Manganese-Induced Neurotoxicity and Alterations in Gene Expression in Human Neuroblastoma SH-SY5Y Cells.

PubMed

Gandhi, Deepa; Sivanesan, Saravanadevi; Kannan, Krishnamurthi

2018-06-01

Manganese (Mn) is an essential trace element required for many physiological functions including proper biochemical and cellular functioning of the central nervous system (CNS). However, exposure to excess level of Mn through occupational settings or from environmental sources has been associated with neurotoxicity. The cellular and molecular mechanism of Mn-induced neurotoxicity remains unclear. In the current study, we investigated the effects of 30-day exposure to a sub-lethal concentration of Mn (100 μM) in human neuroblastoma cells (SH-SY5Y) using transcriptomic approach. Microarray analysis revealed differential expression of 1057 transcripts in Mn-exposed SH-SY5Y cells as compared to control cells. Gene functional annotation cluster analysis exhibited that the differentially expressed genes were associated with several biological pathways. Specifically, genes involved in neuronal pathways including neuron differentiation and development, regulation of neurogenesis, synaptic transmission, and neuronal cell death (apoptosis) were found to be significantly altered. KEGG pathway analysis showed upregulation of p53 signaling pathways and neuroactive ligand-receptor interaction pathways, and downregulation of neurotrophin signaling pathway. On the basis of the gene expression profile, possible molecular mechanisms underlying Mn-induced neuronal toxicity were predicted.

Potential pathways by which maternal second-hand smoke exposure during pregnancy causes full-term low birth weight.

PubMed

Niu, Zhongzheng; Xie, Chuanbo; Wen, Xiaozhong; Tian, Fuying; Yuan, Shixin; Jia, Deqin; Chen, Wei-Qing

2016-04-29

It is well documented that maternal exposure to second-hand smoke (SHS) during pregnancy causes low birth weight (LBW), but its mechanism remains unknown. This study explored the potential pathways. We enrolled 195 pregnant women who delivered full-term LBW newborns, and 195 who delivered full-term normal birth weight newborns as the controls. After controlling for maternal age, education level, family income, pre-pregnant body mass index, newborn gender and gestational age, logistic regression analysis revealed that LBW was significantly and positively associated with maternal exposure to SHS during pregnancy, lower placental weight, TNF-α and IL-1β, and that SHS exposure was significantly associated with lower placental weight, TNF-α and IL-1β. Structural equation modelling identified two plausible pathways by which maternal exposure to SHS during pregnancy might cause LBW. First, SHS exposure induced the elevation of TNF-α, which might directly increase the risk of LBW by transmission across the placenta. Second, SHS exposure first increased maternal secretion of IL-1β and TNF-α, which then triggered the secretion of VCAM-1; both TNF-α and VCAM-1 were significantly associated with lower placental weight, thus increasing the risk of LBW. In conclusion, maternal exposure to SHS during pregnancy may lead to LBW through the potential pathways of maternal inflammation and lower placental weight.

Molecular pathway activation in cancer and tissue following space radiation exposure

NASA Astrophysics Data System (ADS)

Kovyrshina, Tatiana A.

Space radiation exposure is an important safety concern for astronauts, especially since one of the risks is carcinogenesis. This thesis explores the link between lung, colorectal, and breast cancer and iron particles and gamma radiation on a molecular level. We obtained DNA microarrays for each condition from the Gene Expression Omnibus (GEO), a public functional genomics data repository, cleaned up the data, and analysed overexpression and underexpression of pathway analysis. Our results show that pathways which participate in DNA replication appear to be overexpressed in cancer cells and cells exposed to ionizing radiation.

Complementary proteomic approaches reveal mitochondrial dysfunction, immune and inflammatory dysregulation in a mouse model of Gulf War Illness.

PubMed

Zakirova, Zuchra; Reed, Jon; Crynen, Gogce; Horne, Lauren; Hassan, Samira; Mathura, Venkatarajan; Mullan, Michael; Crawford, Fiona; Ait-Ghezala, Ghania

2017-09-01

Long-term consequences of combined pyridostigmine bromide (PB) and permethrin (PER) exposure in C57BL6/J mice using a well-characterized mouse model of exposure to these Gulf War (GW) agents were explored at the protein level. We used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches-stable isotope dimethyl labeling and iTRAQ. The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation. Collectively, our work identified key pathways which were chronically impacted in the mouse CNS following acute GW agent exposure, this may lead to the identification of potential targets for therapeutic intervention in the future. Long-term consequences of combined PB and PER exposure in C57BL6/J mice using a well-characterized mouse model of exposure to these GW agents were explored at the protein level. Expanding on earlier work, we used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane-bound protein fractions from brain samples using two orthogonal isotopic labeling LC-MS/MS proteomic approaches-stable isotope dimethyl labeling and iTRAQ. The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation at 5 months postexposure to PB + PER. © 2017 The Authors. PROTEOMICS - Clinical Applications published by WILEY-VCH Verlag GmbH & Co. KGaA.

Complementary proteomic approaches reveal mitochondrial dysfunction, immune and inflammatory dysregulation in a mouse model of Gulf War Illness

PubMed Central

Zakirova, Zuchra; Reed, Jon; Crynen, Gogce; Horne, Lauren; Hassan, Samira; Mathura, Venkatarajan; Mullan, Michael; Crawford, Fiona

2017-01-01

Purpose Long‐term consequences of combined pyridostigmine bromide (PB) and permethrin (PER) exposure in C57BL6/J mice using a well‐characterized mouse model of exposure to these Gulf War (GW) agents were explored at the protein level. Experimental design We used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane‐bound protein fractions from brain samples using two orthogonal isotopic labeling LC‐MS/MS proteomic approaches—stable isotope dimethyl labeling and iTRAQ. Results The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. Conclusions and clinical relevance The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation. Collectively, our work identified key pathways which were chronically impacted in the mouse CNS following acute GW agent exposure, this may lead to the identification of potential targets for therapeutic intervention in the future. Long‐term consequences of combined PB and PER exposure in C57BL6/J mice using a well‐characterized mouse model of exposure to these GW agents were explored at the protein level. Expanding on earlier work, we used orthogonal proteomic approaches to identify pathways that are chronically impacted in the mouse CNS due to semiacute GW agent exposure early in life. These analyses were performed on soluble and membrane‐bound protein fractions from brain samples using two orthogonal isotopic labeling LC‐MS/MS proteomic approaches—stable isotope dimethyl labeling and iTRAQ. The use of these approaches allowed for greater coverage of proteins than was possible by either one alone and revealed both distinct and overlapping datasets. This combined analysis identified changes in several mitochondrial, as well as immune and inflammatory pathways after GW agent exposure. The work discussed here provides insight into GW agent exposure dependent mechanisms that adversely affect mitochondrial function and immune and inflammatory regulation at 5 months postexposure to PB + PER. PMID:28371386

Genome-wide expression analysis of human in vivo irritated epidermis: differential profiles induced by sodium lauryl sulfate and nonanoic acid.

PubMed

Clemmensen, Anders; Andersen, Klaus E; Clemmensen, Ole; Tan, Qihua; Petersen, Thomas K; Kruse, Torben A; Thomassen, Mads

2010-09-01

The pathogenesis of irritant contact dermatitis (ICD) is poorly understood, and genes participating in the epidermal response to chemical irritants are only partly known. It is commonly accepted that different irritants have different mechanisms of action in the development of ICD. To define the differential molecular events induced in the epidermis by different irritants, we collected sequential biopsies ((1/2), 4, and 24 hours after a single exposure and at day 11 after repeated exposure) from human volunteers exposed to either sodium lauryl sulfate (SLS) or nonanoic acid (NON). Gene expression analysis using high-density oligonucleotide microarrays (representing 47,000 transcripts) revealed essentially different pathway responses (1/2)hours after exposure: NON transiently induced the IL-6 pathway as well as a number of mitogen-activated signaling cascades including extracellular signal-regulated kinase and growth factor receptor signaling, whereas SLS transiently downregulated cellular energy metabolism pathways. Differential expression of the cyclooxygenase-2 and matrix metalloproteinase 3 transcripts was confirmed immunohistochemically. After cumulative exposure, 883 genes were differentially expressed, whereas we identified 23 suggested common biomarkers for ICD. In conclusion, we bring new insights into two hitherto less well-elucidated phases of skin irritancy: the very initial as well as the late phase after single and cumulative mild exposures, respectively.

Digital gene expression analysis in the gills of Ruditapes philippinarum exposed to short- and long-term exposures of ammonia nitrogen.

PubMed

Cong, Ming; Wu, Huifeng; Cao, Tengfei; Lv, Jiasen; Wang, Qing; Ji, Chenglong; Li, Chenghua; Zhao, Jianmin

2018-01-01

Previous study revealed severe toxic effects of ammonia nitrogen on Ruditapes philippinarum including lysosomal instability, disturbed metabolic profiles, gill tissues with damaged structure, and variation of neurotransmitter concentrations. However, the underlying molecular mechanism was not fully understood yet. In the present study, digital gene expression technology (DGE) was applied to globally screen the key genes and pathways involved in the responses to short- and long-term exposures of ammonia nitrogen. Results of DGE analysis indicated that short-term duration of ammonia exposure affected pathways in Dorso-ventral axis formation, Notch signaling, thyroid hormone signaling and protein processing in endoplasmic reticulum. The long-term exposure led to DEGs significantly enriched in gap junction, immunity, signal and hormone transduction, as well as key substance metabolism pathways. Functional research of significantly changed DEGs suggested that the immunity of R. philippinarum was weakened heavily by toxic effects of ammonia nitrogen, as well as neuro-transduction and metabolism of important substances. Taken together, the present study provides a molecular support for the previous results of the detrimental toxicity of ammonia exposure in R. philippinarum, further work will be performed to investigate the specific genes and their certain functions involved in ammonia toxicity to molluscs. Copyright © 2017 Elsevier B.V. All rights reserved.

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

EPA Science Inventory

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...

Temporal effects in porcine skin following bromine vapor exposure.

PubMed

Price, Jennifer A; Rogers, James V; Wendling, Morgan Q S; Plahovinsak, Jennifer L; Perry, Mark R; Reid, Frances M; Kiser, Robyn C; Graham, John S

2011-09-01

Bromine is an industrial chemical that causes severe cutaneous burns. When selecting or developing effective treatments for bromine burns, it is important to understand the molecular mechanisms of tissue damage and wound healing. This study investigated the effect of cutaneous bromine vapor exposure on gene expression using a weanling swine burn model by microarray analysis. Ventral abdominal sites were exposed to a mean calculated bromine vapor concentration of 0.51 g/L for 7 or 17 min. At 6 h, 48 h, and 7 days post-exposure, total RNA from skin samples was isolated, processed, and analyzed with Affymetrix GeneChip® Porcine Genome Arrays (N = 3 per experimental group). Differences in gene expression were observed with respect to exposure duration and sampling time. Ingenuity Pathways Analysis (IPA) revealed four common biological functions (cancer, cellular movement, cell-to-cell signaling and interaction, and tissue development) among the top ten functions of each experimental group, while canonical pathway analysis revealed 9 genes (ARG2, CCR1, HMOX1, ATF2, IL-8, TIMP1, ESR1, HSPAIL, and SELE) that were commonly shared among four significantly altered signaling pathways. Among these, the transcripts encoding HMOX1 and ESR1 were identified using IPA as common potential therapeutic targets for Phase II/III clinical trial or FDA-approved drugs. The present study describes the transcriptional responses to cutaneous bromine vapor exposure identifying molecular networks and genes that could serve as targets for developing therapeutics for bromine-induced skin injury.

Genome-wide gene–environment interaction analysis for asbestos exposure in lung cancer susceptibility

PubMed Central

Wei, Qingyi Wei

2012-01-01

Asbestos exposure is a known risk factor for lung cancer. Although recent genome-wide association studies (GWASs) have identified some novel loci for lung cancer risk, few addressed genome-wide gene–environment interactions. To determine gene–asbestos interactions in lung cancer risk, we conducted genome-wide gene–environment interaction analyses at levels of single nucleotide polymorphisms (SNPs), genes and pathways, using our published Texas lung cancer GWAS dataset. This dataset included 317 498 SNPs from 1154 lung cancer cases and 1137 cancer-free controls. The initial SNP-level P-values for interactions between genetic variants and self-reported asbestos exposure were estimated by unconditional logistic regression models with adjustment for age, sex, smoking status and pack-years. The P-value for the most significant SNP rs13383928 was 2.17×10–6, which did not reach the genome-wide statistical significance. Using a versatile gene-based test approach, we found that the top significant gene was C7orf54, located on 7q32.1 (P = 8.90×10–5). Interestingly, most of the other significant genes were located on 11q13. When we used an improved gene-set-enrichment analysis approach, we found that the Fas signaling pathway and the antigen processing and presentation pathway were most significant (nominal P < 0.001; false discovery rate < 0.05) among 250 pathways containing 17 572 genes. We believe that our analysis is a pilot study that first describes the gene–asbestos interaction in lung cancer risk at levels of SNPs, genes and pathways. Our findings suggest that immune function regulation-related pathways may be mechanistically involved in asbestos-associated lung cancer risk. Abbreviations:CIconfidence intervalEenvironmentFDRfalse discovery rateGgeneGSEAgene-set-enrichment analysisGWASgenome-wide association studiesi-GSEAimproved gene-set-enrichment analysis approachORodds ratioSNPsingle nucleotide polymorphism PMID:22637743

Sun exposure and skin cancer, and the puzzle of cutaneous melanoma: A perspective on Fears et al. Mathematical models of age and ultraviolet effects on the incidence of skin cancer among whites in the United States. American Journal of Epidemiology 1977; 105: 420-427.

PubMed

Armstrong, Bruce K; Cust, Anne E

2017-06-01

Sunlight has been known as an important cause of skin cancer since around the turn of the 20th Century. A 1977 landmark paper of US scientists Fears, Scotto, and Schneiderman advanced a novel hypothesis whereby cutaneous melanoma was primarily caused by intermittent sun exposure (i.e. periodic, brief episodes of exposure to high-intensity ultraviolet radiation) while the keratinocyte cancers, squamous cell carcinoma and basal cell carcinoma, were primarily caused by progressive accumulation of sun exposure. With respect to cutaneous melanoma, this became known as the intermittent exposure hypothesis. The hypothesis stemmed from analysis of measured ambient ultraviolet radiation and age-specific incidence rates of melanoma and keratinocyte cancers collected as an extension to the US Third National Cancer Survey in several US States. In this perspective paper, we put this novel hypothesis into the context of knowledge at the time, and describe subsequent epidemiological and molecular research into melanoma that elaborated the intermittent exposure hypothesis and ultimately replaced it with a dual pathway hypothesis. Our present understanding is of two distinct biological pathways by which cutaneous melanoma might develop; a nevus prone pathway initiated by early sun exposure and promoted by intermittent sun exposure or possibly host factors; and a chronic sun exposure pathway in sun sensitive people who progressively accumulate sun exposure to the sites of future melanomas. Copyright © 2017 Elsevier Ltd. All rights reserved.

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

44 CFR 350.2 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-10-01

... plume and ingestion exposure pathways respectively. (h) Plume Exposure Pathway refers to whole body... to days. (i) Ingestion Exposure Pathway refers to exposure primarily from ingestion of water or foods... exposure pathway EPZ when any of these entities has specific roles in emergency planning and preparedness...

Inflammatory response in rat lungs with recurrent exposure to welding fumes: a transcriptomic approach.

PubMed

Oh, Jung-Hwa; Yang, Mi-Jin; Heo, Jeong-Doo; Yang, Young-Su; Park, Han-Jin; Park, Se-Myo; Kwon, Myung-Sang; Song, Chang-Woo; Yoon, Seokjoo; Yu, Il Je

2012-04-01

As chronic exposure to welding fumes causes pulmonary diseases, such as pneumoconiosis, public concern has increased regarding continued exposure to these hazardous gases in the workplace. In a previous study, the inflammatory response to welding fume exposure was analysed in rat lungs in the case of recurrent exposure and recovery periods. Thus using lung samples, well-annotated by histological observation and biochemical analysis, this study examines the gene expression profiles to identify phenotype-anchored genes corresponding to lung inflammation and the repair phenomenon after recurrent welding fume exposure. Seven genes (Mmp12, Cd5l, LOC50101, LOC69183, Spp1, and Slc26a4) were found to be significantly up-regulated according to the severity of the lung injury. In addition, the transcription and translation of Trem2, which was up-regulated in response to the repair process, were validated using a real-time polymerase chain reaction, Western blotting, and immunohistochemistry. The differentially expressed genes in the exposure and recovery groups were also classified using k-means and hierarchical clustering, plus their toxicological function and canonical pathways were further analysed using Ingenuity Pathways Analysis Software. As a result, this comprehensive and integrative analysis of the transcriptional changes that occur during repeated exposure provides important information on the inflammation and repair processes after welding-fume-induced lung injury.

Relation of pediatric blood lead levels to lead in gasoline.

PubMed Central

Billick, I H; Curran, A S; Shier, D R

1980-01-01

Analysis of a large data set of pediatric blood lead levels collected in New York City (1970-1976) shows a highly significant association between geometric mean blood lead levels and the amount of lead present in gasoline sold during the same period. This association was observed for all age and ethnic groups studied, and it suggests that possible exposure pathways other than ambient air should be considered. Even without detailed knowledge of the exact exposure pathways, sufficient information now exists for policy analysis and decisions relevant to controls and standards related to lead in gasoline and its effect on subsets of the population. PMID:7389685

Transcriptomic analyses of tributyltin-induced sexual dimorphisms in rare minnow (Gobiocypris rarus) brains.

