-regulation of Bax, thus providing basis for clinical application of quercetin in colon cancer cases.

  11. Additive Effects of Millimeter Waves and 2-Deoxyglucose Co-Exposure on the Human Keratinocyte Transcriptome

    Science.gov (United States)

    Soubere Mahamoud, Yonis; Aite, Meziane; Martin, Catherine; Zhadobov, Maxim; Sauleau, Ronan; Le Dréan, Yves

    2016-01-01

    Millimeter Waves (MMW) will be used in the next-generation of high-speed wireless technologies, especially in future Ultra-Broadband small cells in 5G cellular networks. Therefore, their biocompatibilities must be evaluated prior to their massive deployment. Using a microarray-based approach, we analyzed modifications to the whole genome of a human keratinocyte model that was exposed at 60.4 GHz-MMW at an incident power density (IPD) of 20 mW/cm2 for 3 hours in athermic conditions. No keratinocyte transcriptome modifications were observed. We tested the effects of MMWs on cell metabolism by co-treating MMW-exposed cells with a glycolysis inhibitor, 2-deoxyglucose (2dG, 20 mM for 3 hours), and whole genome expression was evaluated along with the ATP content. We found that the 2dG treatment decreased the cellular ATP content and induced a high modification in the transcriptome (632 coding genes). The affected genes were associated with transcriptional repression, cellular communication and endoplasmic reticulum homeostasis. The MMW/2dG co-treatment did not alter the keratinocyte ATP content, but it did slightly alter the transcriptome, which reflected the capacity of MMW to interfere with the bioenergetic stress response. The RT-PCR-based validation confirmed 6 MMW-sensitive genes (SOCS3, SPRY2, TRIB1, FAM46A, CSRNP1 and PPP1R15A) during the 2dG treatment. These 6 genes encoded transcription factors or inhibitors of cytokine pathways, which raised questions regarding the potential impact of long-term or chronic MMW exposure on metabolically stressed cells. PMID:27529420

  12. Exposure to Anisakis extracts can induce inflammation on in vitro cultured human colonic cells.

    Science.gov (United States)

    Speciale, Antonio; Trombetta, Domenico; Saija, Antonella; Panebianco, Antonio; Giarratana, Filippo; Ziino, Graziella; Minciullo, Paola Lucia; Cimino, Francesco; Gangemi, Sebastiano

    2017-07-12

    Anisakis spp. is a parasitic nematode whose infective third-stage larvae may be found within the flesh of fish species commonly consumed by humans. Thorough cooking or freezing should render the fish safe for consumption; furthermore, marinating solutions containing biocidal agents might have a significant action against Anisakis larvae. Some studies suggest a relationship between some parasitic infections and development of inflammatory bowel disorders, and Anisakis infection might be a risk factor for stomach or colon cancer. The aim of our study was to investigate if crude extracts (CEs) obtained from Anisakis larvae marinated in a solution with added allyl isothiocyanate (ACE-AITC) and frozen, or from frozen only Anisakis larvae (ACE), can induce an inflammatory effect on in vitro differentiated colonic Caco-2 cells exposed or not to LPS. Caco-2 exposure to the two CEs induced a marked COX-2 expression and potentiated LPS-induced COX-2 overexpression, confirming that substances present in Anisakis larvae can induce an inflammatory response in the intestinal epithelium, possibly also exacerbating the effects of other inflammatory stimuli. ACE induced a marked decrease in caspase-3 activation, while AITC-ACE increased its activation. However, LPS-induced caspase-3 activation appeared lower in cells treated with ACE and with the lower concentration of AITC-ACE. Thus, it is evident that Anisakis CEs may affect various cell pathways crucial not only in the inflammatory process but also in cell growth and death. Thus, CEs obtained from nonviable Anisakis larvae retain or are otherwise provided with noxious properties able to induce a strong inflammation response in intestinal epithelial cells. Furthermore, their influence may persist also following pretreatment with the biocidal agent AITC, indicating that the harmful substances contained in crude extracts from Anisakis larvae are resistant to the thermal or biocidal agent treatments.

  13. Additive Effects of Millimeter Waves and 2-Deoxyglucose Co-Exposure on the Human Keratinocyte Transcriptome.

    Science.gov (United States)

    Soubere Mahamoud, Yonis; Aite, Meziane; Martin, Catherine; Zhadobov, Maxim; Sauleau, Ronan; Le Dréan, Yves; Habauzit, Denis

    2016-01-01

    Millimeter Waves (MMW) will be used in the next-generation of high-speed wireless technologies, especially in future Ultra-Broadband small cells in 5G cellular networks. Therefore, their biocompatibilities must be evaluated prior to their massive deployment. Using a microarray-based approach, we analyzed modifications to the whole genome of a human keratinocyte model that was exposed at 60.4 GHz-MMW at an incident power density (IPD) of 20 mW/cm2 for 3 hours in athermic conditions. No keratinocyte transcriptome modifications were observed. We tested the effects of MMWs on cell metabolism by co-treating MMW-exposed cells with a glycolysis inhibitor, 2-deoxyglucose (2dG, 20 mM for 3 hours), and whole genome expression was evaluated along with the ATP content. We found that the 2dG treatment decreased the cellular ATP content and induced a high modification in the transcriptome (632 coding genes). The affected genes were associated with transcriptional repression, cellular communication and endoplasmic reticulum homeostasis. The MMW/2dG co-treatment did not alter the keratinocyte ATP content, but it did slightly alter the transcriptome, which reflected the capacity of MMW to interfere with the bioenergetic stress response. The RT-PCR-based validation confirmed 6 MMW-sensitive genes (SOCS3, SPRY2, TRIB1, FAM46A, CSRNP1 and PPP1R15A) during the 2dG treatment. These 6 genes encoded transcription factors or inhibitors of cytokine pathways, which raised questions regarding the potential impact of long-term or chronic MMW exposure on metabolically stressed cells.

  14. Potential Role of Pet Cats As a Sentinel Species for Human Exposure to Flame Retardants

    Directory of Open Access Journals (Sweden)

    Luis A. Henríquez-Hernández

    2017-05-01

    Full Text Available Flame retardants are a wide group of chemicals used by the industry to avoid combustion of materials. These substances are commonly found in plastics, electronic equipment, fabrics, and in many other everyday articles. Subsequently, ubiquitous environmental contamination by these common chemical is frequently reported. In the present study, we have evaluated the level of exposure to polychlorinated biphenyls (PCBs, brominated diphenyl ethers (BDEs, and organophosphorous flame retardants (OPFRs in pet cats through the analysis of their serum. We also analyzed the level exposure to such chemicals in a series of 20 cat owners, trying to disclose the role of pet cats as sentinel species of human exposure to FRs. Our results showed that PCBs, banned 40 years ago, showed the lowest levels of exposure, followed by BDEs—banned recently. Congeners PCB-138 and PCB-180 were detected in ≥50% of the series, while BDE-47 was detected in near 90% of the pet cats. On the other hand, the highest levels were that of OPFRs, whose pattern of detection was similar to that observed in humans, thus suggesting a potential role of cats as a sentinel species for human exposure to these currently used FRs. Six out of 11 OPFRs determined [2-ethylhexyldiphenyl phosphate, tributylphosphate, triisobutylphosphate, triphenylphosphate, tris (2-chloroethyl phosphate, and tris (2-chloroisopropyl phosphate] were detected in 100% of the samples. It will be interesting to perform future studied aimed to elucidating the potential toxicological effects of these highly detected chemicals both, in cats and humans.