PubMed

Zhang, Ji-Liang; Liu, Min; Zhang, Chun-Nuan; Li, Er-Chao; Fan, Ming-Zhen; Huang, Mao-Xian

2018-07-30

The brain of fish displays sexual dimorphisms and exhibits remarkable sexual plasticity throughout their life span. Although reproductive toxicity of tributyltin (TBT) in fish is well documented in fish, it remains unknown whether TBT interrupts sexual dimorphisms of fish brains. In this work, brain transcriptomic profiles of rare minnow (Gobiocypris rarus) was characterized and sex-biased genes were identified using RNA sequencing. Functional annotation and enrichment analysis were performed to reveal differences of gene products and pathways between the brains of male and female fish. Furthermore, transcriptomic responses of male and female brains to TBT at 10 ng/L were also investigated to understand effects of TBT on brain sexual dimorphisms. Only 345 male-biased and 273 female-biased genes were found in the brains. However, significant female-biased pathways of circadian rhythm and phototransduction were identified in the brains by enrichment analysis. Interestingly, following TBT exposure in the female fish, the circadian rhythm pathway was significantly disrupted based on enrichment analysis, while in the male fish, the phototransduction pathway was significantly disrupted. In the female fish, expression of genes (Per, Cry, Rev-Erb α, Ror, Dec and CK1δ/ε) in the circadian rhythm pathway was down-regulated after TBT exposure; while in the male fish, expression of genes (Rec, GNAT1_2, GNGT1, Rh/opsin, PDE and Arr) in the phototransduction pathway was up-regulated after TBT exposure. Overall, our results not only provide key data on the molecular basis of brain sexual dimorphisms in fish, but also offer valuable resources for investigating molecular mechanisms by which environmental chemicals might influence brain sexual plasticity. Copyright © 2018 Elsevier Inc. All rights reserved.

Nonradiological chemical pathway analysis and identification of chemicals of concern for environmental monitoring at the Hanford Site

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blanton, M.L.; Cooper, A.T.; Castleton, K.J.

1995-11-01

Pacific Northwest`s Surface Environmental Surveillance Project (SESP) is an ongoing effort tot design, review, and conducted monitoring on and off the Hanford site. Chemicals of concern that were selected are listed. Using modeled exposure pathways, the offsite cancer incidence and hazard quotient were calculated and a retrospective pathway analysis performed to estimate what onsite concentrations would be required in the soil for each chemical of concern and other detected chemicals that would be required to obtain an estimated offsite human-health risk of 1.0E-06 cancer incidence or 1.0 hazard quotient. This analysis indicates that current nonradiological chemical contamination occurring on themore » site does not pose a significant offsite human-health risk; the highest cancer incidence to the offsite maximally exposed individual was from arsenic (1.76E-10); the highest hazard quotient was chromium(VI) (1.48E-04). The most sensitive pathways of exposure were surfacewater and aquatic food consumption. Combined total offsite excess cancer incidence was 2.09E-10 and estimated hazard quotient was 2.40E-04. Of the 17 identified chemicals of concern, the SESP does not currently (routinely) monitor arsenic, benzo(a)pyrene, bis(2- ethylhexyl)phthalate (BEHP), and chrysene. Only 3 of the chemicals of concern (arsenic, BEHP, chloroform) could actually occur in onsite soil at concern high enough to cause a 1.0E-06 excess cancer incidence or a 1.0 hazard index for a given offsite exposure pathway. During the retrospective analysis, 20 other chemicals were also evaluated; only vinyl chloride and thallium could reach targeted offsite risk values.« less

Incorporation of additional radionuclides and the external exposure pathway into the BECAMP (Basic Environmental Compliance and Monitoring Program) radiological assessment model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ng, Yook C.; Rodean, H.C.; Anspaugh, L.R.

The Nevada Applied Ecology Group (NAEG) Model of transport and dose for transuranic radionuclides was modified and expanded for the analysis of radionuclides other than pure alpha-emitters. Doses from internal and external exposures were estimated for the inventories and soil distributions of the individual radionuclides quantified in Areas 2 and 4 of the Nevada Test Site (NTS). We found that the dose equivalents via inhalation to liver, lungs, bone marrow, and bone surface from the plutonium isotopes and /sup 241/Am, those via ingestion to bone marrow and bone surfaces from /sup 90/Sr, and those via ingestion to all the targetmore » organs from /sup 137/Cs were the highest from internal exposures. The effective dose equivalents from /sup 137/Cs, /sup 152/Eu, and /sup 154/Eu were the highest from the external exposures. The /sup 60/Co, /sup 152/Eu, /sup 154/Eu, and /sup 155/Eu dose estimates for external exposures greatly exceeded those for internal exposures. The /sup 60/Co, /sup 90/Sr, and /sup 137/Cs dose equivalents from internal exposures were underestimated due to the adoption of some of the foodchain parameter values originally selected for /sup 239/Pu. Nonetheless, the ingestion pathway contributed significantly to the dose estimates for /sup 90/Sr and /sup 137/Cs, but contributed very much less than external exposures to the dose estimates for /sup 60/Co. Therefore, the use of more appropriate values would not alter the identification of important radionuclides, pathways, target organs, and exposure modes in this analysis. 19 refs., 13 figs., 12 tabs.« less

Potential physiological effects of pharmaceutical compounds in Atlantic salmon (Salmo salar) implied by transcriptomic analysis.

PubMed

Hampel, Miriam; Alonso, Esteban; Aparicio, Irene; Bron, James E; Santos, Juan Luis; Taggart, John B; Leaver, Michael J

2010-05-01

Pharmaceuticals are emerging pollutants widely used in everyday urban activities which can be detected in surface, ground, and drinking waters. Their presence is derived from consumption of medicines, disposal of expired medications, release of treated and untreated urban effluents, and from the pharmaceutical industry. Their growing use has become an alarming environmental problem which potentially will become dangerous in the future. However, there is still a lack of knowledge about long-term effects in non-target organisms as well as for human health. Toxicity testing has indicated a relatively low acute toxicity to fish species, but no information is available on possible sublethal effects. This study provides data on the physiological pathways involved in the exposure of Atlantic salmon as representative test species to three pharmaceutical compounds found in ground, surface, and drinking waters based on the evaluation of the xenobiotic-induced impairment resulting in the activation and silencing of specific genes. Individuals of Atlantic salmon (Salmo salar) parr were exposed during 5 days to environmentally relevant concentrations of three representative pharmaceutical compounds with high consumption rates: the analgesic acetaminophen (54.77+/-34.67 microg L(-1)), the anticonvulsant carbamazepine (7.85+/-0.13 microg L(-1)), and the beta-blocker atenolol (11.08+/-7.98 microg L(-1)). Five immature males were selected for transcriptome analysis in brain tissues by means of a 17k salmon cDNA microarray. For this purpose, mRNA was isolated and reverse-transcribed into cDNA which was labeled with fluorescent dyes and hybridized against a common pool to the arrays. Lists of significantly up- and down-regulated candidate genes were submitted to KEGG (Kyoto Encyclopedia of Genes and Genomes) in order to analyze for induced pathways and to evaluate the usefulness of this method in cases of not completely annotated test organisms. Exposure during 5 days to environmentally relevant concentrations of the selected pharmaceutical compounds acetaminophen, carbamazepine, and atenolol produced differences in the expression of 659, 700, and 480 candidate genes, respectively. KEGG annotation numbers (KO annotations) were obtained for between 26.57% and 33.33% of these differently expressed genes per treatment in comparison to non-exposure conditions. Pathways that showed to be induced did not always follow previously reported targets or metabolic routes for the employed treatments; however, several other pathways have been found (four or more features) to be significantly induced. Energy-related pathways have been altered under exposure in all the selected treatments, indicating a possible energy budget leakage due to additional processes resulting from the exposure to environmental contaminants. Observed induction of pathways may indicate additional processes involved in the mode of action of the selected pharmaceuticals which may not have been detected with conventional methods like quantitative PCR in which only suspected features are analyzed punctually for effects. The employment of novel high-throughput screening techniques in combination with global pathway analysis methods, even if the organism is not completely annotated, allows the examination of a much broader range of candidates for potential effects of exposure at the gene level. The continuously growing number of annotations of representative species relevant for environmental quality testing is facilitating pathway analysis processes for not completely annotated organisms. KEGG has shown to be a useful tool for the analysis of induced pathways from data generated by microarray techniques with the selected pharmaceutical contaminants acetaminophen, carbamazepine, and atenolol, but further studies have to be carried out in order to determine if a similar expression pattern in terms of fold change quantity and pathways is observed after long-term exposure. Together with the information obtained in this study, it will then be possible to evaluate the potential risk that the continuous release of these compounds may have on the environment and ecosystem functioning.

Shotgun metabolomic approach based on mass spectrometry for hepatic mitochondria of mice under arsenic exposure.

PubMed

García-Sevillano, M A; García-Barrera, T; Navarro, F; Montero-Lobato, Z; Gómez-Ariza, J L

2015-04-01

Mass spectrometry (MS)-based toxicometabolomics requires analytical approaches for obtaining unbiased metabolic profiles. The present work explores the general application of direct infusion MS using a high mass resolution analyzer (a hybrid systems triple quadrupole-time-of-flight) and a complementary gas chromatography-MS analysis to mitochondria extracts from mouse hepatic cells, emphasizing on mitochondria isolation from hepatic cells with a commercial kit, sample treatment after cell lysis, comprehensive metabolomic analysis and pattern recognition from metabolic profiles. Finally, the metabolomic platform was successfully checked on a case-study based on the exposure experiment of mice Mus musculus to inorganic arsenic during 12 days. Endogenous metabolites alterations were recognized by partial least squares-discriminant analysis. Subsequently, metabolites were identified by combining MS/MS analysis and metabolomics databases. This work reports for the first time the effects of As-exposure on hepatic mitochondria metabolic pathways based on MS, and reveals disturbances in Krebs cycle, β-oxidation pathway, amino acids degradation and perturbations in creatine levels. This non-target analysis provides extensive metabolic information from mitochondrial organelle, which could be applied to toxicology, pharmacology and clinical studies.

Developmental effects of tobacco smoke exposure during human embryonic stem cell differentiation are mediated through the transforming growth factor-β superfamily member, Nodal

PubMed Central

Liszewski, Walter; Ritner, Carissa; Aurigui, Julian; Wong, Sharon S. Y.; Hussain, Naveed; Krueger, Winfried; Oncken, Cheryl; Bernstein, Harold S.

2012-01-01

While the pathologies associated with in utero smoke exposure are well established, their underlying molecular mechanisms are incompletely understood. We differentiated human embryonic stem cells in the presence of physiological concentrations of tobacco smoke and nicotine. Using post hoc microarray analysis, quantitative PCR, and immunoblot analysis, we demonstrated that tobacco smoke has lineage- and stage-specific effects on human embryonic stem cell differentiation, through both nicotine-dependent and -independent pathways. We show that three major stem cell pluripotency/differentiation pathways, Notch, canonical Wnt, and transforming growth factor-β, are affected by smoke exposure, and that Nodal signaling through SMAD2 is specifically impacted by effects on Lefty1, Nodal, and FoxH1. These events are associated with upregulation of microRNA-302a, a post-transcriptional silencer of Lefty1. The described studies provide insight into the mechanisms by which tobacco smoke influences fetal development at the cellular level, and identify specific transcriptional, post-transcriptional, and signaling pathways by which this likely occurs. PMID:22381624

Implied Maximum Dose Analysis of Standard Values of 25 Pesticides Based on Major Human Exposure Pathways

PubMed Central

Li, Zijian; Jennings, Aaron A.

2017-01-01

Worldwide jurisdictions are making efforts to regulate pesticide standard values in residential soil, drinking water, air, and agricultural commodity to lower the risk of pesticide impacts on human health. Because human may exposure to pesticides from many ways, such as ingestion, inhalation, and dermal contact, it is important to examine pesticide standards by considering all major exposure pathways. Analysis of implied maximum dose limits for commonly historical and current used pesticides was adopted in this study to examine whether worldwide pesticide standard values are enough to prevent human health impact or not. Studies show that only U.S. has regulated pesticides standard in the air. Only 4% of the total number of implied maximum dose limits is based on three major exposures. For Chlorpyrifos, at least 77.5% of the total implied maximum dose limits are above the acceptable daily intake. It also shows that most jurisdictions haven't provided pesticide standards in all major exposures yet, and some of the standards are not good enough to protect human health. PMID:29546224

Gene expression profiles following exposure to a developmental neurotoxicant, Aroclor 1254: Pathway analysis for possible mode(s) of action.

EPA Science Inventory

Epidemiological studies indicate that low levels of polychlorinated biphenyl (PCB) exposure can adversely affect neurocognitive development. In animal models, perturbations in calcium signaling, neurotransmitters, and thyroid hormones have been postulated as potential mechanisms...

Assessment of relative potential for Legionella species or surrogates inhalation exposure from common water uses.

PubMed

Hines, Stephanie A; Chappie, Daniel J; Lordo, Robert A; Miller, Brian D; Janke, Robert J; Lindquist, H Alan; Fox, Kim R; Ernst, Hiba S; Taft, Sarah C

2014-06-01

The Legionella species have been identified as important waterborne pathogens in terms of disease morbidity and mortality. Microbial exposure assessment is a tool that can be utilized to assess the potential of Legionella species inhalation exposure from common water uses. The screening-level exposure assessment presented in this paper developed emission factors to model aerosolization, quantitatively assessed inhalation exposures of aerosolized Legionella species or Legionella species surrogates while evaluating two generalized levels of assumed water concentrations, and developed a relative ranking of six common in-home uses of water for potential Legionella species inhalation exposure. Considerable variability in the calculated exposure dose was identified between the six identified exposure pathways, with the doses differing by over five orders of magnitude in each of the evaluated exposure scenarios. The assessment of exposure pathways that have been epidemiologically associated with legionellosis transmission (ultrasonic and cool mist humidifiers) produced higher estimated inhalation exposure doses than pathways where epidemiological evidence of transmission has been less strong (faucet and shower) or absent (toilets and therapy pool). With consideration of the large uncertainties inherent in the exposure assessment process used, a relative ranking of exposure pathways from highest to lowest exposure doses was produced using culture-based measurement data and the assumption of constant water concentration across exposure pathways. In this ranking, the ultrasonic and cool mist humidifier exposure pathways were estimated to produce the highest exposure doses, followed by the shower and faucet exposure pathways, and then the toilet and therapy pool exposure pathways. Published by Elsevier Ltd.

SAGE Analysis of Transcriptome Responses in Arabidopsis Roots Exposed to 2,4,6-Trinitrotoluene1

PubMed Central

Ekman, Drew R.; Lorenz, W. Walter; Przybyla, Alan E.; Wolfe, N. Lee; Dean, Jeffrey F.D.

2003-01-01

Serial analysis of gene expression was used to profile transcript levels in Arabidopsis roots and assess their responses to 2,4,6-trinitrotoluene (TNT) exposure. SAGE libraries representing control and TNT-exposed seedling root transcripts were constructed, and each was sequenced to a depth of roughly 32,000 tags. More than 19,000 unique tags were identified overall. The second most highly induced tag (27-fold increase) represented a glutathione S-transferase. Cytochrome P450 enzymes, as well as an ABC transporter and a probable nitroreductase, were highly induced by TNT exposure. Analyses also revealed an oxidative stress response upon TNT exposure. Although some increases were anticipated in light of current models for xenobiotic metabolism in plants, evidence for unsuspected conjugation pathways was also noted. Identifying transcriptome-level responses to TNT exposure will better define the metabolic pathways plants use to detoxify this xenobiotic compound, which should help improve phytoremediation strategies directed at TNT and other nitroaromatic compounds. PMID:14551330

Transcriptomic configuration of mouse brain induced by adolescent exposure to 3,4-methylenedioxymethamphetamine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eun, Jung Woo; Kwack, Seung Jun; Noh, Ji Heon

The amphetamine derivative ({+-})-3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a synthetic amphetamine analogue used recreationally to obtain an enhanced affiliative emotional response. MDMA is a potent monoaminergic neurotoxin with the potential to damage brain serotonin and/or dopamine neurons. As the majority of MDMA users are young adults, the risk that users may expose the fetus to MDMA is a concern. However, the majority of studies on MDMA have investigated the effects on adult animals. Here, we investigated whether long-term exposure to MDMA, especially in adolescence, could induce comprehensive transcriptional changes in mouse brain. Transcriptomic analysis of mouse brain regions demonstrated significantmore » gene expression changes in the cerebral cortex. Supervised analysis identified 1028 genes that were chronically dysregulated by long-term exposure to MDMA in adolescent mice. Functional categories most represented by this MDMA characteristic signature are intracellular molecular signaling pathways of neurotoxicity, such as, the MAPK signaling pathway, the Wnt signaling pathway, neuroactive ligand-receptor interaction, long-term potentiation, and the long-term depression signaling pathway. Although these resultant large-scale molecular changes remain to be studied associated with functional brain damage caused by MDMA, our observations delineate the possible neurotoxic effects of MDMA on brain function, and have therapeutic implications concerning neuro-pathological conditions associated with MDMA abuse.« less

Cell cycle pathway dysregulation in human keratinocytes during chronic exposure to low arsenite.

PubMed

Al-Eryani, Laila; Waigel, Sabine; Jala, Venkatakrishna; Jenkins, Samantha F; States, J Christopher

2017-09-15

Arsenic is naturally prevalent in the earth's crust and widely distributed in air and water. Chronic low arsenic exposure is associated with several cancers in vivo, including skin cancer, and with transformation in vitro of cell lines including immortalized human keratinocytes (HaCaT). Arsenic also is associated with cell cycle dysregulation at different exposure levels in multiple cell lines. In this work, we analyzed gene expression in HaCaT cells to gain an understanding of gene expression changes contributing to transformation at an early time point. HaCaT cells were exposed to 0 or 100nM NaAsO 2 for 7weeks. Total RNA was purified and analyzed by microarray hybridization. Differential expression with fold change≥|1.5| and p-value≤0.05 was determined using Partek Genomic Suite™ and pathway and network analyses using MetaCore™ software (FDR≤0.05). Cell cycle analysis was performed using flow cytometry. 644 mRNAs were differentially expressed. Cell cycle/cell cycle regulation pathways predominated in the list of dysregulated pathways. Genes involved in replication origin licensing were enriched in the network. Cell cycle assay analysis showed an increase in G2/M compartment in arsenite-exposed cells. Arsenite exposure induced differential gene expression indicating dysregulation of cell cycle control, which was confirmed by cell cycle analysis. The results suggest that cell cycle dysregulation is an early event in transformation manifested in cells unable to transit G2/M efficiently. Further study at later time points will reveal additional changes in gene expression related to transformation processes. Copyright © 2017 Elsevier Inc. All rights reserved.

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Consideration of exposure pathways... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Consideration of exposure pathways... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Consideration of exposure pathways... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 26 2012-07-01 2011-07-01 true Consideration of exposure pathways. 194... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

40 CFR 194.52 - Consideration of exposure pathways.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Consideration of exposure pathways... Individual and Ground-Water Protection Requirements § 194.52 Consideration of exposure pathways. In compliance assessments that analyze compliance with § 191.15 of this chapter, all potential exposure pathways...