  15. The Activation Pathway of Human Rhodopsin in Comparison to Bovine Rhodopsin*

    Science.gov (United States)

    Kazmin, Roman; Rose, Alexander; Szczepek, Michal; Elgeti, Matthias; Ritter, Eglof; Piechnick, Ronny; Hofmann, Klaus Peter; Scheerer, Patrick; Hildebrand, Peter W.; Bartl, Franz J.

    2015-01-01

    Rhodopsin, the photoreceptor of rod cells, absorbs light to mediate the first step of vision by activating the G protein transducin (Gt). Several human diseases, such as retinitis pigmentosa or congenital night blindness, are linked to rhodopsin malfunctions. Most of the corresponding in vivo studies and structure-function analyses (e.g. based on protein x-ray crystallography or spectroscopy) have been carried out on murine or bovine rhodopsin. Because these rhodopsins differ at several amino acid positions from human rhodopsin, we conducted a comprehensive spectroscopic characterization of human rhodopsin in combination with molecular dynamics simulations. We show by FTIR and UV-visible difference spectroscopy that the light-induced transformations of the early photointermediates are very similar. Significant differences between the pigments appear with formation of the still inactive Meta I state and the transition to active Meta II. However, the conformation of Meta II and its activity toward the G protein are essentially the same, presumably reflecting the evolutionary pressure under which the active state has developed. Altogether, our results show that although the basic activation pathways of human and bovine rhodopsin are similar, structural deviations exist in the inactive conformation and during receptor activation, even between closely related rhodopsins. These differences between the well studied bovine or murine rhodopsins and human rhodopsin have to be taken into account when the influence of point mutations on the activation pathway of human rhodopsin are investigated using the bovine or murine rhodopsin template sequences. PMID:26105054

  16. Translational Targeted Proteomics Profiling of Mitochondrial Energy Metabolic Pathways in Mouse and Human Samples.

    Science.gov (United States)

    Wolters, Justina C; Ciapaite, Jolita; van Eunen, Karen; Niezen-Koning, Klary E; Matton, Alix; Porte, Robert J; Horvatovich, Peter; Bakker, Barbara M; Bischoff, Rainer; Permentier, Hjalmar P

    2016-09-01

    Absolute measurements of protein abundance are important in the understanding of biological processes and the precise computational modeling of biological pathways. We developed targeted LC-MS/MS assays in the selected reaction monitoring (SRM) mode to quantify over 50 mitochondrial proteins in a single run. The targeted proteins cover the tricarboxylic acid cycle, fatty acid β-oxidation, oxidative phosphorylation, and the detoxification of reactive oxygen species. Assays used isotopically labeled concatemers as internal standards designed to target murine mitochondrial proteins and their human orthologues. Most assays were also suitable to quantify the corresponding protein orthologues in rats. After exclusion of peptides that did not pass the selection criteria, we arrived at SRM assays for 55 mouse, 52 human, and 51 rat proteins. These assays were optimized in isolated mitochondrial fractions from mouse and rat liver and cultured human fibroblasts and in total liver extracts from mouse, rat, and human. The developed proteomics approach is suitable for the quantification of proteins in the mitochondrial energy metabolic pathways in mice, rats, and humans as a basis for translational research. Initial data show that the assays have great potential for elucidating the adaptive response of human patients to mutations in mitochondrial proteins in a clinical setting.

  17. A multi-platform metabolomics approach demonstrates changes in energy metabolism and the transsulfuration pathway in Chironomus tepperi following exposure to zinc

    Energy Technology Data Exchange (ETDEWEB)

    Long, Sara M., E-mail: hoskins@unimelb.edu.au [Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, 3052 (Australia); Tull, Dedreia L., E-mail: dedreia@unimelb.edu.au [Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, 3052 (Australia); Jeppe, Katherine J., E-mail: k.jeppe@unimelb.edu.au [Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, 3052 (Australia); Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, The University of Melbourne, 3010 (Australia); De Souza, David P., E-mail: desouzad@unimelb.edu.au [Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, 3052 (Australia); Dayalan, Saravanan, E-mail: sdayalan@unimelb.edu.au [Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, 3052 (Australia); Pettigrove, Vincent J., E-mail: vpet@unimelb.edu.au [Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, The University of Melbourne, 3010 (Australia); McConville, Malcolm J., E-mail: malcolmm@unimelb.edu.au [Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, 3052 (Australia); Hoffmann, Ary A., E-mail: ary@unimelb.edu.au [Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, 3052 (Australia); School of BioSciences, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, 3052 (Australia)

    2015-05-15

    Highlights: • An integrated metabolomics approach was applied to examine zinc exposure in midges. • Changes in carbohydrate and energy metabolism were observed using GC–MS. • Transsulfuration pathway is affected by zinc exposure. • Heavy metals other than zinc affect the transsulfuration pathways differently. - Abstract: Measuring biological responses in resident biota is a commonly used approach to monitoring polluted habitats. The challenge is to choose sensitive and, ideally, stressor-specific endpoints that reflect the responses of the ecosystem. Metabolomics is a potentially useful approach for identifying sensitive and consistent responses since it provides a holistic view to understanding the effects of exposure to chemicals upon the physiological functioning of organisms. In this study, we exposed the aquatic non-biting midge, Chironomus tepperi, to two concentrations of zinc chloride and measured global changes in polar metabolite levels using an untargeted gas chromatography–mass spectrometry (GC–MS) analysis and a targeted liquid chromatography–mass spectrometry (LC–MS) analysis of amine-containing metabolites. These data were correlated with changes in the expression of a number of target genes. Zinc exposure resulted in a reduction in levels of intermediates in carbohydrate metabolism (i.e., glucose 6-phosphate, fructose 6-phosphate and disaccharides) and an increase in a number of TCA cycle intermediates. Zinc exposure also resulted in decreases in concentrations of the amine containing metabolites, lanthionine, methionine and cystathionine, and an increase in metallothionein gene expression. Methionine and cystathionine are intermediates in the transsulfuration pathway which is involved in the conversion of methionine to cysteine. These responses provide an understanding of the pathways affected by zinc toxicity, and how these effects are different to other heavy metals such as cadmium and copper. The use of complementary

  18. Functional and pharmacological characterization of the natriuretic peptide-dependent lipolytic pathway in human fat cells.

    Science.gov (United States)

    Moro, Cedric; Galitzky, Jean; Sengenes, Coralie; Crampes, François; Lafontan, Max; Berlan, Michel

    2004-03-01

    A lipolytic pathway involving natriuretic peptides has recently been discovered in human fat cells. Its functional characteristics and the interactions of the atrial natriuretic peptide (ANP)-induced effects with adrenergic and insulin pathways were studied. Characterization of the action of ANP antagonists, i.e., A71915, anantin, S-28-Y (Ser-28-Tyr, a synthesized peptide), and HS-142-1 (a microbial polysaccharide), was performed. Lipolytic assays and intracellular cGMP and cAMP determinations were performed on isolated fat cells. Cell membranes were used for binding studies. At low concentrations ANP and isoproterenol [beta-adrenergic receptor (beta-AR) agonist] exerted additive lipolytic effects. The alpha(2)-AR pathway did not interfere with that of ANP. Lipolytic effects of ANP were unaltered by a 2-h pretreatment of fat cells with insulin, whereas beta-AR-induced lipolysis was reduced. Homologous desensitization occurred for ANP-dependent lipolytic pathways. Dendroapsis natriuretic peptide exhibited a similar maximal effect but a 10-fold higher lipolytic potency than ANP and mini-ANP (the shortest form of ANP). The antagonist A71915 exhibited competitive antagonistic properties with a pA(2) value of 7.51. Anantin displayed noncompetitive antagonism and exerted an inhibitory action on basal and beta-adrenergic receptor-induced lipolytic response. S-28-Y exhibited antagonist potencies toward ANP-induced lipolysis and behaved as a partial lipolytic agonist with a lower pD(2) value (7.4 +/- 0.2) than ANP (9.4 +/- 0.3). HS-142-1 exerted the weakest antagonistic effects. The results demonstrate that ANP-dependent effects do not interfere with beta- and alpha(2)-adrenergic pathways in human fat cells. They are unaffected by insulin pretreatments of fat cells but undergo desensitization. In the search of potent and specific natriuretic peptide receptor-A antagonist, in the human fat cell, A71915 was the only reliable one found.

  19. Signaling pathways involved in LPS induced TNFalpha production in human adipocytes

    Directory of Open Access Journals (Sweden)

    Festy Franck

    2010-01-01

    Full Text Available Abstract Background The development of obesity has been linked to an inflammatory process, and the role of adipose tissue in the secretion of pro-inflammatory molecules such as IL-6 or TNFalpha has now been largely confirmed. Although TNFalpha secretion by adipose cells is probably induced, most notably by TLR ligands, the activation and secretion pathways of this cytokine are not yet entirely understood. Moreover, given that macrophagic infiltration is a characteristic of obesity, it is difficult to clearly establish the level of involvement of the different cellular types present within the adipose tissue during inflammation. Methods Primary cultures of human adipocytes and human peripheral blood mononuclear cells were used. Cells were treated with a pathogen-associated molecular pattern: LPS, with and without several kinase inhibitors. Western blot for p38 MAP Kinase was performed on cell lysates. TNFalpha mRNA was detected in cells by RT-PCR and TNFalpha protein was detected in supernatants by ELISA assays. Results We show for the first time that the production of TNFalpha in mature human adipocytes is mainly dependent upon two pathways: NFkappaB and p38 MAP Kinase. Moreover, we demonstrate that the PI3Kinase pathway is clearly involved in the first step of the LPS-pathway. Lastly, we show that adipocytes are able to secrete a large amount of TNFalpha compared to macrophages. Conclusion This study clearly demonstrates that the LPS induced activation pathway is an integral part of the inflammatory process linked to obesity, and that adipocytes are responsible for most of the secreted TNFalpha in inflamed adipose tissue, through TLR4 activation.

  20. Steroids in marine aquaculture farms surrounding Hailing Island, South China: occurrence, bioconcentration, and human dietary exposure.

    Science.gov (United States)

    Liu, Shan; Chen, Hui; Xu, Xiang-Rong; Liu, Shuang-Shuang; Sun, Kai-Feng; Zhao, Jian-Liang; Ying, Guang-Guo

    2015-01-01

    The occurrence, bioconcentration, and human dietary exposure via seafood consumption of 24 steroids were investigated by rapid resolution liquid chromatography-tandem mass spectrometry (RRLC-MS/MS) in six typical marine aquaculture farms surrounding Hailing Island, South China. Ten, 9, 10, 15 of 24 steroids were detected at concentrations ranging from 18 years), respectively. Even though no significant risk from dietary exposure arises from individual steroid, elevated risk to humans can result from the occurrence of multiple steroids in the seafood raised in the aquaculture farms, especially for the sensitive populations, such as pregnant women and children.

  1. LeY oligosaccharide upregulates DAG/PKC signaling pathway in the human endometrial cells.

    Science.gov (United States)

    Li, Yali; Ma, Keli; Sun, Ping; Liu, Shuai; Qin, Huamin; Zhu, Zhengmei; Wang, Xiaoqi; Yan, Qiu

    2009-11-01

    LeY oligosaccharide is stage specifically expressed by the embryo and uterine endometrium, and it plays important roles in embryo implantation. In addition to participating in the recognition and adhesion on fetal-maternal interface, LeY potentially regulates the expression of some implantation-related factors. However, it remains elusive whether it can mediate the involved signaling pathway. In this study, agarose-LeY beads were used to mimic the embryos, and the effects of LeY oligosaccharide on DAG/PKC signaling pathway was studied in human endometrial epithelial cells. Results showed that LeY could significantly trigger the activation of cPKCalpha and cPKCbeta2, and their translocation from the cytosol to the plasma membrane. The cellular DAG content was also upregulated, and the activation of PLCgamma1 was promoted. On the contrary, DAG/PKC signaling pathway was significantly inhibited when anti-LeY antibody was used after confirmation of LeY expression in human endometrial epithelial cells by immunohistochemistry and flow cytometry. These results suggest that LeY oligosaccharide acts as a signal molecule to modulate DAG/PKC signaling pathway.