Cancer risk of polycyclic aromatic hydrocarbons (PAHs) in the soils from Jiaozhou Bay wetland.

PubMed

Yang, Wei; Lang, Yinhai; Li, Guoliang

2014-10-01

To estimate the cancer risk exposed to the PAHs in Jiaozhou Bay wetland soils, a probabilistic health risk assessment was conducted based on Monte Carlo simulations. A sensitivity analysis was performed to determine the input variables that contribute most to the cancer risk assessment. Three age groups were selected to estimate the cancer risk via four exposure pathways (soil ingestion, food ingestion, dermal contact and inhalation). The results revealed that the 95th percentiles cancer risks for children, teens and adults were 9.11×10(-6), 1.04×10(-5) and 7.08×10(-5), respectively. The cancer risks for three age groups were at acceptable range (10(-6)-10(-4)), indicating no potential cancer risk. For different exposure pathways, food ingestion was the major exposure pathway. For 7 carcinogenic PAHs, the cancer risk caused by BaP was the highest. Sensitivity analysis demonstrated that the parameters of exposure duration (ED) and sum of converted 7 carcinogenic PAHs concentrations in soil based on BaPeq (CSsoil) contribute most to the total uncertainty. This study provides a comprehensive risk assessment on carcinogenic PAHs in Jiaozhou Bay wetland soils, and might be useful in providing potential strategies of cancer risk prevention and controlling. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

PubMed Central

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

2016-01-01

Synopsis Driven by major scientific advances in analytical methods, biomonitoring, computational tools, 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 “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. Aggregate exposure pathways offer an intuitive framework to organize exposure 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 pathways and adverse outcome pathways, completing the source to outcome continuum for more efficient integration of exposure assessment and hazard identification. Together, the two pathways form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making. PMID:26759916

Transcriptome profiling and pathway analysis of hepatotoxicity induced by tris (2-ethylhexyl) trimellitate (TOTM) in mice.

PubMed

Chen, Xian-Hua; Ma, Li; Hu, Yi-Xiang; Wang, Dan-Xian; Fang, Li; Li, Xue-Lai; Zhao, Jin-Chuan; Yu, Hai-Rong; Ying, Hua-Zhong; Yu, Chen-Huan

2016-01-01

Tris (2-ethylhexyl) trimellitate (TOTM) is commonly used as an alternative plasticizer for medical devices. But very little information was available on its biological effects. In this study, we investigated toxicity effects of TOTM on hepatic differential gene expression analyzed by using high-throughput sequencing analysis for over-represented functions and phenotypically anchored to complementary histopathologic, and biochemical data in the liver of mice. Among 1668 candidate genes, 694 genes were up-regulated and 974 genes were down-regulated after TOTM exposure. Using Gene Ontology analysis, TOTM affected three processes: the cell cycle, metabolic process and oxidative activity. Furthermore, 11 key genes involved in the above processes were validated by real time PCR. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these genes were involved in the cell cycle pathway, lipid metabolism and oxidative process. It revealed the transcriptome gene expression response to TOTM exposure in mouse, and these data could contribute to provide a clearer understanding of the molecular mechanisms of TOTM-induced hepatotoxicity in human. Copyright © 2015 Elsevier B.V. All rights reserved.

A risk assessment of direct and indirect exposure to emissions from a proposed hazardous waste incinerator in Puerto Rico

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hallinger, K.; Huggins, A.; Warner, L.

1995-12-31

An Indirect Exposure Assessment (IEA) was conducted, under USEPA`s RCRA Combustion Strategy, as part of the Part B permitting process for a proposed hazardous waste incinerator. The IEA involved identification of constituents of concern, emissions estimations, air dispersion and deposition modeling, evaluation of site-specific exposure pathways/scenarios, and food chain modeling in order to evaluate potential human health and environmental risks. The COMPDEP model was used to determine ambient ground level concentrations and dry and wet deposition rates of constituents of concern. The air modeling results were input into 50th percentile (Central) and 95th percentile (High-End) exposure scenarios which evaluated directmore » exposure via inhalation, dermal contact, and soil ingestion pathways, and indirect exposure through the food chain. The indirect pathway analysis considered the accumulation of constituents in plants and animals used as food sources by local inhabitants. Local food consumption data obtained from the Puerto Rico USDA were combined with realistic present-day and future-use exposure scenarios such as residential use, pineapple farming, and subsistence farming to obtain a comprehensive evaluation of risk, Overall risk was calculated using constituent doses and toxicity factors associated with the various routes of exposure. Risk values for each exposure pathway were summed to determine total carcinogenic and non-carcinogenic hazard to exposed individuals. A population risk assessment was also conducted in order to assess potential risks to the population surrounding the facility. Results of the assessment indicated no acute effects from constituents of concern, and a high-end excess lifetime cancer risk of approximately 6 in a million with dioxins (as 2,3,7,8-TCDD) and arsenic dominating the risk estimate.« less

Model framework for integrating multiple exposure pathways to chemicals in household cleaning products.

PubMed

Shin, H-M; McKone, T E; Bennett, D H

2017-07-01

We present a screening-level exposure-assessment method which integrates exposure from all plausible exposure pathways as a result of indoor residential use of cleaning products. The exposure pathways we considered are (i) exposure to a user during product use via inhalation and dermal, (ii) exposure to chemical residues left on clothing, (iii) exposure to all occupants from the portion released indoors during use via inhalation and dermal, and (iv) exposure to the general population due to down-the-drain disposal via inhalation and ingestion. We use consumer product volatilization models to account for the chemical fractions volatilized to air (f volatilized ) and disposed down the drain (f down-the-drain ) during product use. For each exposure pathway, we use a fate and exposure model to estimate intake rates (iR) in mg/kg/d. Overall, the contribution of the four exposure pathways to the total exposure varies by the type of cleaning activities and with chemical properties. By providing a more comprehensive exposure model and by capturing additional exposures from often-overlooked exposure pathways, our method allows us to compare the relative contribution of various exposure routes and could improve high-throughput exposure assessment for chemicals in cleaning products. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

PubMed

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, computation, 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 "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. Aggregate exposure pathways offer an intuitive framework to organize exposure 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 pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.

Ethnic Diversity, Inter-group Attitudes and Countervailing Pathways of Positive and Negative Inter-group Contact: An Analysis Across Workplaces and Neighbourhoods.

PubMed

Laurence, James; Schmid, Katharina; Hewstone, Miles

2018-01-01

This study advances the current literature investigating the relationship between contextual out-group exposure, inter-group attitudes and the role of inter-group contact. Firstly, it introduces the concept of contact-valence into this relationship; that is, whether contact is experienced positively or negatively. Secondly, it presents a comparative analysis of how processes of out-group exposure and frequency of (valenced) contact affect prejudice across both neighbourhoods and workplaces. Applying path analysis modelling to a nationally-representative sample of white British individuals in England, we demonstrate, across both contexts, that increasing out-group exposure is associated with higher rates of both positively- and negatively-valenced contact. This results in exposure exhibiting both positive and negative indirect associations with prejudice via more frequent inter-group mixing. These countervailing contact-pathways help explain how out-group exposure is associated with inter-group attitudes. In neighbourhoods, increasing numbers of individuals experiencing positive-contact suppress an otherwise negative effect of neighbourhood diversity (driven partly by increasing numbers of individuals reporting negative contact). Across workplaces the effect differs such that increasing numbers of individuals experiencing negative-contact suppress an otherwise positive effect of workplace diversity (driven largely by increasing numbers of individuals experiencing positive contact).

Health assessment of future PM2.5 exposures from indoor, outdoor, and secondhand tobacco smoke concentrations under alternative policy pathways in Ulaanbaatar, Mongolia

PubMed Central

Edwards, Rufus; Turner, Jay R.; Argo, Yuma D.; Olkhanud, Purevdorj B.; Odsuren, Munkhtuul; Guttikunda, Sarath; Ochir, Chimedsuren; Smith, Kirk R.

2017-01-01

Introduction Winter air pollution in Ulaanbaatar, Mongolia is among the worst in the world. The health impacts of policy decisions affecting air pollution exposures in Ulaanbaatar were modeled and evaluated under business as usual and two more-strict alternative emissions pathways through 2024. Previous studies have relied on either outdoor or indoor concentrations to assesses the health risks of air pollution, but the burden is really a function of total exposure. This study combined projections of indoor and outdoor concentrations of PM2.5 with population time-activity estimates to develop trajectories of total age-specific PM2.5 exposure for the Ulaanbaatar population. Indoor PM2.5 contributions from secondhand tobacco smoke (SHS) were estimated in order to fill out total exposures, and changes in population and background disease were modeled. The health impacts were derived using integrated exposure-response curves from the Global Burden of Disease Study. Results Annual average population-weighted PM2.5 exposures at baseline (2014) were estimated at 59 μg/m3. These were dominated by exposures occurring indoors, influenced considerably by infiltrated outdoor pollution. Under current control policies, exposures increased slightly to 60 μg/m3 by 2024; under moderate emissions reductions and under a switch to clean technologies, exposures were reduced from baseline levels by 45% and 80%, respectively. The moderate improvement pathway decreased per capita annual disability-adjusted life year (DALY) and death burdens by approximately 40%. A switch to clean fuels decreased per capita annual DALY and death burdens by about 85% by 2024 with the relative SHS contribution increasing substantially. Conclusion This study demonstrates a way to combine estimated changes in total exposure, background disease and population levels, and exposure-response functions to project the health impacts of alternative policy pathways. The resulting burden analysis highlights the need for aggressive action, including the elimination of residential coal burning and the reduction of current smoking rates. PMID:29088256

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

EPA Science Inventory

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...

Transcriptome changes induced in vitro by alcohol-containing mouthwashes in normal and dysplastic oral keratinocytes.

PubMed

Fox, Simon A; Currie, Sean S; Dalley, Andrew J; Farah, Camile S

2018-05-01

The role of alcohol-containing mouthwash as a risk factor for the development of oral cancer is a subject of conflicting epidemiological evidence in the literature despite alcohol being a recognised carcinogen. The aim of this study was to use in vitro models to investigate mechanistic and global gene expression effects of exposure to alcohol-containing mouthwash. Two brands of alcohol-containing mouthwash and their alcohol-free counterparts were used to treat two oral cell lines derived from normal (OKF6-TERT) and dysplastic (DOK) tissues. Genotoxicity was determined by Comet assay. RNA-seq was performed using the Ion Torrent platform. Bioinformatics analysis used R/Bioconductor packages with differential expression using DEseq2. Pathway enrichment analysis used EnrichR with the WikiPathways and Kegg databases. Both cell lines displayed dose-dependent DNA damage in response to acute exposure to ethanol and alcohol-containing mouthwashes as well as alcohol-free mouthwashes reconstituted with ethanol as shown by Comet assay. The transcriptomic effects of alcohol-containing mouthwash exposure were more complex with significant differential gene expression ranging from >2000 genes in dysplastic (DOK) cells to <100 genes in normal (OKF6-TERT) cells. Pathway enrichment analysis in DOK cells revealed alcohol-containing mouthwashes showed common features between the two brands used including DNA damage response as well as cancer-associated pathways. In OKF6-TERT cells, the most significantly enriched pathways involved inflammatory signalling. Alcohol-containing mouthwashes are genotoxic in vitro to normal and dysplastic oral keratinocytes and induce widespread changes in gene expression. Dysplastic cells are more susceptible to the transcriptomic effects of mouthwash. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Assessing natural direct and indirect effects through multiple pathways.

PubMed

Lange, Theis; Rasmussen, Mette; Thygesen, Lau Caspar

2014-02-15

Within the fields of epidemiology, interventions research and social sciences researchers are often faced with the challenge of decomposing the effect of an exposure into different causal pathways working through defined mediator variables. The goal of such analyses is often to understand the mechanisms of the system or to suggest possible interventions. The case of a single mediator, thus implying only 2 causal pathways (direct and indirect) from exposure to outcome, has been extensively studied. By using the framework of counterfactual variables, researchers have established theoretical properties and developed powerful tools. However, in practical problems, it is not uncommon to have several distinct causal pathways from exposure to outcome operating through different mediators. In this article, we suggest a widely applicable approach to quantifying and ranking different causal pathways. The approach is an extension of the natural effect models proposed by Lange et al. (Am J Epidemiol. 2012;176(3):190-195). By allowing the analysis of distinct multiple pathways, the suggested approach adds to the capabilities of modern mediation techniques. Furthermore, the approach can be implemented using standard software, and we have included with this article implementation examples using R (R Foundation for Statistical Computing, Vienna, Austria) and Stata software (StataCorp LP, College Station, Texas).

Transcriptional responses associated with sulfur mustard and thermal burns in porcine skin.

PubMed

Rogers, James V; McDougal, James N; Price, Jennifer A; Reid, Frances M; Graham, John S

2008-01-01

In military and civilian environments, serious cutaneous damage can result from thermal burns or exposure to the blistering agent sulfur mustard [bis (2-chloroethyl) sulfide; HD]. Similar therapies have historically been used to treat cutaneous thermal and HD injuries; however, the underlying molecular mechanisms of tissue damage and wound healing may differ between the types of burns. Using microarray analysis, this study assessed the transcriptional responses to cutaneous HD and thermal injury at 48 hours post-exposure to identify molecular networks and genes associated with each type of skin injury. Ventral abdominal sites on each of 4 weanling swine were exposed to 400 mul of undiluted HD or a heated brass rod (70 degrees C) for 8 minutes and 45-60 seconds, respectively. At 48 hours post-exposure, total RNA was isolated from excised skin samples and hybridized to Affymetrix GeneChip Porcine Genome Arrays (containing 20,201 genes). Both HD and thermal exposure promoted significant transcriptional changes where 290 and 267 transcripts were increased and 197 and 707 transcripts were decreased with HD and thermal exposure, respectively. HD- and thermal-injured skin expressed 149 increased and 148 decreased common transcripts. Comparison of the 10 most significantly changed biological functions for HD and thermal exposures identified 7 overlapping functional groups. Canonical pathways analysis revealed 15 separate signaling pathways containing transcripts associated with both HD and thermal exposure. Within these pathways, 5 transcripts (CXCR4, FGFR2, HMOX1, IL1R1, and TLR4) were identified as known targets for existing phase II/III clinical trial or Food and Drug Administration (FDA)-approved drugs. This study is the first to directly assess transcriptional changes in porcine skin subjected to HD or thermal injury over the same time period.

Transcriptomic Responses During Early Development Following Arsenic Exposure in Western Clawed Frogs, Silurana tropicalis.

PubMed

Zhang, Jing; Koch, Iris; Gibson, Laura A; Loughery, Jennifer R; Martyniuk, Christopher J; Button, Mark; Caumette, Guilhem; Reimer, Kenneth J; Cullen, William R; Langlois, Valerie S

2015-12-01

Arsenic compounds are widespread environmental contaminants and exposure elicits serious health issues, including early developmental anomalies. Depending on the oxidation state, the intermediates of arsenic metabolism interfere with a range of subcellular events, but the fundamental molecular events that lead to speciation-dependent arsenic toxicity are not fully elucidated. This study therefore assesses the impact of arsenic exposure on early development by measuring speciation and gene expression profiles in the developing Western clawed frog (Silurana tropicalis) larvae following the environmental relevant 0.5 and 1 ppm arsenate exposure. Using HPLC-ICP-MS, arsenate, dimethylarsenic acid, arsenobetaine, arsenocholine, and tetramethylarsonium ion were detected. Microarray and pathway analyses were utilized to characterize the comprehensive transcriptomic responses to arsenic exposure. Clustering analysis of expression data showed distinct gene expression patterns in arsenate treated groups when compared with the control. Pathway enrichment revealed common biological themes enriched in both treatments, including cell signal transduction, cell survival, and developmental pathways. Moreover, the 0.5 ppm exposure led to the enrichment of pathways and biological processes involved in arsenic intake or efflux, as well as histone remodeling. These compensatory responses are hypothesized to be responsible for maintaining an in-body arsenic level comparable to control animals. With no appreciable changes observed in malformation and mortality between control and exposed larvae, this is the first study to suggest that the underlying transcriptomic regulations related to signal transduction, cell survival, developmental pathways, and histone remodeling may contribute to maintaining ongoing development while coping with the potential arsenic toxicity in S. tropicalis during early development. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

EVALUATION OF VADOSE ZONE AND SORUCE MODULES FOR MULTI-MEDIA, MULTI-PATHWAY, AND MULTI-RECEPTOR RISK ASSESSMENT USING LARGE-SOIL-COLUMN EXPERIMENTAL DATA

EPA Science Inventory

The United States Environmental Protection Agency (EPA) is developing a comprehensive environmental exposure and risk analysis software system for agency-wide application using the methodology of a Multi-media, Multi-pathway, Multi-receptor Risk Assessment (3MRA) model. This sof...

EVALUATION OF VADOSE ZONE AND SOURCE MODELS FOR MULTI-MEDIA, MULTI-PATHWAY, MULTI-RECEPTOR RISK ASSESSMENT USING LARGE SOIL COLUMN EXPERIMENT DATA

EPA Science Inventory

The U.S. Environmental Protection Agency (EPA) is developing a comprehensive environmental exposure and risk analysis software system for agency-wide application using the methodology of a Multi-media, Multi-pathway, Multi-receptor Risk Assessment (3MRA) model. This software sys...