  2. Redifferentiation of adult human β cells expanded in vitro by inhibition of the WNT pathway.

    Directory of Open Access Journals (Sweden)

    Ayelet Lenz

    Full Text Available In vitro expansion of adult human islet β cells is an attractive solution for the shortage of tissue for cell replacement therapy of type 1 diabetes. Using a lineage tracing approach we have demonstrated that β-cell-derived (BCD cells rapidly dedifferentiate in culture and can proliferate for up to 16 population doublings. Dedifferentiation is associated with changes resembling epithelial-mesenchymal transition (EMT. The WNT pathway has been shown to induce EMT and plays key roles in regulating replication and differentiation in many cell types. Here we show that BCD cell dedifferentiation is associated with β-catenin translocation into the nucleus and activation of the WNT pathway. Inhibition of β-catenin expression in expanded BCD cells using short hairpin RNA resulted in growth arrest, mesenchymal-epithelial transition, and redifferentiation, as judged by activation of β-cell gene expression. Furthermore, inhibition of β-catenin expression synergized with redifferentiation induced by a combination of soluble factors, as judged by an increase in the number of C-peptide-positive cells. Simultaneous inhibition of the WNT and NOTCH pathways also resulted in a synergistic effect on redifferentiation. These findings, which were reproducible in cells derived from multiple human donors, suggest that inhibition of the WNT pathway may contribute to a therapeutically applicable way for generation of functional insulin-producing cells following ex-vivo expansion.

  3. Curcumin and emodin down-regulate TGF-β signaling pathway in human cervical cancer cells.

    Directory of Open Access Journals (Sweden)

    Pooja Chandrakant Thacker

    Full Text Available Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF-β signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-β signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-β and Wnt/β-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-β on β-catenin (an important player in Wnt/β-catenin signaling and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-β signaling pathway by decreasing the expression of TGF-β Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-β by inhibiting the TGF-β-induced migration and invasion. Expression of downstream effectors of TGF-β signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-β activates Wnt/β-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting β-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer.

  4. BAD-mediated apoptotic pathway is associated with human cancer development.

    Science.gov (United States)

    Stickles, Xiaomang B; Marchion, Douglas C; Bicaku, Elona; Al Sawah, Entidhar; Abbasi, Forough; Xiong, Yin; Bou Zgheib, Nadim; Boac, Bernadette M; Orr, Brian C; Judson, Patricia L; Berry, Amy; Hakam, Ardeshir; Wenham, Robert M; Apte, Sachin M; Berglund, Anders E; Lancaster, Johnathan M

    2015-04-01

    The malignant transformation of normal cells is caused in part by aberrant gene expression disrupting the regulation of cell proliferation, apoptosis, senescence and DNA repair. Evidence suggests that the Bcl-2 antagonist of cell death (BAD)-mediated apoptotic pathway influences cancer chemoresistance. In the present study, we explored the role of the BAD-mediated apoptotic pathway in the development and progression of cancer. Using principal component analysis to derive a numeric score representing pathway expression, we evaluated clinico-genomic datasets (n=427) from corresponding normal, pre-invasive and invasive cancers of different types, such as ovarian, endometrial, breast and colon cancers in order to determine the associations between the BAD-mediated apoptotic pathway and cancer development. Immunofluorescence was used to compare the expression levels of phosphorylated BAD [pBAD (serine-112, -136 and -155)] in immortalized normal and invasive ovarian, colon and breast cancer cells. The expression of the BAD-mediated apoptotic pathway phosphatase, PP2C, was evaluated by RT-qPCR in the normal and ovarian cancer tissue samples. The growth-promoting effects of pBAD protein levels in the immortalized normal and cancer cells were assessed using siRNA depletion experiments with MTS assays. The expression of the BAD-mediated apoptotic pathway was associated with the development and/or progression of ovarian (n=106, pcancers, as well as with ovarian endometriosis (n=20, pcancer cells compared to the immortalized normal cells, whereas PP2C gene expression was lower in the cancer compared to the ovarian tumor tissue samples (n=76, pcancer cells. The BAD-mediated apoptotic pathway is thus associated with the development of human cancers likely influenced by the protein levels of pBAD.

  5. Comparison of human cell signaling pathway databases—evolution, drawbacks and challenges

    Science.gov (United States)

    Chowdhury, Saikat; Sarkar, Ram Rup

    2015-01-01

    Elucidating the complexities of cell signaling pathways is of immense importance to gain understanding about various biological phenomenon, such as dynamics of gene/protein expression regulation, cell fate determination, embryogenesis and disease progression. The successful completion of human genome project has also helped experimental and theoretical biologists to analyze various important pathways. To advance this study, during the past two decades, systematic collections of pathway data from experimental studies have been compiled and distributed freely by several databases, which also integrate various computational tools for further analysis. Despite significant advancements, there exist several drawbacks and challenges, such as pathway data heterogeneity, annotation, regular update and automated image reconstructions, which motivated us to perform a thorough review on popular and actively functioning 24 cell signaling databases. Based on two major characteristics, pathway information and technical details, freely accessible data from commercial and academic databases are examined to understand their evolution and enrichment. This review not only helps to identify some novel and useful features, which are not yet included in any of the databases but also highlights their current limitations and subsequently propose the reasonable solutions for future database development, which could be useful to the whole scientific community. PMID:25632107

  6. TFF3 knockout in human pituitary adenoma cell HP75 facilitates cell apoptosis via mitochondrial pathway.

    Science.gov (United States)

    Gao, Feng; Pan, Suxia; Liu, Bing; Zhang, Huanzhi

    2015-01-01

    Trefoil factor 3 (TFF3), a regulatory protein composed of 59 amino acids, has been suggested to be involved in pathogenesis, proliferation, differentiation, invasion, migration and apoptosis in multiple malignant tumors. This study thus investigated the effect of TFF3 knockout in human pituitary adenoma cell line HP75 on cell apoptosis and related pathways. RNA interference approach was used to knock down the expression of TFF3 protein. The gene silencing was validated by RNA denaturing gel electrophoresis and Western blotting. The effect of TFF3 knockout on cell apoptosis was analyzed by Western blotting and flow cytometry. TFF3 protein level in pituitary adenoma was about 3.61 ± 0.48 folds of that in normal tissues (P TFF3, the apoptotic ration was significantly elevated (P TFF3 protein knockout can facilitate apoptosis of human pituitary adenoma HP75 cells via mitochondrial pathway.