Embryotoxic and pharmacologic potency ranking of six azoles in the rat whole embryo culture by morphological and transcriptomic analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dimopoulou, Myrto, E-mail: myrto.dimopoulou@wur.nl

Differential gene expression analysis in the rat whole embryo culture (WEC) assay provides mechanistic insight into the embryotoxicity of test compounds. In our study, we hypothesized that comparative analysis of the transcriptomes of rat embryos exposed to six azoles (flusilazole, triadimefon, ketoconazole, miconazole, difenoconazole and prothioconazole) could lead to a better mechanism-based understanding of their embryotoxicity and pharmacological action. For evaluating embryotoxicity, we applied the total morphological scoring system (TMS) in embryos exposed for 48 h. The compounds tested showed embryotoxicity in a dose-response fashion. Functional analysis of differential gene expression after 4 h exposure at the ID{sub 10} (effectivemore » dose for 10% decreased TMS), revealed the sterol biosynthesis pathway and embryonic development genes, dominated by genes in the retinoic acid (RA) pathway, albeit in a differential way. Flusilazole, ketoconazole and triadimefon were the most potent compounds affecting the RA pathway, while in terms of regulation of sterol function, difenoconazole and ketoconazole showed the most pronounced effects. Dose-dependent analysis of the effects of flusilazole revealed that the RA pathway related genes were already differentially expressed at low dose levels while the sterol pathway showed strong regulation at higher embryotoxic doses, suggesting that this pathway is less predictive for the observed embryotoxicity. A similar analysis at the 24-hour time point indicated an additional time-dependent difference in the aforementioned pathways regulated by flusilazole. In summary, the rat WEC assay in combination with transcriptomics could add a mechanistic insight into the embryotoxic potency ranking and pharmacological mode of action of the tested compounds. - Highlights: • Embryonic exposure to azoles revealed concentration-dependent malformations. • Transcriptomics could enhance the mechanistic knowledge of embryotoxicants. • Retinoic acid gene set identifies early embryotoxic responses to azoles. • Toxic versus pharmacologic potency determines functional efficacy.« less

Air concentrations of PBDEs on in-flight airplanes and assessment of flight crew inhalation exposure.

PubMed

Allen, Joseph G; Sumner, Ann Louise; Nishioka, Marcia G; Vallarino, Jose; Turner, Douglas J; Saltman, Hannah K; Spengler, John D

2013-07-01

To address the knowledge gaps regarding inhalation exposure of flight crew to polybrominated diphenyl ethers (PBDEs) on airplanes, we measured PBDE concentrations in air samples collected in the cabin air at cruising altitudes and used Bayesian Decision Analysis (BDA) to evaluate the likelihood of inhalation exposure to result in the average daily dose (ADD) of a member of the flight crew to exceed EPA Reference Doses (RfDs), accounting for all other aircraft and non-aircraft exposures. A total of 59 air samples were collected from different aircraft and analyzed for four PBDE congeners-BDE 47, 99, 100 and 209 (a subset were also analyzed for BDE 183). For congeners with a published RfD, high estimates of ADD were calculated for all non-aircraft exposure pathways and non-inhalation exposure onboard aircraft; inhalation exposure limits were then derived based on the difference between the RfD and ADDs for all other exposure pathways. The 95th percentile measured concentrations of PBDEs in aircraft air were <1% of the derived inhalation exposure limits. Likelihood probabilities of 95th percentile exposure concentrations >1% of the defined exposure limit were zero for all congeners with published RfDs.

Chiral PCB 91 and 149 Toxicity Testing in Embryo and Larvae (Danio rerio): Application of Targeted Metabolomics via UPLC-MS/MS

NASA Astrophysics Data System (ADS)

Chai, Tingting; Cui, Feng; Yin, Zhiqiang; Yang, Yang; Qiu, Jing; Wang, Chengju

2016-09-01

In this study, we aimed to investigate the dysfunction of zebrafish embryos and larvae induced by rac-/(+)-/(-)- PCB91 and rac-/(-)-/(+)- PCB149. UPLC-MS/MS (Ultra-performance liquid chromatography coupled with mass spectrometry) was employed to perform targeted metabolomics analysis, including the quantification of 22 amino acids and the semi-quantitation of 22 other metabolites. Stereoselective changes in target metabolites were observed in embryos and larvae after exposure to chiral PCB91 and PCB149, respectively. In addition, statistical analyses, including PCA and PLS-DA, combined with targeted metabolomics were conducted to identify the characteristic metabolites and the affected pathways. Most of the unique metabolites in embryos and larvae after PCB91/149 exposure were amino acids, and the affected pathways for zebrafish in the developmental stage were metabolic pathways. The stereoselective effects of PCB91/149 on the metabolic pathways of zebrafish embryos and larvae suggest that chiral PCB91/149 exposure has stereoselective toxicity on the developmental stages of zebrafish.

Completing the link between exposure science and toxicology for improved environmental health decision making: The aggregate exposure pathway framework

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teeguarden, Justin G.; Tan, Yu -Mei; Edwards, Stephen W.

Here, driven by major scientific advances in analytical methods, biomonitoring, computation, 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 “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.more » Aggregate exposure pathways offer an intuitive framework to organize exposure 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 pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.« less

Completing the link between exposure science and toxicology for improved environmental health decision making: The aggregate exposure pathway framework

DOE PAGES

Teeguarden, Justin G.; Tan, Yu -Mei; Edwards, Stephen W.; ...

2016-01-13

Here, driven by major scientific advances in analytical methods, biomonitoring, computation, 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 “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.more » Aggregate exposure pathways offer an intuitive framework to organize exposure 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 pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.« less

Benzo[a]pyrene affects Jurkat T cells in the activated state via the antioxidant response element dependent Nrf2 pathway leading to decreased IL-2 secretion and redirecting glutamine metabolism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murugaiyan, Jayaseelan; Rockstroh, Maxie; Wagner, Juliane

2013-06-15

There is a clear evidence that environmental pollutants, such as benzo[a]pyrene (B[a]P), can have detrimental effects on the immune system, whereas the underlying mechanisms still remain elusive. Jurkat T cells share many properties with native T lymphocytes and therefore are an appropriate model to analyze the effects of environmental pollutants on T cells and their activation. Since environmental compounds frequently occur at low, not acute toxic concentrations, we analyzed the effects of two subtoxic concentrations, 50 nM and 5 μM, on non- and activated cells. B[a]P interferes directly with the stimulation process as proven by an altered IL-2 secretion. Furthermore,more » B[a]P exposure results in significant proteomic changes as shown by DIGE analysis. Pathway analysis revealed an involvement of the AhR independent Nrf2 pathway in the altered processes observed in unstimulated and stimulated cells. A participation of the Nrf2 pathway in the change of IL-2 secretion was confirmed by exposing cells to the Nrf2 activator tBHQ. tBHQ and 5 μM B[a]P caused similar alterations of IL-2 secretion and glutamine/glutamate metabolism. Moreover, the proteome changes in unstimulated cells point towards a modified regulation of the cytoskeleton and cellular stress response, which was proven by western blotting. Additionally, there is a strong evidence for alterations in metabolic pathways caused by B[a]P exposure in stimulated cells. Especially the glutamine/glutamate metabolism was indicated by proteome pathway analysis and validated by metabolite measurements. The detrimental effects were slightly enhanced in stimulated cells, suggesting that stimulated cells are more vulnerable to the environmental pollutant model compound B[a]P. - Highlights: • B[a]P affects the proteome of Jurkat T cells also at low concentrations. • Exposure to B[a]P (50 nM, 5 μM) did not change Jurkat T cell viability. • Both B[a]P concentrations altered the IL-2 secretion of stimulated cells. • 608 different protein spots of Jurkat T cells were quantified using 2-DE-DIGE. • Pathway analysis identified Nrf2 and AhR pathway as regulated.« less

Evidence for non-linear metabolism at low benzene exposures? A reanalysis of data.

PubMed

McNally, K; Sams, C; Loizou, G D; Jones, K

2017-12-25

The presence of a high-affinity metabolic pathway for low level benzene exposures of less than one part per million (ppm) has been proposed although a pathway has not been identified. The variation of metabolite molar fractions with increasing air benzene concentrations was suggested as evidence of significantly more efficient benzene metabolism at concentrations <0.1 ppm The evidence for this pathway is predicated on a rich data set from a study of Chinese shoe workers exposed to a wide range of benzene concentrations (not just "low level"). In this work we undertake a further independent re-analysis of this data with a focus on the evidence for an increase in the rate of metabolism of benzene exposures of less than 1 ppm. The analysis dataset consisted of measurements of benzene and toluene from personal air samplers, and measurements of unmetabolised benzene and toluene and five metabolites (phenol hydroquinone, catechol, trans, trans-muconic acid and s-phenylmercapturic acid) from post-shift urine samples for 213 workers with an occupational exposure to benzene (and toluene) and 139 controls. Measurements from control subjects were used to estimate metabolite concentrations resulting from non-occupational sources, including environmental sources of benzene. Data from occupationally exposed subjects were used to estimate metabolite concentrations as a function of benzene exposure. Correction for background (environmental exposure) sources of metabolites was achieved through a comparison of geometric means in occupationally exposed and control populations. The molar fractions of the five metabolites as a function of benzene exposure were computed. A supra-linear relationship between metabolite concentrations and benzene exposure was observed over the range 0.1-10 ppm benzene, however over the range benzene exposures of between 0.1 and 1 ppm only a modest departure from linearity was observed. The molar fractions estimated in this work were near constant over the range 0.1-10 ppm. No evidence of high affinity metabolism at these low level exposures was observed. Our reanalysis brings in to question the appropriateness of the dataset for commenting on low dose exposures and the use of a purely statistical approach to the analysis. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Editor's Highlight: Hydroxyurea Exposure Activates the P53 Signaling Pathway in Murine Organogenesis-Stage Embryos

PubMed Central

El Husseini, Nazem; Schlisser, Ava E.; Hales, Barbara F.

2016-01-01

Hydroxyurea, an anticancer agent and potent teratogen, induces oxidative stress and activates a DNA damage response pathway in the gestation day (GD) 9 mouse embryo. To delineate the stress response pathways activated by this drug, we investigated the effect of hydroxyurea exposure on the transcriptome of GD 9 embryos. Timed pregnant CD-1 mice were treated with saline or hydroxyurea (400 mg/kg or 600 mg/kg) on GD 9; embryonic gene and protein expression were examined 3 h later. Microarray analysis revealed that the expression of 1346 probe sets changed significantly in embryos exposed to hydroxyurea compared with controls; the P53 signaling pathway was highly affected. In addition, P53 related family members, P63 and P73, were predicted to be activated and had common and unique downstream targets. Western blot analysis revealed that active phospho-P53 was significantly increased in drug-exposed embryos; confocal microscopy showed that the translocation of phospho-P53 to the nucleus was widespread in the embryo. Furthermore, qRT-PCR showed that the expression of P53-regulated genes (Cdkn1A, Fas, and Trp53inp1) was significantly upregulated in hydroxyurea-exposed embryos; the concentration of the redox sensitive P53INP1 protein was also increased in a hydroxyurea dose-dependent fashion. Thus, hydroxyurea elicits a significant effect on the transcriptome of the organogenesis stage murine embryo, activating several key developmental signaling pathways related to DNA damage and oxidative stress. We propose that the P53 pathway plays a central role in the embryonic stress response and the developmental outcome after teratogen exposure. PMID:27208086

A COMPARISON OF URINARY ARSENIC SPECIATION VIA DIRECT NEBULIZATION AND ON-LINE PHOTOOXIDATION-HYDRIDE GENERATION WITH DETECTION BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY

EPA Science Inventory

Arsenic speciation continues to be important in assessing human and environmental exposure risk. Urinary arsenic analysis provides information on recent arsenic exposure. In this study, two sample introduction pathways: direct nebulization (DN) and hydride generation (HG) were ut...

Economic Analysis of Costs Incurred from Chemical Exposures in the Workplace Resulting in Non-Carcinogenic Responses as Additional Justification for Pollution Prevention Projects

DTIC Science & Technology

1993-08-26

Exposure 1CI RfC / RfD Hazard Pathway Total Chemical Index (mg/kg-d) (a/kg-d) Qotient Hazard Eposure index Hazard Index Exposure Pathway: Inhalation...4229 3.0 71651 16.9 CONTAINER 15808 11.1 273386 17.3 DOOR/WINDOW/GATE/FENCE 1476 1.0 22778 15.4 FORM/FRAME/ MOLD 94 0.1 1555 16.5 RACK/SHELF 1332 0.9...DOOR/WINDOW/GATE/FENCE 0 0.0 0 0.0 FORM/FRAME/ MOLD 0 0.0 0 0.0 RACK/SHELF 0 0.0 0 0.0 SKID/PALLET 0 0.0 0 0.0 MACHINES 1 7.1 3 3.0 CASTING/FORGING

Dietary grape seed proanthocyanidin extract regulates metabolic disturbance in rat liver exposed to lead associated with PPARα signaling pathway.

PubMed

Yang, Daqian; Jiang, Huijie; Lu, Jingjing; Lv, Yueying; Baiyun, Ruiqi; Li, Siyu; Liu, Biying; Lv, Zhanjun; Zhang, Zhigang

2018-06-01

Lead, a pervasive environmental hazard worldwide, causes a wide range of physiological and biochemical destruction, including metabolic dysfunction. Grape seed proanthocyanidin extract (GSPE) is a natural production with potential metabolic regulation in liver. This study was performed to investigate the protective role of GSPE against lead-induced metabolic dysfunction in liver and elucidate the potential molecular mechanism of this event. Wistar rats received GSPE (200 mg/kg) daily with or without lead acetate (PbA, 0.5 g/L) exposure for 56 d. According to biochemical and histopathologic analysis, GSPE attenuated lead-induced metabolic dysfunction, oxidative stress, and liver dysfunction. Liver gene expression profiling was assessed by RNA sequencing and validated by qRT-PCR. Expression of some genes in peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway was significantly suppressed in PbA group and revived in PbA + GSPE group, which was manifested by Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis and validated by western blot analysis. This study supports that dietary GSPE ameliorates lead-induced fatty acids metabolic disturbance in rat liver associated with PPARα signaling pathway, and suggests that dietary GSPE may be a protector against lead-induced metabolic dysfunction and liver injury, providing a novel therapy to protect liver against lead exposure. Copyright © 2018 Elsevier Ltd. All rights reserved.

Caged mudsnail Potamopyrgus antipodarum (Gray) as an integrated field biomonitoring tool: exposure assessment and reprotoxic effects of water column contamination.

PubMed

Gust, M; Gagné, F; Berlioz-Barbier, A; Besse, J P; Buronfosse, T; Tournier, M; Tutundjian, R; Garric, J; Cren-Olivé, C

2014-05-01

This study highlights the usefulness of gastropods for water quality monitoring. Gastropods were caged upstream and downstream of an effluent discharge. Exposure was assessed by measurement of organic contaminants in water. Contamination of the Potamopyrgus antipodarum mudsnail was also measured using innovative techniques at the end of the 42 days of exposure. Biological effects were measured at the individual level (growth, reproduction) and subindividual level (energy reserves, vitellin-like proteins, steroid levels, expression of genes involved in estrogen signaling pathways), thus providing a better understanding of reprotoxic effects. The effluent was mainly contaminated by pharmaceutical compounds, as was the mudsnail. The highest concentrations were measured for oxazepam and were higher than 2 mg/kg downstream of the effluent discharge. Alkylphenols, bisphenol A, and vertebrate-like sex-steroid hormones were also bioaccumulated by the mudsnail downstream of the effluent. The combined use of water and snail contamination provided a complete exposure assessment. Exposure was further linked to biological effects. The mudsnail was shown to be a better adapted species for in situ exposures than Valvata piscinalis. Reproduction was sharply decreased after 6 weeks of exposure in the mudsnail. Feeding issues were excluded, confirming the toxic origin. These effects were related to estrogen signaling pathways using genomic analysis. Genes coding for proteins involved in nongenomic signaling pathways were inhibited, and those of genomic pathway repressors were induced. These results suggest that the chemical contamination due to the effluent discharge altered steroid control of reproduction and blocked the transition between oocyte and unshelled embryo, resulting in a drastic decrease of embryo production, while survival was not affected. Copyright © 2014 Elsevier Ltd. All rights reserved.

USE OF PHARMACOKINETIC MODELING TO DESIGN STUDIES FOR PATHWAY-SPECIFIC EXPOSURE MODEL EVALUATION

EPA Science Inventory

Validating an exposure pathway model is difficult because the biomarker, which is often used to evaluate the model prediction, is an integrated measure for exposures from all the exposure routes/pathways. The purpose of this paper is to demonstrate a method to use pharmacokeneti...

Radiographic abnormalities and exposure to asbestos-contaminated vermiculite in the community of Libby, Montana, USA.

PubMed

Peipins, Lucy A; Lewin, Michael; Campolucci, Sharon; Lybarger, Jeffrey A; Miller, Aubrey; Middleton, Dan; Weis, Christopher; Spence, Michael; Black, Brad; Kapil, Vikas

2003-11-01

Mining, handling, processing, and personal or commercial use of asbestos-contaminated vermiculite have led to widespread contamination of the Libby, Montana, area. We initiated a medical testing program in response to reports of respiratory illness in the community. The purpose of this analysis was to identify and quantify asbestos-related radiographic abnormalities among persons exposed to vermiculite in Libby and to examine associations between these outcomes and participants' self-reported exposures. A cross-sectional interview and medical testing were conducted in Libby from July through November 2000 and from July through September 2001. A total of 7,307 persons who had lived, worked, or played in Libby for at least 6 months before 31 December 1990 completed the interview. Of those, 6,668 participants > or = 18 years of age received chest radiographs to assess the prevalence of pleural and interstitial abnormalities. We observed pleural abnormalities in 17.8% of participants and interstitial abnormalities in < 1% of participants undergoing chest radiography. We examined 29 occupational, recreational, household, and other exposure pathways in the analysis. The prevalence of pleural abnormalities increased with increasing number of exposure pathways, ranging from 6.7% for those who reported no apparent exposures to 34.6% for those who reported > or = 12 pathways. The factors most strongly associated with pleural abnormalities were being a former W.R. Grace worker, being older, having been a household contact of a W.R. Grace worker, and being a male. In addition to being a former W.R. Grace worker, environmental exposures and other nonoccupational risk factors were also important predictors of asbestos-related radiographic abnormalities.

Leaching of plastic additives to marine organisms.

PubMed

Koelmans, Albert A; Besseling, Ellen; Foekema, Edwin M

2014-04-01

It is often assumed that ingestion of microplastics by aquatic species leads to increased exposure to plastic additives. However, experimental data or model based evidence is lacking. Here we assess the potential of leaching of nonylphenol (NP) and bisphenol A (BPA) in the intestinal tracts of Arenicola marina (lugworm) and Gadus morhua (North Sea cod). We use a biodynamic model that allows calculations of the relative contribution of plastic ingestion to total exposure of aquatic species to chemicals residing in the ingested plastic. Uncertainty in the most crucial parameters is accounted for by probabilistic modeling. Our conservative analysis shows that plastic ingestion by the lugworm yields NP and BPA concentrations that stay below the lower ends of global NP and BPA concentration ranges, and therefore are not likely to constitute a relevant exposure pathway. For cod, plastic ingestion appears to be a negligible pathway for exposure to NP and BPA. Copyright © 2013 Elsevier Ltd. All rights reserved.