  7. TFF3 knockout in human pituitary adenoma cell HP75 facilitates cell apoptosis via mitochondrial pathway

    Science.gov (United States)

    Gao, Feng; Pan, Suxia; Liu, Bing; Zhang, Huanzhi

    2015-01-01

    Trefoil factor 3 (TFF3), a regulatory protein composed of 59 amino acids, has been suggested to be involved in pathogenesis, proliferation, differentiation, invasion, migration and apoptosis in multiple malignant tumors. This study thus investigated the effect of TFF3 knockout in human pituitary adenoma cell line HP75 on cell apoptosis and related pathways. RNA interference approach was used to knock down the expression of TFF3 protein. The gene silencing was validated by RNA denaturing gel electrophoresis and Western blotting. The effect of TFF3 knockout on cell apoptosis was analyzed by Western blotting and flow cytometry. TFF3 protein level in pituitary adenoma was about 3.61 ± 0.48 folds of that in normal tissues (P TFF3, the apoptotic ration was significantly elevated (P TFF3 protein knockout can facilitate apoptosis of human pituitary adenoma HP75 cells via mitochondrial pathway. PMID:26823779

  8. Persistent increases in inflammatory cytokines, Akt, and MAPK/ERK pathways after inhalation exposure of rats to Libby amphibole (LA) or amosite: comparison to effects after intratracheal exposure to LA or naturally occurring asbestos.

    Science.gov (United States)

    Human exposure to LA and other mined or processed asbestos increases risk of lung inflammation, fibrosis, and cancer. Health risks from exposure to naturally occurring asbestos (NOA) are not as well-understood. Mechanisms of long-term toxicity were compared in male F344 rats expo...

  9. Persistent increases in inflammatory cytokines, Akt, and MAPK/ERK pathways after inhalation exposure of rats to Libby amphibole (LA) or amosite: comparison to effects after intratracheal exposure to LA or naturally occurring asbestos.

    Science.gov (United States)

    Human exposure to LA and other mined or processed asbestos increases risk of lung inflammation, fibrosis, and cancer. Health risks from exposure to naturally occurring asbestos (NOA) are not as well-understood. Mechanisms of long-term toxicity were compared in male F344 rats expo...

  10. Human anthrax outbreak associated with livestock exposure: Georgia, 2012.

    Science.gov (United States)

    Navdarashvili, A; Doker, T J; Geleishvili, M; Haberling, D L; Kharod, G A; Rush, T H; Maes, E; Zakhashvili, K; Imnadze, P; Bower, W A; Walke, H T; Shadomy, S V

    2016-01-01

    Human anthrax cases reported in the country of Georgia increased 75% from 2011 (n = 81) to 2012 (n = 142). This increase prompted a case-control investigation using 67 culture- or PCR-confirmed cases and 134 controls matched by residence and gender to investigate risk factor(s) for infection during the month before case onset. Independent predictors most strongly associated with disease in the multivariable modelling were slaughtering animals [odds ratio (OR) 7·3, 95% confidence interval (CI) 2·9-18·1, P 1 km; 15 (12%) of 125 had sick livestock; and 11 (9%) of 128 respondents reported finding dead livestock. We recommend joint public health and veterinary anthrax case investigations to identify areas of increased risk for livestock anthrax outbreaks, annual anthrax vaccination of livestock in those areas, and public awareness education.

  11. Groundwater: Quality Levels and Human Exposure, SW Nigeria

    Directory of Open Access Journals (Sweden)

    Olusola Adeyemi

    2017-04-01

    Full Text Available Groundwater serves as a source of freshwater for agricultural, industrial and domestic purposes and it accounts for about 42%, 27% and 36% respectively. As it remains the only source of all-year-round supply of freshwater globally, it is of vital importance as regards water security, human survival and sustainable agriculture. The main goal of this study is to identify the main cause-effect relationship between human activities and the state of groundwater quality using a communication tool (the DPSIR Model; Drivers, Pressures, State, Impact and Response. A total of twenty-one samples were collected from ten peri-urban communities scattered across three conterminous Local Government Areas in Southwestern Nigeria. Each of the groundwater samples was tested for twelve parameters - total dissolved solids, pH, bicarbonate, chloride, lead, electrical conductivity, dissolved oxygen, nitrate, sulphate, magnesium and total suspended solids. The study revealed that the concentrations of DO and Pb were above threshold limits, while pH and N were just below the threshold and others elements were within acceptable limits based on Guidelines for Drinking Water Quality and Nigeria Standard for Drinking Water Quality. The study revealed that groundwater quality levels from the sampled wells are under pressure leading to reduction in the amount of freshwater availability. This is a first-order setback in achieving access to freshwater as a sustainable development goal across Less Developed Communities (LDCs globally. To combat this threat, there is the need for an integrated approach in response towards groundwater conservation and sustainability by all stakeholders.

  12. Exposure of embryos to cyclically cold incubation temperatures durably affects energy metabolism and antioxidant pathways in broiler chickens.

    Science.gov (United States)

    Loyau, T; Collin, A; Yenisey, C; Crochet, S; Siegel, P B; Akşit, M; Yalçin, S

    2014-08-01

    Cyclically cold incubation temperatures have been suggested as a means to improve resistance of broiler chickens to ascites; however, the underlying mechanisms are not known. Nine hundred eggs obtained from 48 wk Ross broiler breeders were randomly assigned to 2 incubation treatments: control I eggs were incubated at 37.6°C throughout, whereas for cold I eggs the incubation temperature was reduced by 1°C for 6 h daily from 10 to 18 d of incubation. Thereafter, chickens were reared at standard temperatures or under cold exposure that was associated or not with a postnatal cold acclimation at d 5 posthatch. At hatch, hepatic catalase activity and malondialdehyde content were measured. Serum thyroid hormone and triglyceride concentrations, and muscle expression of several genes involved in the regulation of energy metabolism and oxidative stress were also measured at hatch and 5 and 25 d posthatch. Cold incubation induced modifications in antioxidant pathways with higher catalase activity, but lower expression of avian uncoupling protein 3 at hatch. However, long-term enhancement in the expression of avian uncoupling protein 3 was observed, probably caused by an increase in the expression of the transcription factor peroxisome proliferator activated receptor-γ coactivator-1α. These effects were not systematically associated with an increase in serum triiodothyronine concentrations that were observed only in chickens exposed to both cold incubation and later acclimation at 5 d with cold rearing. Our results suggest that these conditions of cyclically cold incubation resulted in the long-term in changes in antioxidant pathways and energy metabolism, which could enhance the health of chickens reared under cold conditions.

  13. The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans

    OpenAIRE

    Pant, Vinod; Quintás-Cardama, Alfonso; Lozano, Guillermina

    2012-01-01

    Aberrations in the p53 tumor suppressor pathway are associated with hematologic malignancies. p53-dependent cell cycle control, senescence, and apoptosis functions are actively involved in maintaining hematopoietic homeostasis under normal and stress conditions. Whereas loss of p53 function promotes leukemia and lymphoma development in humans and mice, increased p53 activity inhibits hematopoietic stem cell function and results in myelodysplasia. Thus, exquisite regulation of p53 activity is ...

  14. The kisspeptin-GnRH pathway in human reproductive health and disease

    OpenAIRE

    Skorupskaite, Karolina; George, Jyothis T.; Anderson, Richard A.

    2014-01-01

    BACKGROUND The discovery of kisspeptin as key central regulator of GnRH secretion has led to a new level of understanding of the neuroendocrine regulation of human reproduction. The related discovery of the kisspeptin-neurokinin B-dynorphin (KNDy) pathway in the last decade has further strengthened our understanding of the modulation of GnRH secretion by endocrine, metabolic and environmental inputs. In this review, we summarize current understanding of the physiological roles of these novel ...

  15. pathDIP: an annotated resource for known and predicted human gene-pathway associations and pathway enrichment analysis

    Science.gov (United States)

    Rahmati, Sara; Abovsky, Mark; Pastrello, Chiara; Jurisica, Igor

    2017-01-01

    Molecular pathway data are essential in current computational and systems biology research. While there are many primary and integrated pathway databases, several challenges remain, including low proteome coverage (57%), low overlap across different databases, unavailability of direct information about underlying physical connectivity of pathway members, and high fraction of protein-coding genes without any pathway annotations, i.e. ‘pathway orphans’. In order to address all these challenges, we developed pathDIP, which integrates data from 20 source pathway databases, ‘core pathways’, with physical protein–protein interactions to predict biologically relevant protein–pathway associations, referred to as ‘extended pathways’. Cross-validation determined 71% recovery rate of our predictions. Data integration and predictions increase coverage of pathway annotations for protein-coding genes to 86%, and provide novel annotations for 5732 pathway orphans. PathDIP (http://ophid.utoronto.ca/pathdip) annotates 17 070 protein-coding genes with 4678 pathways, and provides multiple query, analysis and output options. PMID:27899558

  16. Subchronic Exposure to Arsenic Represses the TH/TRβ1-CaMK IV Signaling Pathway in Mouse Cerebellum

    Directory of Open Access Journals (Sweden)

    Huai Guan

    2016-01-01

    Full Text Available We previously reported that arsenic (As impaired learning and memory by down-regulating calmodulin-dependent protein kinase IV (CaMK IV in mouse cerebellum. It has been documented that the thyroid hormone receptor (TR/retinoid X receptor (RXR heterodimer and thyroid hormone (TH may be involved in the regulation of CaMK IV. To investigate whether As affects the TR/RXR heterodimer and TH, we determined As concentration in serum and cerebellum, 3,5,3’-triiodothyronine (T3 and thyroxin (T4 levels in serum, and expression of CaMK IV, TR and RXR in cerebellum of mice exposed to As. Cognition function was examined by the step-down passive avoidance task and Morris water maze (MWM tests. Morphology of the cerebellum was observed by Hematoxylin-Eosin staining under light microscope. Our results showed that the concentrations of As in the serum and cerebellum of mice both increased with increasing As-exposure level. A significant positive correlation was found between the two processes. Adeficit in learning and memory was found in the exposed mice. Abnormal morphologic changes of Purkinje cells were observed in cerebellum of the exposed mice. Moreover, the cerebellar expressions of CaMK IV protein and the TRβ gene, and TRβ1 protein were significantly lower in As-exposed mice than those in controls. Subchronic exposure to As appears to increase its level in serum and cerebella of mice, impairing learning and memory and down-regulating expression of TRβ1 as well as down-stream CaMK IV. It is also suggested that the increased As may be responsible for down-regulation of TRβ1 and CaMK IV in cerebellum and that the down-regulated TRβ1 may be involved in As-induced impairment of learning and memory via inhibiting CaMK IV and its down-stream pathway.

  17. Simulation of biatrial conduction via different pathways during sinus rhythm with a detailed human atrial model

    Institute of Scientific and Technical Information of China (English)

    Dong-dong DENG; Ying-lan GONG; Guo-fa SHOU; Pei-feng JIAO; Heng-gui ZHANG; Xue-song YE; Ling XIA

    2012-01-01

    In order to better understand biatrial conduction,investigate various conduction pathways,and compare the differences between isotropic and anisotropic conductions in human atria,we present a simulation study of biatrial conduction with known/assumed conduction pathways using a recently developed human atrial model.In addition to known pathways:(1) Bachmann's bundle (BB),(2) limbus of fossa ovalis (LFO),and (3) coronary sinus (CS),we also hypothesize that there exist two fast conduction bundles that connect the crista terminalis (CT),LFO,and CS.Our simulation demonstrates that use of these fast conduction bundles results in a conduction pattern consistent with experimental data.The comparison of isotropic and anisotropoic conductions in the BB case showed that the atrial working muscles had small effect on conduction time and conduction speed,although the conductivities assigned in anisotropic conduction were two to four times higher than the isotropic conduction.In conclusion,we suggest that the hypothesized intercaval bundles play a significant role in the biatrial conduction and that myofiber orientation has larger effects on the conduction system than the atrial working muscles.This study presents readers with new insights into human atrial conduction.

  18. TGFβ Pathway Inhibition Redifferentiates Human Pancreatic Islet β Cells Expanded In Vitro.

    Directory of Open Access Journals (Sweden)

    Ginat Toren-Haritan

    Full Text Available In-vitro expansion of insulin-producing cells from adult human pancreatic islets could provide an abundant cell source for diabetes therapy. However, proliferation of β-cell-derived (BCD cells is associated with loss of phenotype and epithelial-mesenchymal transition (EMT. Nevertheless, BCD cells maintain open chromatin structure at β-cell genes, suggesting that they could be readily redifferentiated. The transforming growth factor β (TGFβ pathway has been implicated in EMT in a range of cell types. Here we show that human islet cell expansion in vitro involves upregulation of the TGFβ pathway. Blocking TGFβ pathway activation using short hairpin RNA (shRNA against TGFβ Receptor 1 (TGFBR1, ALK5 transcripts inhibits BCD cell proliferation and dedifferentiation. Treatment of expanded BCD cells with ALK5 shRNA results in their redifferentiation, as judged by expression of β-cell genes and decreased cell proliferation. These effects, which are reproducible in cells from multiple human donors, are mediated, at least in part, by AKT-FOXO1 signaling. ALK5 inhibition synergizes with a soluble factor cocktail to promote BCD cell redifferentiation. The combined treatment may offer a therapeutically applicable way for generating an abundant source of functional insulin-producing cells following ex-vivo expansion.