Genome-Wide Identification of Molecular Pathways and Biomarkers in Response to Arsenic Exposure in Zebrafish Liver

PubMed Central

Xu, Hongyan; Lam, Siew Hong; Shen, Yuan; Gong, Zhiyuan

2013-01-01

Inorganic arsenic is a worldwide metalloid pollutant in environment. Although extensive studies on arsenic-induced toxicity have been conducted using in vivo and in vitro models, the exact molecular mechanism of arsenate toxicity remains elusive. Here, the RNA-SAGE (serial analysis of gene expression) sequencing technology was used to analyse hepatic response to arsenic exposure at the transcriptome level. Based on more than 12 million SAGE tags mapped to zebrafish genes, 1,444 differentially expressed genes (750 up-regulated and 694 down-regulated) were identified from a relatively abundant transcripts (>10 TPM [transcripts per million]) based on minimal two-fold change. By gene ontology analyses, these differentially expressed genes were significantly enriched in several major biological processes including oxidation reduction, translation, iron ion transport, cell redox, homeostasis, etc. Accordingly, the main pathways disturbed include metabolic pathways, proteasome, oxidative phosphorylation, cancer, etc. Ingenity Pathway Analysis further revealed a network with four important upstream factors or hub genes, including Jun, Kras, APoE and Nr2f2. The network indicated apparent molecular events involved in oxidative stress, carcinogenesis, and metabolism. In order to identify potential biomarker genes for arsenic exposure, 27 out of 29 up-regulated transcripts were validated by RT-qPCR analysis in pooled RNA samples. Among these, 14 transcripts were further confirmed for up-regulation by a lower dosage of arsenic in majority of individual zebrafish. Finally, at least four of these genes, frh3 (ferrintin H3), mgst1 (microsomal glutathione S-transferase-like), cmbl (carboxymethylenebutenolidase homolog) and slc40a1 (solute carrier family 40 [iron-regulated transporter], member 1) could be confirmed in individual medaka fish similarly treated by arsenic; thus, these four genes might be robust arsenic biomarkers across species. Thus, our work represents the first comprehensive investigation of molecular mechanism of asenic toxicity and genome-wide search for potential biomarkers for arsenic exposure. PMID:23922661

In vivo Assessment and Potential Diagnosis of Xenobiotics that Perturb the Thyroid Pathway: Proteomic Analysis of Xenopus laevis Brain Tissue following Exposure to Model T4 Inhibitors

EPA Science Inventory

As part of a multi-endpoint systems approach to develop comprehensive methods for assessing endocrine stressors in vertebrates, differential protein profiling was used to investigate expression profiles in the brain of an amphibian model (Xenopus laevis) following in vivo exposur...

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

PubMed Central

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

Nitrogen Mustard-Induced Corneal Injury Involves DNA Damage and Pathways Related to Inflammation, Epithelial-Stromal Separation, and Neovascularization.

PubMed

Goswami, Dinesh G; Tewari-Singh, Neera; Dhar, Deepanshi; Kumar, Dileep; Agarwal, Chapla; Ammar, David A; Kant, Rama; Enzenauer, Robert W; Petrash, J Mark; Agarwal, Rajesh

2016-02-01

To evaluate the toxic effects and associated mechanisms in corneal tissue exposed to the vesicating agent, nitrogen mustard (NM), a bifunctional alkylating analog of the chemical warfare agent sulfur mustard. Toxic effects and associated mechanisms were examined in maximally affected corneal tissue using corneal cultures and human corneal epithelial (HCE) cells exposed to NM. Analysis of ex vivo rabbit corneas showed that NM exposure increased apoptotic cell death, epithelial thickness, epithelial-stromal separation, and levels of vascular endothelial growth factor, cyclooxygenase 2, and matrix metalloproteinase-9. In HCE cells, NM exposure resulted in a dose-dependent decrease in cell viability and proliferation, which was associated with DNA damage in terms of an increase in p53 ser15, total p53, and H2A.X ser139 levels. NM exposure also induced caspase-3 and poly ADP ribose polymerase cleavage, suggesting their involvement in NM-induced apoptotic death in the rabbit cornea and HCE cells. Similar to rabbit cornea, NM exposure caused an increase in cyclooxygenase 2, matrix metalloproteinase-9, and vascular endothelial growth factor levels in HCE cells, indicating a role of these molecules and related pathways in NM-induced corneal inflammation, epithelial-stromal separation, and neovascularization. NM exposure also induced activation of activator protein 1 transcription factor proteins and upstream signaling pathways including mitogen-activated protein kinases and Akt protein kinase, suggesting that these could be key factors involved in NM-induced corneal injury. Results from this study provide insight into the molecular targets and pathways that could be involved in NM-induced corneal injuries laying the background for further investigation of these pathways in vesicant-induced ocular injuries, which could be helpful in the development of targeted therapies.

Extracellular vesicle-driven information mediates the long-term effects of particulate matter exposure on coagulation and inflammation pathways.

PubMed

Pavanello, Sofia; Bonzini, Matteo; Angelici, Laura; Motta, Valeria; Pergoli, Laura; Hoxha, Mirjam; Cantone, Laura; Pesatori, Angela Cecilia; Apostoli, Pietro; Tripodi, Armando; Baccarelli, Andrea; Bollati, Valentina

2016-09-30

Continuous exposure to particulate air pollution (PM) is a serious worldwide threat to public health as it coherently links with increased morbidity and mortality of cardiorespiratory diseases (CRD), and of type 2 diabetes (T2D). Extracellular vesicles (EVs) are circular plasma membrane fragments released from human cells that transfer microRNAs between tissues. In the present work it was explored the hypothesis that EVs with their encapsulated microRNAs (EVmiRNAs) contents might mediate PM effects by triggering key pathways in CRD and T2D. Expression of EVmiRNAs analyzed by real-time PCR was correlated with oxidative stress, coagulation and inflammation markers, from healthy steel plant workers (n=55) with a well-characterized exposure to PM and PM-associated metals. All p-values were adjusted for multiple comparisons. In-silico Ingenuity Pathway Analysis (IPA) was performed to identify biological pathways regulated by PM-associated EVmiRNAs. Increased expression in 17 EVmiRNAs is associated with PM and metal exposure (p<0.01). Mir-196b that tops the list, being related to 9 different metals, is fundamental in insulin biosynthesis, however three (miR-302b, miR-200c, miR-30d) out of these 17 EVmiRNAs are in turn also related to disruptions (p<0.01) in inflammatory and coagulation markers. The study's findings support the hypothesis that adverse cardiovascular and metabolic effects stemming from inhalation exposures in particular to PM metallic component may be mediated by EVmiRNAs that target key factors in the inflammation, coagulation and glucose homeostasis pathways. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Nitrogen mustard-induced corneal injury involves DNA damage and pathways related to inflammation, epithelial-stromal separation and neovascularization

PubMed Central

Goswami, Dinesh G; Tewari-Singh, Neera; Dhar, Deepanshi; Kumar, Dileep; Agarwal, Chapla; Ammar, David A; Kant, Rama; Enzenauer, Robert W; Petrash, J Mark; Agarwal, Rajesh

2015-01-01

Purpose To evaluate the toxic effects and associated mechanisms in corneal tissue exposed to vesicating agent, nitrogen mustard (NM), a bi-functional alkylating analog of chemical warfare agent sulfur mustard (SM). Methods Toxic effects and associated mechanisms were examined in maximal affected corneal tissue employing corneal cultures and human corneal epithelial (HCE) cells exposed to nitrogen mustard (NM). Results Analysis of ex vivo rabbit corneas showed that NM exposure increased apoptotic cell death, epithelial thickness, epithelial-stromal separation and levels of VEGF, COX-2 and MMP-9. In HCE cells, NM exposure resulted in a dose-dependent decrease in cell viability and proliferation, which was associated with DNA damage in terms of an increase in p53 ser15, total p53 and H2A.X ser139 levels. NM exposure also induced caspase-3 and PARP cleavage, suggesting their involvement in NM-induced apoptotic death in rabbit cornea and HCE cells. Similar to rabbit cornea, NM exposure caused an increase in COX-2, MMP-9 and VEGF levels in HCE cells, indicating a role of these molecules and related pathways in NM-induced corneal inflammation, epithelial-stromal separation and neovascularization. NM exposure also induced activation of AP-1 transcription factor proteins and upstream signaling pathways including MAPKs and Akt, suggesting that these could be key factors involved in NM-induced corneal injury. Conclusion Results from this study provide insight into the molecular targets and pathways that could be involved in NM-induced corneal injuries laying the background for further investigation of these pathways in vesicant–induced ocular injuries, which could be helpful in the development of targeted therapies. PMID:26555588

A Review of Nonoccupational Pathways for Pesticide Exposure in Women Living in Agricultural Areas

PubMed Central

Friesen, Melissa C.; Hoppin, Jane A.; Hines, Cynthia J.; Thomas, Kent; Freeman, Laura E. Beane

2015-01-01

Background Women living in agricultural areas may experience high pesticide exposures compared with women in urban or suburban areas because of their proximity to farm activities. Objective Our objective was to review the evidence in the published literature for the contribution of nonoccupational pathways of pesticide exposure in women living in North American agricultural areas. Methods We evaluated the following nonoccupational exposure pathways: paraoccupational (i.e., take-home or bystander exposure), agricultural drift, residential pesticide use, and dietary ingestion. We also evaluated the role of hygiene factors (e.g., house cleaning, shoe removal). Results Among 35 publications identified (published 1995–2013), several reported significant or suggestive (p < 0.1) associations between paraoccupational (n = 19) and agricultural drift (n = 10) pathways and pesticide dust or biomarker levels, and 3 observed that residential use was associated with pesticide concentrations in dust. The 4 studies related to ingestion reported low detection rates of most pesticides in water; additional studies are needed to draw conclusions about the importance of this pathway. Hygiene factors were not consistently linked to exposure among the 18 relevant publications identified. Conclusions Evidence supported the importance of paraoccupational, drift, and residential use pathways. Disentangling exposure pathways was difficult because agricultural populations are concurrently exposed to pesticides via multiple pathways. Most evidence was based on measurements of pesticides in residential dust, which are applicable to any household member and are not specific to women. An improved understanding of nonoccupational pesticide exposure pathways in women living in agricultural areas is critical for studying health effects in women and for designing effective exposure-reduction strategies. Citation Deziel NC, Friesen MC, Hoppin JA, Hines CJ, Thomas K, Beane Freeman LE. 2015. A review of nonoccupational pathways for pesticide exposure in women living in agricultural areas. Environ Health Perspect 123:515–524; http://dx.doi.org/10.1289/ehp.1408273 PMID:25636067

Type I interferon and pattern recognition receptor signaling following particulate matter inhalation

PubMed Central

2012-01-01

Background Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc – stainless steel (GMA-SS) welding fume at 40 mg/m3 for 3 hr/d for 10 d and sacrificed 4 hr, 14 d and 28 d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling. Results The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28 d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10). In addition, pulmonary expression of interferon α and β and Irf7 specific pattern recognition receptors (PRR) and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3) were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88) to inhalation of GMA-SS. Conclusion This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure. PMID:22776377

Type I interferon and pattern recognition receptor signaling following particulate matter inhalation.

PubMed

Erdely, Aaron; Antonini, James M; Salmen-Muniz, Rebecca; Liston, Angie; Hulderman, Tracy; Simeonova, Petia P; Kashon, Michael L; Li, Shengqiao; Gu, Ja K; Stone, Samuel; Chen, Bean T; Frazer, David G; Zeidler-Erdely, Patti C

2012-07-09

Welding, a process that generates an aerosol containing gases and metal-rich particulates, induces adverse physiological effects including inflammation, immunosuppression and cardiovascular dysfunction. This study utilized microarray technology and subsequent pathway analysis as an exploratory search for markers/mechanisms of in vivo systemic effects following inhalation. Mice were exposed by inhalation to gas metal arc - stainless steel (GMA-SS) welding fume at 40 mg/m3 for 3 hr/d for 10 d and sacrificed 4 hr, 14 d and 28 d post-exposure. Whole blood cells, aorta and lung were harvested for global gene expression analysis with subsequent Ingenuity Pathway Analysis and confirmatory qRT-PCR. Serum was collected for protein profiling. The novel finding was a dominant type I interferon signaling network with the transcription factor Irf7 as a central component maintained through 28 d. Remarkably, these effects showed consistency across all tissues indicating a systemic type I interferon response that was complemented by changes in serum proteins (decreased MMP-9, CRP and increased VCAM1, oncostatin M, IP-10). In addition, pulmonary expression of interferon α and β and Irf7 specific pattern recognition receptors (PRR) and signaling molecules (Ddx58, Ifih1, Dhx58, ISGF3) were induced, an effect that showed specificity when compared to other inflammatory exposures. Also, a canonical pathway indicated a coordinated response of multiple PRR and associated signaling molecules (Tlr7, Tlr2, Clec7a, Nlrp3, Myd88) to inhalation of GMA-SS. This methodological approach has the potential to identify consistent, prominent and/or novel pathways and provides insight into mechanisms that contribute to pulmonary and systemic effects following toxicant exposure.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cartularo, Laura; Laulicht, Freda; Sun, Hong

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 h; 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 181more » 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, 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 h indicated a reduction in global levels of histone methylation and acetylation that persisted 72 h post-treatment. - Highlights: • A common route of human exposure to the carcinogenic metal cadmium is via diet. • HepG2 cells were treated acutely or chronically with varying doses of cadmium. • Gene expression analysis was performed using Affymetrix Human Gene 1.0 Arrays. • Acute and chronic exposures altered the expression of 333 and 181 genes, respectively. • Acute cadmium exposure altered global levels of histone methylation and acetylation.« less

Completing the Link between Exposure Science and ...

EPA Pesticide Factsheets

Driven by major scientific advances in analytical methods, biomonitoring, computation, 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 “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. Aggregate exposure pathways offer an intuitive framework to organize exposure 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 pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making. The National Exposure Research Laboratory (NERL) Human Exposure and Atmospheric Sciences Division (HEASD) conducts research in support of EPA mission to protect human health and the environment. HEASD research program supports G

INDIRECT EXPOSURE ASSESSMENT AT THE U.S. EPA

EPA Science Inventory

In the early 1980s, exposures and subsequent health impact assessments from contaminants emitted into the air from stationary sources focused on the inhalation pathway. This 'direct' pathway of exposure was thought to be the most critical pathway, as it is for many contaminants. ...

EPA EcoBox Tools by Exposure Pathways - Exposure Pathways In ERA

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guardiola, John J.

Background: Occupational vinyl chloride (VC) exposures have been associated with toxicant-associated steatohepatitis and liver cancer. Metabolomics has been used to clarify mode of action in drug-induced liver injury but has not been performed following VC exposures. Methods: Plasma samples from 17 highly exposed VC workers without liver cancer and 27 unexposed healthy volunteers were obtained for metabolite extraction and GC/MS and LC/MS{sup 2} analysis. Following ion identification/quantification, Ingenuity pathway analysis was performed. Results: 613 unique named metabolites were identified. Of these, 189 metabolites were increased in the VC exposure group while 94 metabolites were decreased. Random Forest analysis indicated thatmore » the metabolite signature could separate the groups with 94% accuracy. VC exposures were associated with increased long chain (including arachidonic acid) and essential (including linoleic acid) fatty acids. Occupational exposure increased lipid peroxidation products including monohydroxy fatty acids (including 13-HODE); fatty acid dicarboxylates; and oxidized arachidonic acid products (including 5,9, and 15-HETE). Carnitine and carnitine esters were decreased, suggesting peroxisomal/mitochondrial dysfunction and alternate modes of lipid oxidation. Differentially regulated metabolites were shown to interact with extracellular-signal-regulated kinase 1/2 (ERK1/2), Akt, AMP-activated protein kinase (AMPK), and the N-Methyl-D-aspartate (NMDA) receptor. The top canonical pathways affected by occupational exposure included tRNA charging, nucleotide degradation, amino acid synthesis/degradation and urea cycle. Methionine and homocysteine was increased with decreased cysteine, suggesting altered 1-carbon metabolism. Conclusions: Occupational exposure generated a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. ERK1/2, Akt, AMPK, and NMDA were identified as protein targets for vinyl chloride toxicity. - Highlights: • Occupational vinyl chloride exposure is linked to toxicant-associated steatohepatitis, liver cancer, and other diseases. • Vinyl chloride exposure led to a distinct plasma metabolome with markedly altered lipid and amino acid metabolites. • A metabolomics approach can provide useful information regarding exposure in chemical workers.« less

An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: A model approach for replication

PubMed Central

Rijlaarsdam, Jolien; Pappa, Irene; Walton, Esther; Bakermans-Kranenburg, Marian J.; Mileva-Seitz, Viara R.; Rippe, Ralph C.A.; Roza, Sabine J.; Jaddoe, Vincent W.V.; Verhulst, Frank C.; Felix, Janine F.; Cecil, Charlotte A.M.; Relton, Caroline L.; Gaunt, Tom R.; McArdle, Wendy; Mill, Jonathan; Barker, Edward D.; Tiemeier, Henning; van IJzendoorn, Marinus H.

2016-01-01

ABSTRACT Prenatal maternal stress exposure has been associated with neonatal differential DNA methylation. However, the available evidence in humans is largely based on candidate gene methylation studies, where only a few CpG sites were evaluated. The aim of this study was to examine the association between prenatal exposure to maternal stress and offspring genome-wide cord blood methylation using different methods. First, we conducted a meta-analysis and follow-up pathway analyses. Second, we used novel region discovery methods [i.e., differentially methylated regions (DMRs) analyses]. To this end, we used data from two independent population-based studies, the Generation R Study (n = 912) and the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 828), to (i) measure genome-wide DNA methylation in cord blood and (ii) extract a prenatal maternal stress composite. The meta-analysis (ntotal = 1,740) revealed no epigenome-wide (meta P <1.00e-07) associations of prenatal maternal stress exposure with neonatal differential DNA methylation. Follow-up analyses of the top hits derived from our epigenome-wide meta-analysis (meta P <1.00e-04) indicated an over-representation of the methyltransferase activity pathway. We identified no Bonferroni-corrected (P <1.00e-06) DMRs associated with prenatal maternal stress exposure. Combining data from two independent population-based samples in an epigenome-wide meta-analysis, the current study indicates that there are no large effects of prenatal maternal stress exposure on neonatal DNA methylation. Such replication efforts are essential in the search for robust associations, whether derived from candidate gene methylation or epigenome-wide studies. PMID:26889969

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teeguarden, Justin G.; Tan, Yu-Mei; Edwards, Stephen W.