  19. Noscapine induces apoptosis in human glioma cells by an apoptosis-inducing factor-dependent pathway.

    Science.gov (United States)

    Newcomb, Elizabeth W; Lukyanov, Yevgeniy; Smirnova, Iva; Schnee, Tona; Zagzag, David

    2008-07-01

    Previously, we identified noscapine as a small molecule inhibitor of the hypoxia-inducible factor-1 pathway in hypoxic human glioma cells and human umbilical vein endothelial cells. Noscapine is a nontoxic ingredient in cough medicine currently used in clinical trials for patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia to assess antitumor efficacy. Here, we have evaluated the sensitivity of four human glioma cell lines to noscapine-induced apoptosis. Noscapine was a potent inhibitor of proliferation and inducer of apoptosis. Induction of apoptosis was associated with activation of the c-jun N-terminal kinase signaling pathway concomitant with inactivation of the extracellular signal regulated kinase signaling pathway and phosphorylation of the antiapoptotic protein Bcl-2. Noscapine-induced apoptosis was associated with the release of mitochondrial proteins apoptosis-inducing factor (AIF) and/or cytochrome c. In some glioma cell lines, only AIF release occurred without cytochrome c release or poly (ADP-ribose) polymerase cleavage. Knock-down of AIF decreased noscapine-induced apoptosis. Our results suggest the potential importance of noscapine as a novel agent for use in patients with glioblastoma owing to its low toxicity profile and its potent anticancer activity.

  20. Expression of SHH signaling pathway components in the developing human lung.

    Science.gov (United States)

    Zhang, Mingfeng; Wang, Hong; Teng, Hongqi; Shi, Jueping; Zhang, Yanding

    2010-10-01

    The Sonic hedgehog (Shh) cascade is crucial for the patterning of the early lung morphogenesis in mice, but its role in the developing human lung remains to be determined. In the present study, the expression patterns of SHH signaling pathway components, including SHH, PTCH1, SMO, GLI1, GLI2 and GLI3 were examined by in situ hybridization and immunohistochemistry, and compared with the equivalent patterns in mice. Our results showed that, as in mice, SHH was expressed in the epithelium of the developing human lung. However, SHH receptors (PTCH1 and SMO) and SHH signaling effectors (GLI1-3) were strongly detected in the human lung epithelium, but weakly in the mesenchyme, slightly different from their expressions in mice. Furthermore, the expression levels of SHH signaling pathway genes in human lung, but not that of GLI1, were subsequently downregulated at the canalicular stage evaluated by real-time PCR, coincident with a decline in the developing murine lung. In conclusion, in spite of slight differences, the considerable similarities of gene expression in human and mice suggest that conserved molecular networks regulate mammalian lung development.

  1. Comparison of LAIR-1 genetic pathways in murine vs human internal organs.

    Science.gov (United States)

    Sun, Shuqiu; Jiao, Yan; Wei, Wei; Postlethwaite, Arnold E; Gu, Weikuan; Sun, Dianjun

    2014-11-15

    Growing evidence suggests that defective expression or dysfunction of LAIR-1, a novel immunoinhibitory receptor for collagen, is closely associated with some autoimmune diseases, cancers, as well as viral infections. We analyzed the variation of LAIR-1 genetic pathways in murine versus human internal organs, including the lung and brain. The results showed that, under physiological conditions, LAIR-1 links more closely to the common genes in mouse than in human, which poses tissue specificity. It means that mice experimental data in relation to the role of LAIR-1 immune regulation may be overestimated when applied to assess human conditions. Moreover, we found that the in vivo interaction of LAIR-1 with LAIR-2 rarely occurs, implying that the species difference in LAIR-1 genetic pathways could not be primarily attributed to the existence of human LAIR-2. In summary, this study opens the door for insight into LAIR-1 functions inside the human body, and raises concern as to extrapolative credibility of the murine model in biomedical research.

  2. Human aflatoxin exposure in Kenya, 2007: a cross-sectional study

    Science.gov (United States)

    Yard, Ellen E.; Daniel, Johnni H.; Lewis, Lauren S.; Rybak, Michael E.; Paliakov, Ekaterina M.; Kim, Andrea A.; Montgomery, Joel M.; Bunnell, Rebecca; Abudo, Mamo Umuro; Akhwale, Willis; Breiman, Robert F.; Sharif, Shahnaaz K.

    2013-01-01

    Aflatoxins contaminate approximately 25% of agricultural products worldwide. They can cause liver failure and liver cancer. Kenya has experienced multiple aflatoxicosis outbreaks in recent years, often resulting in fatalities. However, the full extent of aflatoxin exposure in Kenya has been unknown. Our objective was to quantify aflatoxin exposure across Kenya. We analysed aflatoxin levels in serum specimens from the 2007 Kenya AIDS Indicator Survey – a nationally representative, cross-sectional serosurvey. KAIS collected 15,853 blood specimens. Of the 3180 human immunodeficiency virus-negative specimens with ≥1 mL sera, we randomly selected 600 specimens stratified by province and sex. We analysed serum specimens for aflatoxin albumin adducts by using isotope dilution MS/MS to quantify aflatoxin B1-lysine, and normalised with serum albumin. Aflatoxin concentrations were then compared by demographic, socioeconomic and geographic characteristics. We detected serum aflatoxin B1-lysine in 78% of serum specimens (range = Aflatoxin exposure did not vary by sex, age group, marital status, religion or socioeconomic characteristics. Aflatoxin exposure varied by province (p aflatoxin exposure is a public health problem throughout Kenya, and it could be substantially impacting human health. Wide-scale, evidence-based interventions are urgently needed to decrease exposure and subsequent health effects. PMID:23767939

  3. Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity

    Science.gov (United States)

    Yang, Daqian; Tan, Xiao; Lv, Zhanjun; Liu, Biying; Baiyun, Ruiqi; Lu, Jingjing; Zhang, Zhigang

    2016-01-01

    Inorganic mercury, though a key component of pediatric vaccines, is an environmental toxicant threatening human health via accumulating oxidative stress in part. Luteolin has been of great interest because of its antiinflammatory, anticarcinogenic and antioxidative effects. Here we hypothesized that luteolin would attenuate hepatotoxicity induced by acute inorganic mercury exposure. Kunming mice were treated with luteolin (100 mg/kg) 24 h after administration of 4 mg/kg mercuric chloride (HgCl2). The results showed that luteolin ameliorated HgCl2 induced anemia and hepatotoxicity, regulating radical oxygen species (ROS) production and hepatocyte viability in vitro and oxidative stress and apoptosis in vivo. Furthermore, luteolin reversed the changes in levels of inflammation- and apoptosis-related proteins involving NF-κB, TNF-α, Sirt1, mTOR, Bax, p53, and Bcl-2, and inhibited p38 MAPK activation. Luteolin enhanced antioxidant defense system based on Keap1, Nrf2, HO-1, NQO1, and KLF9. Moreover, luteolin did not affect miRNA-146a expression. Collectively, our findings, for the first time, elucidate a precise mechanism for attenuation of HgCl2-induced liver dysfunction by dietary luteolin via regulating Sirt1/Nrf2/TNF-α signaling pathway, and provide a foundation for further study of luteolin as a novel therapeutic agent against inorganic mercury poisoning. PMID:27853236