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) conceptmore » 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.« less

10 CFR 50.47 - Emergency plans.

Code of Federal Regulations, 2011 CFR

2011-01-01

... clear instruction to the populace within the plume exposure pathway Emergency Planning Zone have been... protective actions has been developed for the plume exposure pathway EPZ for emergency workers and the public... and in place, and protective actions for the ingestion exposure pathway EPZ appropriate to the locale...

Fish Reproduction Is Disrupted upon Lifelong Exposure to Environmental PAHs Fractions Revealing Different Modes of Action

PubMed Central

Vignet, Caroline; Larcher, Thibaut; Davail, Blandine; Joassard, Lucette; Le Menach, Karyn; Guionnet, Tiphaine; Lyphout, Laura; Ledevin, Mireille; Goubeau, Manon; Budzinski, Hélène; Bégout, Marie-Laure; Cousin, Xavier

2016-01-01

Polycyclic aromatic hydrocarbons (PAHs) constitute a large family of organic pollutants emitted in the environment as complex mixtures, the compositions of which depend on origin. Among a wide range of physiological defects, PAHs are suspected to be involved in disruption of reproduction. In an aquatic environment, the trophic route is an important source of chronic exposure to PAHs. Here, we performed trophic exposure of zebrafish to three fractions of different origin, one pyrolytic and two petrogenic. Produced diets contained PAHs at environmental concentrations. Reproductive traits were analyzed at individual, tissue and molecular levels. Reproductive success and cumulative eggs number were disrupted after exposure to all three fractions, albeit to various extents depending on the fraction and concentrations. Histological analyses revealed ovary maturation defects after exposure to all three fractions as well as degeneration after exposure to a pyrolytic fraction. In testis, hypoplasia was observed after exposure to petrogenic fractions. Genes expression analysis in gonads has allowed us to establish common pathways such as endocrine disruption or differentiation/maturation defects. Taken altogether, these results indicate that PAHs can indeed disrupt fish reproduction and that different fractions trigger different pathways resulting in different effects. PMID:29051429

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2013 CFR

2013-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2010 CFR

2010-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2011 CFR

2011-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2014 CFR

2014-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

44 CFR 350.9 - Exercises.

Code of Federal Regulations, 2012 CFR

2012-10-01

... its boundaries or is within the 10-mile plume exposure pathway Emergency Planning Zone of such site... planning zone of a site shall exercise their plans and preparedness related to ingestion exposure pathway measures at least once every five years in conjunction with a plume exposure pathway exercise for that site...

Exposure pathway evaluations for sites that processed asbestos-contaminated vermiculite.

PubMed

Anderson, Barbara A; Dearwent, Steve M; Durant, James T; Dyken, Jill J; Freed, Jennifer A; Moore, Susan McAfee; Wheeler, John S

2005-01-01

The Agency for Toxic Substances and Disease Registry (ATSDR) is currently evaluating the potential public health impacts associated with the processing of asbestos-contaminated vermiculite at various facilities around the country. Vermiculite ore contaminated with significant levels of asbestos was mined and milled in Libby, Montana, from the early 1920s until 1990. The majority of the Libby ore was then shipped to processing facilities for exfoliation. ATSDR initiated the National Asbestos Exposure Review (NAER) to identify and evaluate exposure pathways associated with these processing facilities. This manuscript details ATSDR's phased approach in addressing exposure potential around these sites. As this is an ongoing project, only the results from a selected set of completed site analyses are presented. Historical occupational exposures are the most significant exposure pathway for the site evaluations completed to date. Former workers also probably brought asbestos fibers home on their clothing, shoes, and hair, and their household contacts may have been exposed. Currently, most site-related worker and community exposure pathways have been eliminated. One community exposure pathway of indeterminate significance is the current exposure of individuals through direct contact with waste rock brought home for personal use as fill material, driveway surfacing, or soil amendment. Trace levels of asbestos are present in soil at many of the sites and buried waste rock has been discovered at a few sites; therefore, future worker and community exposure associated with disturbing on-site soil during construction or redevelopment at these sites is also a potential exposure pathway.

Potential impact of clinical use of noninvasive FFRCT on radiation dose exposure and downstream clinical event rate.

PubMed

Bilbey, Nicolas; Blanke, Philipp; Naoum, Christopher; Arepalli, Chesnel Dey; Norgaard, Bjarne Linde; Leipsic, Jonathon

2016-01-01

This study aims to determine the potential impact of introducing noninvasive fractional flow reserve based on coronary computed tomography angiography (CTA) into clinical practice, with respect to radiation dose exposure and downstream event rate. We modeled a population of 1000 stable, symptomatic patients with suspected coronary artery disease, using the disease prevalence from the CONFIRM registry to estimate the pretest likelihood. Four potential clinical pathways were modeled based on the first noninvasive diagnostic test performed: (1) dobutamine echo; (2) single-photon emission computerized tomography (SPECT); (3) coronary CTA; and (4) CTA+FFRCT and leading to possible invasive coronary angiography. The posttest likelihood of testing positive/negative by each test was based on the presenting disease burden and diagnostic accuracy of each test. The dobutamine echo pathway resulted in the lowest radiation dose of 5.4 mSv, with 4.0 mSv from angiography and 1.4 mSv from percutaneous coronary intervention (PCI). The highest dose was with SPECT, with 26.5 mSv. The coronary computed tomography angiography (cCTA) pathway demonstrated a dose of 14.2 mSv, 3.7 mSv from cCTA, 7.7 mSv from angiography, and 2.8 mSv from PCI. The CTA+FFRCT pathway exhibited a radiation dose of 9.7 mSv, 3.7 mSv for cCTA, 4.2 mSv for angiography, and 1.8 mSv for PCI. Radiation dose exposure for CTA+FFRCT was lower than for SPECT (P<.001). The CTA+FFRCT pathway resulted in the lowest projected death/myocardial infarction rate at 1 year (2.44%) while the dobutamine stress pathway had the highest 1-year event rate (2.84%). Our analysis suggests that integrating FFRCT into the CTA clinical pathway may result in reduced cumulative radiation exposure, while promoting favorable clinical outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Prioritization of pesticides based on daily dietary exposure potential as determined from the SHEDS model.

PubMed

Melnyk, Lisa Jo; Wang, Zhaohui; Li, Zhilin; Xue, Jianping

2016-10-01

A major pathway for exposure to many pesticides is through diet. The objectives were to rank pesticides by comparing their calculated daily dietary exposure as determined by EPA's Stochastic Human Exposure and Dose Simulation (SHEDS) to single pesticides for different age groups to acceptable daily intakes (ADI), characterize pesticide trends in exposures over different time periods, and determine commodities contributing to pesticide exposures. SHEDS was applied, using Pesticide Data Program (PDP) (1991-2011) and pesticide usage data on crops from USDA combined with NHANES dietary consumption data, to generate exposure estimates by age group. ADI data collected from EPA, WHO, and other sources were used to rank pesticides based on relativeness of the dietary exposure potential to ADI by age groups. Sensitivity analysis provided trends in pesticide exposures. Within SHEDS, commodities contributing the majority of pesticides with greatest exposure potential were determined. The results indicated that the highest ranking pesticides were methamidophos and diazinon which exceeded 100% of the ADI. Sensitivity analysis indicated that exposure to methamidophos, diazinon, malathion, ethion and formetanate hydrochloride had a marked decrease from 1991-1999 to 2000-2011. Contributions analysis indicated that apples, mushroom, carrots, and lettuce contributed to diazinon exposure. Beans and pepper contributed to methamidophos exposure. Published by Elsevier Ltd.

Monoethylhexyl Phthalate Elicits an Inflammatory Response in Adipocytes Characterized by Alterations in Lipid and Cytokine Pathways.

PubMed

Manteiga, Sara; Lee, Kyongbum

2017-04-01

A growing body of evidence links endocrine-disrupting chemicals (EDCs) with obesity-related metabolic diseases. While it has been shown that EDCs can predispose individuals toward adiposity by affecting developmental processes, little is known about the chemicals' effects on adult adipose tissue. Our aim was to study the effects of low, physiologically relevant doses of EDCs on differentiated murine adipocytes. We combined metabolomics, proteomics, and gene expression analysis to characterize the effects of mono-ethylhexyl phthalate (MEHP) in differentiated adipocytes. Repeated exposure to MEHP over several days led to changes in metabolite and enzyme levels indicating elevated lipogenesis and lipid oxidation. The chemical exposure also increased expression of major inflammatory cytokines, including chemotactic factors. Proteomic and gene expression analysis revealed significant alterations in pathways regulated by peroxisome proliferator activated receptor-γ (PPARγ). Inhibiting the nuclear receptor's activity using a chemical antagonist abrogated not only the alterations in PPARγ-regulated metabolic pathways, but also the increases in cytokine expression. Our results show that MEHP can induce a pro-inflammatory state in differentiated adipocytes. This effect is at least partially mediated PPARγ.

Editor's Highlight: Hydroxyurea Exposure Activates the P53 Signaling Pathway in Murine Organogenesis-Stage Embryos.

PubMed

El Husseini, Nazem; Schlisser, Ava E; Hales, Barbara F

2016-08-01

Hydroxyurea, an anticancer agent and potent teratogen, induces oxidative stress and activates a DNA damage response pathway in the gestation day (GD) 9 mouse embryo. To delineate the stress response pathways activated by this drug, we investigated the effect of hydroxyurea exposure on the transcriptome of GD 9 embryos. Timed pregnant CD-1 mice were treated with saline or hydroxyurea (400 mg/kg or 600 mg/kg) on GD 9; embryonic gene and protein expression were examined 3 h later. Microarray analysis revealed that the expression of 1346 probe sets changed significantly in embryos exposed to hydroxyurea compared with controls; the P53 signaling pathway was highly affected. In addition, P53 related family members, P63 and P73, were predicted to be activated and had common and unique downstream targets. Western blot analysis revealed that active phospho-P53 was significantly increased in drug-exposed embryos; confocal microscopy showed that the translocation of phospho-P53 to the nucleus was widespread in the embryo. Furthermore, qRT-PCR showed that the expression of P53-regulated genes (Cdkn1A, Fas, and Trp53inp1) was significantly upregulated in hydroxyurea-exposed embryos; the concentration of the redox sensitive P53INP1 protein was also increased in a hydroxyurea dose-dependent fashion. Thus, hydroxyurea elicits a significant effect on the transcriptome of the organogenesis stage murine embryo, activating several key developmental signaling pathways related to DNA damage and oxidative stress. We propose that the P53 pathway plays a central role in the embryonic stress response and the developmental outcome after teratogen exposure. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Human primordial germ cell formation is diminished by exposure to environmental toxicants acting through the AHR signaling pathway.

PubMed

Kee, Kehkooi; Flores, Martha; Cedars, Marcelle I; Reijo Pera, Renee A

2010-09-01

Historically, effects of environmental toxicants on human development have been deduced via epidemiological studies because direct experimental analysis has not been possible. However, in recent years, the derivation of human pluripotent stem cells has provided a potential experimental system to directly probe human development. Here, we used human embryonic stem cells (hESCs) to study the effect of environmental toxicants on human germ cell development, with a focus on differentiation of the founding population of primordial germ cells (PGCs), which will go on to form the oocytes of the adult. We demonstrate that human PGC numbers are specifically reduced by exposure to polycyclic aromatic hydrocarbons (PAHs), a group of toxicants common in air pollutants released from gasoline combustion or tobacco smoke. Further, we demonstrate that the adverse effects of PAH exposure are mediated through the aromatic hydrocarbon receptor (AHR) and BAX pathway. This study demonstrates the utility of hESCs as a model system for direct examination of the molecular and genetic pathways of environmental toxicants on human germ cell development.

Multiple pathway asbestos exposure assessment for a Superfund community.

PubMed

Noonan, Curtis W; Conway, Kathrene; Landguth, Erin L; McNew, Tracy; Linker, Laura; Pfau, Jean; Black, Brad; Szeinuk, Jaime; Flores, Raja

2015-01-01

Libby, MT, USA, was the home to workers at a historical vermiculite mining facility and served as the processing and distribution center for this industrial product that was contaminated with amphibole asbestos. Several pathways of environmental asbestos exposure to the general population have been identified. The local clinic and health screening program collects data from participants on past occupational and environmental exposures to vermiculite and asbestos. Health studies among this population have demonstrated associations between amphibole exposure and health outcomes, but critical questions regarding the nature and level of exposure associated with specific outcomes remain unanswered. The objective of this study was to develop a comprehensive exposure assessment approach that integrates information on individuals' contact frequency with multiple exposure pathways. For 3031 participants, we describe cumulative exposure metrics for environmental exposures, occupational exposures, and residents' contact with carry-home asbestos from household workers. As expected, cumulative exposures for all three occupational categories were higher among men compared with women, and cumulative exposures for household contact and environmental pathways were higher among women. The comprehensive exposure assessment strategies will advance health studies and risk assessment approaches in this population with a complex history of both occupational and environmental asbestos exposure.

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

EPA Science Inventory

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

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2011 CFR

2011-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2014 CFR

2014-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2013 CFR

2013-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2010 CFR

2010-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

44 CFR 350.7 - Application by State for review and approval.

Code of Federal Regulations, 2012 CFR

2012-10-01

... coverage of response in the ingestion exposure pathway EPZ. The application will also include plans of all.... (b) Generally, the plume exposure pathway EPZ for nuclear power facilities shall consist of an area about 10 miles (16 Km) in radius and the ingestion exposure pathway EPZ shall consist of an area about...

Elevated Metabolites of Steroidogenesis and Amino Acid Metabolism in Preadolescent Female Children With High Urinary Bisphenol A Levels: A High-Resolution Metabolomics Study.

PubMed

Khan, Adnan; Park, Hyesook; Lee, Hye Ah; Park, Bohyun; Gwak, Hye Sun; Lee, Hye-Ra; Jee, Sun Ha; Park, Youngja H

2017-12-01

Health risks associated with bisphenol A (BPA) exposure are controversially highlighted by numerous studies. High-resolution metabolomics (HRM) can confirm these proposed associations and may provide a mechanistic insight into the connections between BPA exposure and metabolic perturbations. This study was aimed to identify the changes in metabolomics profile due to BPA exposure in urine and serum samples collected from female and male children (n = 18) aged 7-9. Urine was measured for BPA concentration, and the children were subsequently classified into high and low BPA groups. HRM, coupled with Liquid chromatography-mass spectrometry/MS, followed by multivariate statistical analysis using MetaboAnalyst 3.0, were performed on urine to discriminate metabolic profiles between high and low BPA children as well as males and females, followed by further validation of our findings in serum samples obtained from same population. Metabolic pathway analysis showed that biosynthesis of steroid hormones and 7 other pathways-amino acid and nucleotide biosynthesis, phenylalanine metabolism, tryptophan metabolism, tyrosine metabolism, lysine degradation, pyruvate metabolism, and arginine biosynthesis-were affected in high BPA children. Elevated levels of metabolites associated with these pathways in urine and serum were mainly observed in female children, while these changes were negligible in male children. Our results suggest that the steroidogenesis pathway and amino acid metabolism are the main targets of perturbation by BPA in preadolescent girls. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Global metabolomic profiling reveals an association of metal fume exposure and plasma unsaturated fatty acids.

PubMed

Wei, Yongyue; Wang, Zhaoxi; Chang, Chiung-yu; Fan, Tianteng; Su, Li; Chen, Feng; Christiani, David C

2013-01-01

Welding-associated air pollutants negatively affect the health of exposed workers; however, their molecular mechanisms in causing disease remain largely unclear. Few studies have systematically investigated the systemic toxic effects of welding fumes on humans. To explore the effects of welding fumes on the plasma metabolome, and to identify biomarkers for risk assessment of welding fume exposure. The two-stage, self-controlled exploratory study included 11 boilermakers from a 2011 discovery panel and 8 boilermakers from a 2012 validation panel. Plasma samples were collected pre- and post-welding fume exposure and analyzed by chromatography/mass spectrometry. Eicosapentaenoic or docosapentaenoic acid metabolic changes post-welding were significantly associated with particulate (PM2.5) exposure (p<0.05). The combined analysis by linear mixed-effects model showed that exposure was associated with a statistically significant decline in metabolite change of eicosapentaenoic acid [β(95% CI) = -0.013(-0.022 ≈ -0.004); p = 0.005], docosapentaenoic acid n3 [β(95% CI) = -0.010(-0.018 ≈ -0.002); p = 0.017], and docosapentaenoic acid n6 [β(95% CI) = -0.007(-0.013 ≈ -0.001); p = 0.021]. Pathway analysis identified an association of the unsaturated fatty acid pathway with exposure (p Study-2011 = 0.025; p Study-2012 = 0.021; p Combined = 0.009). The functional network built by these fatty acids and their interactive genes contained significant enrichment of genes associated with various diseases, including neoplasms, cardiovascular diseases, and lipid metabolism disorders. High-dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. This alteration in fatty acids is a potential biological mediator and biomarker for exposure-related health disorders.

Exploration of potential biomarkers and related biological pathways for PCB exposure in maternal and cord serum: A pilot birth cohort study in Chiba, Japan.

PubMed

Eguchi, Akifumi; Sakurai, Kenichi; Watanabe, Masahiro; Mori, Chisato

2017-05-01

Polychlorinated biphenyls (PCBs) have been associated with adverse human reproductive and fetal developmental measures or outcomes because of their endocrine-disrupting effects; however, the biological mechanisms of adverse effects of PCB exposure in humans are not currently well established. In this study, we aimed to identify the biological pathways and potential biomarkers of PCB exposure in maternal and umbilical cord serum using a hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) metabolomics platform. The median concentration of total PCBs in maternal (n=93) and cord serum (n=93) were 350 and 70pgg -1 wet wt, respectively. PCB levels in maternal and fetal serum from the Chiba Study of Mother and Children's Health (C-MACH) cohort are comparable to those of earlier cohort studies conducted in Japan, the USA, and European countries. We used the random forest model with the metabolome profile to predict exposure levels of PCB (first quartile [Q1] and fourth quartile [Q4]) for pregnant women and fetuses. In the prediction model for classification of Q1 versus Q4 (area-under-curve [AUC]: pregnant women=0.812 and fetuses=0.919), citraconic acid level in maternal serum and ethanolamine, p-hydroxybenzoate, and purine levels in cord serum had >0.70 AUC values. These candidate biomarkers and metabolite included in composited models were related to glutathione and amino acid metabolism in maternal serum and the amino acid metabolism and ubiquinone and other terpenoid-quinone biosynthesis in cord serum (FDR <0.10), indicating disruption of metabolic pathways by PCB exposure in pregnant women and fetuses. These results showed that metabolome analysis might be useful to explore potential biomarkers and related biological pathways for PCB exposure. Thus, more detailed studies are needed to verify sensitivity of the biomarkers and clarify the biochemical changes resulting from PCB exposure. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

A quantitative visual dashboard to explore exposures to ...

EPA Pesticide Factsheets

The Exposure Prioritization (Ex Priori) model features a simplified, quantitative visual dashboard to explore exposures across chemical space. Diverse data streams are integrated within the interface such that different exposure scenarios for “individual,” “population,” or “professional” time-use profiles can be interchanged to tailor exposure and quantitatively explore multi-chemical signatures of exposure, internalized dose (uptake), body burden, and elimination. Ex Priori will quantitatively extrapolate single-point estimates of both exposure and internal dose for multiple exposure scenarios, factors, products, and pathways. Currently, EPA is investigating its usefulness in life cycle analysis, insofar as its ability to enhance exposure factors used in calculating characterization factors for human health. Presented at 2016 Annual ISES Meeting held in Utrecht, The Netherlands, from 9-13 October 2016.

The Global Food System as a Transport Pathway for Hazardous Chemicals: The Missing Link between Emissions and Exposure.

PubMed

Ng, Carla A; von Goetz, Natalie

2017-01-01

Food is a major pathway for human exposure to hazardous chemicals. The modern food system is becoming increasingly complex and globalized, but models for food-borne exposure typically assume locally derived diets or use concentrations directly measured in foods without accounting for food origin. Such approaches may not reflect actual chemical intakes because concentrations depend on food origin, and representative analysis is seldom available. Processing, packaging, storage, and transportation also impart different chemicals to food and are not yet adequately addressed. Thus, the link between environmental emissions and realistic human exposure is effectively broken. We discuss the need for a fully integrated treatment of the modern industrialized food system, and we propose strategies for using existing models and relevant supporting data sources to track chemicals during production, processing, packaging, storage, and transport. Fate and bioaccumulation models describe how chemicals distribute in the environment and accumulate through local food webs. Human exposure models can use concentrations in food to determine body burdens based on individual or population characteristics. New models now include the impacts of processing and packaging but are far from comprehensive. We propose to close the gap between emissions and exposure by utilizing a wider variety of models and data sources, including global food trade data, processing, and packaging models. A comprehensive approach that takes into account the complexity of the modern global food system is essential to enable better prediction of human exposure to chemicals in food, sound risk assessments, and more focused risk abatement strategies. Citation: Ng CA, von Goetz N. 2017. The global food system as a transport pathway for hazardous chemicals: the missing link between emissions and exposure. Environ Health Perspect 125:1-7; http://dx.doi.org/10.1289/EHP168.

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

PubMed

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.

Elevated levels of perfluoroalkyl acids in family members of occupationally exposed workers: the importance of dust transfer.

PubMed

Fu, Jianjie; Gao, Yan; Wang, Thanh; Liang, Yong; Zhang, Aiqian; Wang, Yawei; Jiang, Guibin

2015-03-20

The exposure pathways of perfluoroalkyl acids (PFAAs) to humans are still not clear because of the complex living environment, and few studies have simultaneously investigated the bioaccumulative behaviour of different PFAAs in humans. In this study, serum, dust, duplicate diet, and other matrices were collected around a manufacturing plant in China, and homologous series of PFAAs were analysed. PFAA levels in dust and serum of local residents in this area were considerably higher than those in non-polluted area. Although dietary intake was the major exposure pathway in the present study, dust ingestion played an important role in this case. Serum PFAAs in local residents was significantly correlated with dust PFAAs levels in their living or working microenvironment. Serum PFAAs and dust PFAAs were significantly higher in family members of occupational workers (FM) than in ordinary residents (OR) (p < 0.01). After a careful analysis of the PFAAs exposure pathway, a potential pathway in addition to direct dust ingestion was suggested: PFAAs might transferred from occupational worker's clothes to dinners via cooking processes. The bioaccumulative potential of PFHxS and PFOS were higher than other PFAAs, which suggested a substantial difference between the bioaccumulative ability of perfluorinated sulfonic acids and perfluorinated carboxylic acids.

Elevated levels of perfluoroalkyl acids in family members of occupationally exposed workers: the importance of dust transfer

NASA Astrophysics Data System (ADS)

Fu, Jianjie; Gao, Yan; Wang, Thanh; Liang, Yong; Zhang, Aiqian; Wang, Yawei; Jiang, Guibin

2015-03-01

The exposure pathways of perfluoroalkyl acids (PFAAs) to humans are still not clear because of the complex living environment, and few studies have simultaneously investigated the bioaccumulative behaviour of different PFAAs in humans. In this study, serum, dust, duplicate diet, and other matrices were collected around a manufacturing plant in China, and homologous series of PFAAs were analysed. PFAA levels in dust and serum of local residents in this area were considerably higher than those in non-polluted area. Although dietary intake was the major exposure pathway in the present study, dust ingestion played an important role in this case. Serum PFAAs in local residents was significantly correlated with dust PFAAs levels in their living or working microenvironment. Serum PFAAs and dust PFAAs were significantly higher in family members of occupational workers (FM) than in ordinary residents (OR) (p < 0.01). After a careful analysis of the PFAAs exposure pathway, a potential pathway in addition to direct dust ingestion was suggested: PFAAs might transferred from occupational worker's clothes to dinners via cooking processes. The bioaccumulative potential of PFHxS and PFOS were higher than other PFAAs, which suggested a substantial difference between the bioaccumulative ability of perfluorinated sulfonic acids and perfluorinated carboxylic acids.

Elevated levels of perfluoroalkyl acids in family members of occupationally exposed workers: the importance of dust transfer

PubMed Central

Fu, Jianjie; Gao, Yan; Wang, Thanh; Liang, Yong; Zhang, Aiqian; Wang, Yawei; Jiang, Guibin

2015-01-01

The exposure pathways of perfluoroalkyl acids (PFAAs) to humans are still not clear because of the complex living environment, and few studies have simultaneously investigated the bioaccumulative behaviour of different PFAAs in humans. In this study, serum, dust, duplicate diet, and other matrices were collected around a manufacturing plant in China, and homologous series of PFAAs were analysed. PFAA levels in dust and serum of local residents in this area were considerably higher than those in non-polluted area. Although dietary intake was the major exposure pathway in the present study, dust ingestion played an important role in this case. Serum PFAAs in local residents was significantly correlated with dust PFAAs levels in their living or working microenvironment. Serum PFAAs and dust PFAAs were significantly higher in family members of occupational workers (FM) than in ordinary residents (OR) (p < 0.01). After a careful analysis of the PFAAs exposure pathway, a potential pathway in addition to direct dust ingestion was suggested: PFAAs might transferred from occupational worker's clothes to dinners via cooking processes. The bioaccumulative potential of PFHxS and PFOS were higher than other PFAAs, which suggested a substantial difference between the bioaccumulative ability of perfluorinated sulfonic acids and perfluorinated carboxylic acids. PMID:25791573

System-based Identification of Toxicity Pathways Associated With Multi-Walled Carbon Nanotube-Induced Pathological Responses

PubMed Central

Snyder-Talkington, Brandi N.; Dymacek, Julian; Porter, Dale W.; Wolfarth, Michael G.; Mercer, Robert R.; Pacurari, Maricica; Denvir, James; Castranova, Vincent; Qian, Yong; Guo, Nancy L.

2014-01-01

The fibrous shape and biopersistence of multi-walled carbon nanotubes (MWCNT) have raised concern over their potential toxicity after pulmonary exposure. As in vivo exposure to MWCNT produced a transient inflammatory and progressive fibrotic response, this study sought to identify significant biological processes associated with lung inflammation and fibrosis pathology data, based upon whole genome mRNA expression, bronchoaveolar lavage scores, and morphometric analysis from C57BL/6J mice exposed by pharyngeal aspiration to 0, 10, 20, 40, or 80 µg MWCNT at 1, 7, 28, or 56 days post-exposure. Using a novel computational model employing non-negative matrix factorization and Monte Carlo Markov Chain simulation, significant biological processes with expression similar to MWCNT-induced lung inflammation and fibrosis pathology data in mice were identified. A subset of genes in these processes was determined to be functionally related to either fibrosis or inflammation by Ingenuity Pathway Analysis and were used to determine potential significant signaling cascades. Two genes determined to be functionally related to inflammation and fibrosis, vascular endothelial growth factor A (vegfa) and C-C motif chemokine 2 (ccl2), were confirmed by in vitro studies of mRNA and protein expression in small airway epithelial cells exposed to MWCNT as concordant with in vivo expression. This study identified that the novel computational model was sufficient to determine biological processes strongly associated with the pathology of lung inflammation and fibrosis and could identify potential toxicity signaling pathways and mechanisms of MWCNT exposure which could be used for future animal studies to support human risk assessment and intervention efforts. PMID:23845593

Metabolomics and In-Silico Analysis Reveal Critical Energy Deregulations in Animal Models of Parkinson’s Disease

PubMed Central

Poliquin, Pierre O.; Chen, Jingkui; Cloutier, Mathieu; Trudeau, Louis-Éric; Jolicoeur, Mario

2013-01-01

Parkinson’s disease (PD) is a multifactorial disease known to result from a variety of factors. Although age is the principal risk factor, other etiological mechanisms have been identified, including gene mutations and exposure to toxins. Deregulation of energy metabolism, mostly through the loss of complex I efficiency, is involved in disease progression in both the genetic and sporadic forms of the disease. In this study, we investigated energy deregulation in the cerebral tissue of animal models (genetic and toxin induced) of PD using an approach that combines metabolomics and mathematical modelling. In a first step, quantitative measurements of energy-related metabolites in mouse brain slices revealed most affected pathways. A genetic model of PD, the Park2 knockout, was compared to the effect of CCCP, a complex I blocker. Model simulated and experimental results revealed a significant and sustained decrease in ATP after CCCP exposure, but not in the genetic mice model. In support to data analysis, a mathematical model of the relevant metabolic pathways was developed and calibrated onto experimental data. In this work, we show that a short-term stress response in nucleotide scavenging is most probably induced by the toxin exposure. In turn, the robustness of energy-related pathways in the model explains how genetic perturbations, at least in young animals, are not sufficient to induce significant changes at the metabolite level. PMID:23935941

Regulation of tumor progression via the Snail-RKIP signaling pathway by nicotine exposure in head and neck squamous cell carcinoma.

PubMed

Nieh, Shin; Jao, Shu-Wen; Yang, Chin-Yuh; Lin, Yaoh-Shiang; Tseng, Yi-Han; Liu, Chia-Lin; Lee, Tsai-Yu; Liu, Tsung-Yun; Chu, Yueng-Hsiang; Chen, Su-Feng

2015-12-01

Recent studies suggest that long-term exposure of the carcinogen 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK) found in tobacco smoke is involved in the progression of head and neck squamous cell carcinoma (HNSCC). The underlying nicotine-mediated mechanism remains unclear. An analysis of SCC-25 and Fadu cells with or without NNK exposure focusing on the evaluation of migration and invasion abilities, the expression of epithelial-mesenchymal transition, drug-resistance-related genes, properties of cancer stem cells (CSCs), and anti-apoptosis was performed. Long-term NNK exposure enhances migration and invasion with morphological alterations in a dose-dependently manner. Furthermore, NNK exposure also upregulates Snail, promotes sphere-forming ability, and overexpresses aldehyde dehydrogenase 1 (ALDH1), Nanog, OCT4, ABCG2, and MDR1. The current study confirmed that long-term NNK exposure plays a role in HNSCC by increasing anti-apoptosis and therapeutic resistance via the Snail-RKIP signaling pathway. Our data also suggest that α7 nicotinic acetylcholine receptor (α7-nAChR) inhibition or targeting Snail may provide a feasible rationale for preventing the progression of HNSCC. © 2015 Wiley Periodicals, Inc.

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

NASA Astrophysics Data System (ADS)

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

2015-06-01

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

44 CFR 350.5 - Criteria for review and approval of State and local radiological emergency plans and preparedness.

Code of Federal Regulations, 2013 CFR

2013-10-01

... populace within the plume exposure pathway Emergency Planning Zone have been established. (6) Provisions... plume exposure pathway EPZ for emergency workers and the public. Guidelines for the choice of protective... actions for the ingestion exposure pathway EPZ appropriate to the locale have been developed. (11) Means...

44 CFR 350.5 - Criteria for review and approval of State and local radiological emergency plans and preparedness.

Code of Federal Regulations, 2012 CFR

2012-10-01

... populace within the plume exposure pathway Emergency Planning Zone have been established. (6) Provisions... plume exposure pathway EPZ for emergency workers and the public. Guidelines for the choice of protective... actions for the ingestion exposure pathway EPZ appropriate to the locale have been developed. (11) Means...

44 CFR 350.5 - Criteria for review and approval of State and local radiological emergency plans and preparedness.

Code of Federal Regulations, 2014 CFR

2014-10-01

... populace within the plume exposure pathway Emergency Planning Zone have been established. (6) Provisions... plume exposure pathway EPZ for emergency workers and the public. Guidelines for the choice of protective... actions for the ingestion exposure pathway EPZ appropriate to the locale have been developed. (11) Means...

Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Jintao; Zhu, Dexiao; Zhang, Jing

Methamphetamine (MA) is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to MA causes psychosis and increases the risk of Parkinson's disease. Lithium (Li) is a known mood stabilizer and has neuroprotective effects. Previous studies suggest that MA exposure decreases the phosphorylation of Akt/GSK3β pathway in vivo, whereas Li facilitates the phosphorylation of Akt/GSK3β pathway. Moreover, GSK3β and mTOR are implicated in the locomotor sensitization induced by psychostimulants and mTOR plays a critical role in MA induced toxicity. However, the effect of MA on Akt/GSK3β/mTOR pathway has not been fully investigated in vitro. Here, we found that MA exposure significantly dephosphorylated Akt/GSK3β/mTOR pathwaymore » in PC12 cells. In addition, Li remarkably attenuated the dephosphorylation effect of MA exposure on Akt/GSK3β/mTOR pathway. Furthermore, Li showed obvious protective effects against MA toxicity and LY294002 (Akt inhibitor) suppressed the protective effects of Li. Together, MA exposure dephosphorylates Akt/GSK3β/mTOR pathway in vitro, while lithium protects against MA-induced neurotoxicity via phosphorylation of Akt/GSK3β/mTOR pathway. - Highlights: • Lithium protects against methamphetamine-induced neurotoxicity in vitro. • Methamphetamine exposure dephosphorylates Akt/GSK3β/mTOR pathway. • Lithium attenuates methamphetamine-induced toxicity via phosphorylating Akt/GSK3β/mTOR pathway.« less

Transcriptomic profile of host response in mouse brain after exposure to plant toxin abrin.

PubMed

Bhaskar, A S Bala; Gupta, Nimesh; Rao, P V Lakshmana

2012-09-04

Abrin toxin is a plant glycoprotein, which is similar in structure and properties to ricin and is obtained from the seeds of Abrus precatorius (jequirity bean). Abrin is highly toxic, with an estimated human fatal dose of 0.1-1 μg/kg, and has caused death after accidental and intentional poisoning. Abrin is a potent biological toxin warfare agent. There are no chemical antidotes available against the toxin. Neurological symptoms like delirium, hallucinations, reduced consciousness and generalized seizures were reported in human poisoning cases. Death of a patient with symptoms of acute demyelinating encephalopathy with gastrointestinal bleeding due to ingestion of abrin seeds was reported in India. The aim of this study was to examine both dose and time-dependent transcriptional responses induced by abrin in the adult mouse brain. Mice (n=6) were exposed to 1 and 2 LD50 (2.83 and 5.66 μg/kg respectively) dose of abrin by intraperitoneal route and observed over 3 days. A subset of animals (n=3) were sacrificed at 1 and 2 day intervals for microarray and histopathology analysis. None of the 2 LD50 exposed animals survived till 3 days. The histopathological analysis showed the severe damage in brain and the infiltration of inflammatory cells in a dose and time dependent manner. The abrin exposure resulted in the induction of rapid immune and inflammatory response in brain. Clinical biochemistry parameters like lactate dehydrogenase, aspartate aminotransferase, urea and creatinine showed significant increase at 2-day 2 LD50 exposure. The whole genome microarray data revealed the significant regulation of various pathways like MAPK pathway, cytokine-cytokine receptor interaction, calcium signaling pathway, Jak-STAT signaling pathway and natural killer cell mediated toxicity. The comparison of differential gene expression at both the doses showed dose dependent effects of abrin toxicity. The real-time qRT-PCR analysis of selected genes supported the microarray data. This is the first report on host-gene response using whole genome microarray in an animal model after abrin exposure. The data generated provides leads for developing suitable medical counter measures against abrin poisoning. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Testing pathways linking exposure to community violence and sexual behaviors among African American youth.

PubMed

Voisin, Dexter R; Hotton, Anna L; Neilands, Torsten B

2014-09-01

Exposure to community violence and HIV sexual risks are two major public health concerns among youth. This study tests various pathways linking exposure to community violence and sexual behaviors among African American adolescents. Using a sample of 563 (61% females) African American youth attending high school we examined whether problematic psychological symptoms, low school engagement, and/or negative perceptions of peer norms about safer sex functioned as pathways linking exposure to community violence and sexual behaviors. Major findings indicated that, for boys, the relationship between exposure to community violence and sexual début and sexual risk behaviors were linked by aggression. In addition, the relationship between exposure to community violence and sexual risk behaviors were linked by negative perceptions of peer attitudes about safer sex. For girls, the relationship between exposure to community violence and sexual début was linked by aggression and negative perceptions of peer attitudes about safer sex. These findings provide support for pathways linking exposure to community violence to sexual behaviors.