  4. The nano-TiO2 exposure can induce hepatic inflammation involving in a JAK-STAT signalling pathway

    Science.gov (United States)

    Hong, Jie; Hong, Fashui; Ze, Yuguan; Zhang, Yu-Qing

    2016-06-01

    TiO2 nanoparticles (TiO2 NPs) have unique physiochemical properties and thus are widely used in daily life. However, these nanoparticles also have potential toxic effects in humans and animals, and the issue of the security TiO2 NPs has also gained prominence. In this article, mice were administered a gavage instillation of 2.5, 5, or 10 mg/kg body weight TiO2 NPs (5-6 nm) for 90 days. We investigated whether TiO2 NPs activate the JAK-STAT signalling pathway, causing nano-TiO2-induced hepatic toxicity. The results demonstrated that with increasing doses of TiO2 NPs the body weights of the mice body decreased, and the liver index, liver dysfunction, infiltration of inflammatory cells, and hepatocyte apoptosis and necrosis increased. Moreover, liver inflammation was accompanied by increased expression of Janus kinase 2, the signal transducers and activators of transcription 3, interleukin-6, cyclooxygenase-2, neutrophil gelatinase-associated lipocalin, purinergic receptor-7, and epithelial neutrophil-activating protein-78 and decreased expression of suppressors of cytokine signalling-1, peroxisome proliferator-activated receptor-γ, and peroxisome proliferator-activated receptor gamma coactivator-1 alpha. In summary, the activation of the JAK-STAT pathway may be involved in the hepatic inflammation induced by chronic nano-TiO2 toxicity.

  5. Signal Propagation in the Human Visual Pathways: An Effective Connectivity Analysis.

    Science.gov (United States)

    Youssofzadeh, Vahab; Prasad, Girijesh; Fagan, Andrew J; Reilly, Richard B; Martens, Sven; Meaney, James F; Wong-Lin, KongFatt

    2015-09-30

    Although the visual system has been extensively investigated, an integrated account of the spatiotemporal dynamics of long-range signal propagation along the human visual pathways is not completely known or validated. In this work, we used dynamic causal modeling approach to provide insights into the underlying neural circuit dynamics of pattern reversal visual-evoked potentials extracted from concurrent EEG-fMRI data. A recurrent forward-backward connectivity model, consisting of multiple interacting brain regions identified by EEG source localization aided by fMRI spatial priors, best accounted for the data dynamics. Sources were first identified in the thalamic area, primary visual cortex, as well as higher cortical areas along the ventral and dorsal visual processing streams. Consistent with hierarchical early visual processing, the model disclosed and quantified the neural temporal dynamics across the identified activity sources. This signal propagation is dominated by a feedforward process, but we also found weaker effective feedback connectivity. Using effective connectivity analysis, the optimal dynamic causal modeling revealed enhanced connectivity along the dorsal pathway but slightly suppressed connectivity along the ventral pathway. A bias was also found in favor of the right hemisphere consistent with functional attentional asymmetry. This study validates, for the first time, the long-range signal propagation timing in the human visual pathways. A similar modeling approach can potentially be used to understand other cognitive processes and dysfunctions in signal propagation in neurological and neuropsychiatric disorders. Significance statement: An integrated account of long-range visual signal propagation in the human brain is currently incomplete. Using computational neural modeling on our acquired concurrent EEG-fMRI data under a visual evoked task, we found not only a substantial forward propagation toward "higher-order" brain regions but also a

  6. 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

  7. Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington's Disease human lymphoblasts.

    Science.gov (United States)

    Naia, Luana; Ferreira, I Luísa; Cunha-Oliveira, Teresa; Duarte, Ana I; Ribeiro, Márcio; Rosenstock, Tatiana R; Laço, Mário N; Ribeiro, Maria J; Oliveira, Catarina R; Saudou, Frédéric; Humbert, Sandrine; Rego, A Cristina

    2015-02-01

    Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca(2+) levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca(2+) accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.

  8. In vivo Cigarette Smoke Exposure Decreases CCL20, SLPI, and BD-1 Secretion by Human Primary Nasal Epithelial Cells

    Science.gov (United States)

    Jukosky, James; Gosselin, Benoit J.; Foley, Leah; Dechen, Tenzin; Fiering, Steven; Crane-Godreau, Mardi A.

    2016-01-01

    Smokers and individuals exposed to second-hand cigarette smoke have a higher risk of developing chronic sinus and bronchial infections. This suggests that cigarette smoke (CS) has adverse effects on immune defenses against pathogens. Epithelial cells are important in airway innate immunity and are the first line of defense against infection. Airway epithelial cells not only form a physical barrier but also respond to the presence of microbes by secreting antimicrobials, cytokines, and chemokines. These molecules can lyse infectious microorganisms and/or provide signals critical to the initiation of adaptive immune responses. We examined the effects of CS on antimicrobial secretions of primary human nasal epithelial cells (PHNECs). Compared to non-CS-exposed individuals, PHNEC from in vivo CS-exposed individuals secreted less chemokine ligand (C-C motif) 20 (CCL20), Beta-defensin 1 (BD-1), and SLPI apically, less BD-1 and SLPI basolaterally, and more CCL20 basolaterally. Cigarette smoke extract (CSE) exposure in vitro decreased the apical secretion of CCL20 and beta-defensin 1 by PHNEC from non-CS-exposed individuals. Exposing PHNEC from non-CS exposed to CSE also significantly decreased the levels of many mRNA transcripts that are involved in immune signaling. Our results show that in vivo or in vitro exposure to CS alters the secretion of key antimicrobial peptides from PHNEC, but that in vivo CS exposure is a much more important modifier of antimicrobial peptide secretion. Based on the gene expression data, it appears that CSE disrupts multiple immune signaling pathways in PHNEC. Our results provide mechanistic insight into how CS exposure alters the innate immune response and increases an individual’s susceptibility to pathogen infection. PMID:26793127

  9. In vivo cigarette smoke exposure decreases CCL20, SLPI, and BD-1 secretion by human primary nasal epithelial cells.

    Directory of Open Access Journals (Sweden)

    James eJukosky

    2016-01-01

    Full Text Available AbstractSmokers and individuals exposed to second hand cigarette smoke (SHCS have a higher risk of developing chronic sinus and bronchial infections. This suggests that cigarette smoke (CS has adverse effects on immune defenses against pathogens. Epithelial cells are important in airway innate immunity and are the first line of defense against infection. Airway epithelial cells form a physical barrier, but also respond to the presence of microbes by secreting antimicrobials, cytokines and chemokines. These molecules can lyse infectious microorganisms and/or provide signals critical to the initiation of adaptive immune responses. We examined the effects of cigarette smoke on antimicrobial secretions of primary