Testing Pathways Linking Exposure to Community Violence and Sexual Behaviors Among African American Youth

PubMed Central

Hotton, Anna L.; Neilands, Torsten B.

2014-01-01

Exposure to community violence and HIV sexual risks are two major public health concerns among youth. This study tests various pathways linking exposure to community violence and sexual behaviors among African American adolescents. Using a sample of 563 (61 % females) African American youth attending high school we examined whether problematic psychological symptoms, low school engagement, and/or negative perceptions of peer norms about safer sex functioned as pathways linking exposure to community violence and sexual behaviors. Major findings indicated that, for boys, the relationship between exposure to community violence and sexual début and sexual risk behaviors were linked by aggression. In addition, the relationship between exposure to community violence and sexual risk behaviors were linked by negative perceptions of peer attitudes about safer sex. For girls, the relationship between exposure to community violence and sexual début was linked by aggression and negative perceptions of peer attitudes about safer sex. These findings provide support for pathways linking exposure to community violence to sexual behaviors. PMID:24327295

Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells

PubMed Central

Perkins, Timothy N.; Peeters, Paul M.; Shukla, Arti; Arijs, Ingrid; Dragon, Julie; Wouters, Emiel F.M.; Reynaert, Niki L.; Mossman, Brooke T.

2015-01-01

Occupational and environmental exposures to airborne asbestos and silica are associated with the development of lung fibrosis in the forms of asbestosis and silicosis, respectively. However, both diseases display distinct pathologic presentations, likely associated with differences in gene expression induced by different mineral structures, composition and bio-persistent properties. We hypothesized that effects of mineral exposure in the airway epithelium may dictate deviating molecular events that may explain the different pathologies of asbestosis versus silicosis. Using robust gene expression-profiling in conjunction with in-depth pathway analysis, we assessed early (24 h) alterations in gene expression associated with crocidolite asbestos or cristobalite silica exposures in primary human bronchial epithelial cells (NHBEs). Observations were confirmed in an immortalized line (BEAS-2B) by QRT-PCR and protein assays. Utilization of overall gene expression, unsupervised hierarchical cluster analysis and integrated pathway analysis revealed gene alterations that were common to both minerals or unique to either mineral. Our findings reveal that both minerals had potent effects on genes governing cell adhesion/migration, inflammation, and cellular stress, key features of fibrosis. Asbestos exposure was most specifically associated with aberrant cell proliferation and carcinogenesis, whereas silica exposure was highly associated with additional inflammatory responses, as well as pattern recognition, and fibrogenesis. These findings illustrate the use of gene-profiling as a means to determine early molecular events that may dictate pathological processes induced by exogenous cellular insults. In addition, it is a useful approach for predicting the pathogenicity of potentially harmful materials. PMID:25351596

Integrated Bioinformatics, Environmental Epidemiologic and Genomic Approaches to Identify Environmental and Molecular Links between Endometriosis and Breast Cancer

PubMed Central

Roy, Deodutta; Morgan, Marisa; Yoo, Changwon; Deoraj, Alok; Roy, Sandhya; Yadav, Vijay Kumar; Garoub, Mohannad; Assaggaf, Hamza; Doke, Mayur

2015-01-01

We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by exposure to PCBs, phthalate or BPA. EDCs-modified genes in breast neoplasms and endometriosis are part of steroid hormone signaling and inflammation pathways. All three EDCs–PCB 153, phthalates, and BPA influenced five common genes—CYP19A1, EGFR, ESR2, FOS, and IGF1—in breast cancer as well as in endometriosis. These genes are environmentally and estrogen responsive, altered in human breast and uterine tumors and endometriosis lesions, and part of Mitogen Activated Protein Kinase (MAPK) signaling pathways in cancer. Our findings suggest that breast cancer and endometriosis share some common environmental and molecular risk factors. PMID:26512648

System-based identification of toxicity pathways associated with multi-walled carbon nanotube-induced pathological responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Snyder-Talkington, Brandi N.; Dymacek, Julian; Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506-9300

2013-10-15

The fibrous shape and biopersistence of multi-walled carbon nanotubes (MWCNT) have raised concern over their potential toxicity after pulmonary exposure. As in vivo exposure to MWCNT produced a transient inflammatory and progressive fibrotic response, this study sought to identify significant biological processes associated with lung inflammation and fibrosis pathology data, based upon whole genome mRNA expression, bronchoaveolar lavage scores, and morphometric analysis from C57BL/6J mice exposed by pharyngeal aspiration to 0, 10, 20, 40, or 80 μg MWCNT at 1, 7, 28, or 56 days post-exposure. Using a novel computational model employing non-negative matrix factorization and Monte Carlo Markov Chainmore » simulation, significant biological processes with expression similar to MWCNT-induced lung inflammation and fibrosis pathology data in mice were identified. A subset of genes in these processes was determined to be functionally related to either fibrosis or inflammation by Ingenuity Pathway Analysis and was used to determine potential significant signaling cascades. Two genes determined to be functionally related to inflammation and fibrosis, vascular endothelial growth factor A (vegfa) and C-C motif chemokine 2 (ccl2), were confirmed by in vitro studies of mRNA and protein expression in small airway epithelial cells exposed to MWCNT as concordant with in vivo expression. This study identified that the novel computational model was sufficient to determine biological processes strongly associated with the pathology of lung inflammation and fibrosis and could identify potential toxicity signaling pathways and mechanisms of MWCNT exposure which could be used for future animal studies to support human risk assessment and intervention efforts. - Highlights: • A novel computational model identified toxicity pathways matching in vivo pathology. • Systematic identification of MWCNT-induced biological processes in mouse lungs • MWCNT-induced functional networks of lung inflammation and fibrosis were revealed. • Two functional, representative genes, ccl2 and vegfa, were validated in vitro.« less

Children's Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making.

PubMed

Zartarian, Valerie; Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-09-12

Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)'s National Drinking Water Advisory Council (NDWAC) recommended establishment of a "health-based, household action level" for lead in drinking water based on children's exposure. The primary objective was to develop a coupled exposure-dose modeling approach that can be used to determine what drinking water lead concentrations keep children's blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. A modeling approach using the EPA's Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Modeled BLLs compared well with nationally representative BLLs (0-23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605.

Changes in the Metabolome in Response to Low-Dose Exposure to Environmental Chemicals Used in Personal Care Products during Different Windows of Susceptibility.

PubMed

Houten, Sander M; Chen, Jia; Belpoggi, Fiorella; Manservisi, Fabiana; Sánchez-Guijo, Alberto; Wudy, Stefan A; Teitelbaum, Susan L

2016-01-01

The consequences of ubiquitous exposure to environmental chemicals remain poorly defined. Non-targeted metabolomic profiling is an emerging method to identify biomarkers of the physiological response to such exposures. We investigated the effect of three commonly used ingredients in personal care products, diethyl phthalate (DEP), methylparaben (MPB) and triclosan (TCS), on the blood metabolome of female Sprague-Dawley rats. Animals were treated with low levels of these chemicals comparable to human exposures during prepubertal and pubertal windows as well as chronically from birth to adulthood. Non-targeted metabolomic profiling revealed that most of the variation in the metabolites was associated with developmental stage. The low-dose exposure to DEP, MPB and TCS had a relatively small, but detectable impact on the metabolome. Multiple metabolites that were affected by chemical exposure belonged to the same biochemical pathways including phenol sulfonation and metabolism of pyruvate, lyso-plasmalogens, unsaturated fatty acids and serotonin. Changes in phenol sulfonation and pyruvate metabolism were most pronounced in rats exposed to DEP during the prepubertal period. Our metabolomics analysis demonstrates that human level exposure to personal care product ingredients has detectable effects on the rat metabolome. We highlight specific pathways such as sulfonation that warrant further study.

Changes in the Metabolome in Response to Low-Dose Exposure to Environmental Chemicals Used in Personal Care Products during Different Windows of Susceptibility

PubMed Central

Chen, Jia; Belpoggi, Fiorella; Manservisi, Fabiana; Sánchez-Guijo, Alberto; Wudy, Stefan A.; Teitelbaum, Susan L.

2016-01-01

The consequences of ubiquitous exposure to environmental chemicals remain poorly defined. Non-targeted metabolomic profiling is an emerging method to identify biomarkers of the physiological response to such exposures. We investigated the effect of three commonly used ingredients in personal care products, diethyl phthalate (DEP), methylparaben (MPB) and triclosan (TCS), on the blood metabolome of female Sprague-Dawley rats. Animals were treated with low levels of these chemicals comparable to human exposures during prepubertal and pubertal windows as well as chronically from birth to adulthood. Non-targeted metabolomic profiling revealed that most of the variation in the metabolites was associated with developmental stage. The low-dose exposure to DEP, MPB and TCS had a relatively small, but detectable impact on the metabolome. Multiple metabolites that were affected by chemical exposure belonged to the same biochemical pathways including phenol sulfonation and metabolism of pyruvate, lyso-plasmalogens, unsaturated fatty acids and serotonin. Changes in phenol sulfonation and pyruvate metabolism were most pronounced in rats exposed to DEP during the prepubertal period. Our metabolomics analysis demonstrates that human level exposure to personal care product ingredients has detectable effects on the rat metabolome. We highlight specific pathways such as sulfonation that warrant further study. PMID:27467775

Global Transcriptome and Deletome Profiles of Yeast Exposed to Transition Metals

PubMed Central

Jin, Yong Hwan; Dunlap, Paul E.; McBride, Sandra J.; Al-Refai, Hanan; Bushel, Pierre R.; Freedman, Jonathan H.

2008-01-01

A variety of pathologies are associated with exposure to supraphysiological concentrations of essential metals and to non-essential metals and metalloids. The molecular mechanisms linking metal exposure to human pathologies have not been clearly defined. To address these gaps in our understanding of the molecular biology of transition metals, the genomic effects of exposure to Group IB (copper, silver), IIB (zinc, cadmium, mercury), VIA (chromium), and VB (arsenic) elements on the yeast Saccharomyces cerevisiae were examined. Two comprehensive sets of metal-responsive genomic profiles were generated following exposure to equi-toxic concentrations of metal: one that provides information on the transcriptional changes associated with metal exposure (transcriptome), and a second that provides information on the relationship between the expression of ∼4,700 non-essential genes and sensitivity to metal exposure (deletome). Approximately 22% of the genome was affected by exposure to at least one metal. Principal component and cluster analyses suggest that the chemical properties of the metal are major determinants in defining the expression profile. Furthermore, cells may have developed common or convergent regulatory mechanisms to accommodate metal exposure. The transcriptome and deletome had 22 genes in common, however, comparison between Gene Ontology biological processes for the two gene sets revealed that metal stress adaptation and detoxification categories were commonly enriched. Analysis of the transcriptome and deletome identified several evolutionarily conserved, signal transduction pathways that may be involved in regulating the responses to metal exposure. In this study, we identified genes and cognate signaling pathways that respond to exposure to essential and non-essential metals. In addition, genes that are essential for survival in the presence of these metals were identified. This information will contribute to our understanding of the molecular mechanism by which organisms respond to metal stress, and could lead to an understanding of the connection between environmental stress and signal transduction pathways. PMID:18437200

THE INDOOR FUGACITY MODEL

EPA Science Inventory

Dermal and non-dietary pathways are potentially significant exposure pathways to pesticides used in the home. The exposure pathways include dermal contact through the hands and skin, ingestion from hand to mouth activities, ingestion through contact with toys and other items, ...

Application of a framework for extrapolating chemical effects ...

EPA Pesticide Factsheets

Cross-species extrapolation of toxicity data from limited surrogate test organisms to all wildlife with potential of chemical exposure remains a key challenge in ecological risk assessment. A number of factors affect extrapolation, including the chemical exposure, pharmacokinetics, life-stage, and pathway similarities/differences. Here we propose a framework using a tiered approach for species extrapolation that enables a transparent weight-of-evidence driven evaluation of pathway conservation (or lack thereof) in the context of adverse outcome pathways. Adverse outcome pathways describe the linkages from a molecular initiating event, defined as the chemical-biomolecule interaction, through subsequent key events leading to an adverse outcome of regulatory concern (e.g., mortality, reproductive dysfunction). Tier 1 of the extrapolation framework employs in silico evaluations of sequence and structural conservation of molecules (e.g., receptors, enzymes) associated with molecular initiating events or upstream key events. Such evaluations make use of available empirical and sequence data to assess taxonomic relevance. Tier 2 uses in vitro bioassays, such as enzyme inhibition/activation, competitive receptor binding, and transcriptional activation assays to explore functional conservation of pathways across taxa. Finally, Tier 3 provides a comparative analysis of in vivo responses between species utilizing well-established model organisms to assess departure from

Application of Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling in Cumulative Risk Assessment for N-Methyl Carbamate Insecticides

EPA Science Inventory

Human exposure to xenobiotics may occur through multiple pathways and routes of entry punctuated by exposure intervals throughout a work or leisure day. Exposure to a single environmental chemical along multiple pathways and routes (aggregate exposure) may have an influence on an...

DESIGN STRATEGY FOR ASSESSING MULTI-PATHWAY EXPOSURE FOR CHILDREN: THE MINNESOTA CHILDREN'S PESTICIDE EXPOSURE STUDY (MNCPES)

EPA Science Inventory

Although children are exposed to a variety of environmental hazards, including pesticides, there is a scarcity of information available to estimate exposures realistically. This article reports on one of the first attempts to measure multi-pathway pesticide exposures in a popu...

TPhP exposure disturbs carbohydrate metabolism, lipid metabolism, and the DNA damage repair system in zebrafish liver

NASA Astrophysics Data System (ADS)

Du, Zhongkun; Zhang, Yan; Wang, Guowei; Peng, Jianbiao; Wang, Zunyao; Gao, Shixiang

2016-02-01

Triphenyl phosphate is a high production volume organophosphate flame retardant that has been detected in multiple environmental media at increasing concentrations. The environmental and health risks of triphenyl phosphate have drawn attention because of the multiplex toxicity of this chemical compound. However, few studies have paid close attention to the impacts of triphenyl phosphate on liver metabolism. We investigated hepatic histopathological, metabolomic and transcriptomic responses of zebrafish after exposure to 0.050 mg/L and 0.300 mg/L triphenyl phosphate for 7 days. Metabolomic analysis revealed significant changes in the contents of glucose, UDP-glucose, lactate, succinate, fumarate, choline, acetylcarnitine, and several fatty acids. Transcriptomic analysis revealed that related pathways, such as the glycosphingolipid biosynthesis, PPAR signaling pathway and fatty acid elongation, were significantly affected. These results suggest that triphenyl phosphate exposure markedly disturbs hepatic carbohydrate and lipid metabolism in zebrafish. Moreover, DNA replication, the cell cycle, and non-homologous end-joining and base excision repair were strongly affected, thus indicating that triphenyl phosphate hinders the DNA damage repair system in zebrafish liver cells. The present study provides a systematic analysis of the triphenyl phosphate-induced toxic effects in zebrafish liver and demonstrates that low concentrations of triphenyl phosphate affect normal metabolism and cell cycle.

How life stressors influence modifiable lifestyle factors, depressive symptoms, and physical and mental health among Vietnamese older women?

PubMed

Dao-Tran, Tiet-Hanh; Anderson, Debra; Seib, Charrlotte

2017-06-29

Research has demonstrated that exposure to life stressors can influence health through a number of pathways. However, knowledge about the patterns of life stressors and their contributions to health in different populations is limited. Vietnamese older women have attracted little research to date in this area. This cross-sectional study used an interview-administered-questionnaire to collect data from 440 Vietnamese older women. Descriptive analysis was used to describe life stressors among Vietnamese older women. Binary analysis and Structural Equation Modelling statistical analysis were used to examine the influences of life stressors on modifiable lifestyle factors, depressive symptoms, physical and mental health among Vietnamese older women. Vietnamese older women in this study commonly reported the experience of losing a close person, including a baby/child, serious health or money problems, violence and disaster. Among the study participants, (1) exposure to more life stressors increased their depressive symptoms, and decreased their physical and mental health; (2) exposure to more life stressors also increased their physical health by increasing their physical activity levels. Life stressors influenced health among Vietnamese older women through different pathways. Interventions to manage stress and depressive symptoms are required for Vietnamese older women in the future.

TPhP exposure disturbs carbohydrate metabolism, lipid metabolism, and the DNA damage repair system in zebrafish liver

PubMed Central

Du, Zhongkun; Zhang, Yan; Wang, Guowei; Peng, Jianbiao; Wang, Zunyao; Gao, Shixiang

2016-01-01

Triphenyl phosphate is a high production volume organophosphate flame retardant that has been detected in multiple environmental media at increasing concentrations. The environmental and health risks of triphenyl phosphate have drawn attention because of the multiplex toxicity of this chemical compound. However, few studies have paid close attention to the impacts of triphenyl phosphate on liver metabolism. We investigated hepatic histopathological, metabolomic and transcriptomic responses of zebrafish after exposure to 0.050 mg/L and 0.300 mg/L triphenyl phosphate for 7 days. Metabolomic analysis revealed significant changes in the contents of glucose, UDP-glucose, lactate, succinate, fumarate, choline, acetylcarnitine, and several fatty acids. Transcriptomic analysis revealed that related pathways, such as the glycosphingolipid biosynthesis, PPAR signaling pathway and fatty acid elongation, were significantly affected. These results suggest that triphenyl phosphate exposure markedly disturbs hepatic carbohydrate and lipid metabolism in zebrafish. Moreover, DNA replication, the cell cycle, and non-homologous end-joining and base excision repair were strongly affected, thus indicating that triphenyl phosphate hinders the DNA damage repair system in zebrafish liver cells. The present study provides a systematic analysis of the triphenyl phosphate-induced toxic effects in zebrafish liver and demonstrates that low concentrations of triphenyl phosphate affect normal metabolism and cell cycle. PMID:26898711

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

PubMed

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.

Chemical-agnostic hazard prediction: statistical inference of in vitro toxicity pathways from proteomics responses to chemical mixtures

EPA Science Inventory

Toxicity pathways have been defined as normal cellular pathways that, when sufficiently perturbed as a consequence of chemical exposure, lead to an adverse outcome. If an exposure alters one or more normal biological pathways to an extent that leads to an adverse toxicity outcome...

Chemical-agnostic hazard prediction: statistical inference of in ...

EPA Pesticide Factsheets

Toxicity pathways have been defined as normal cellular pathways that, when sufficiently perturbed as a consequence of chemical exposure, lead to an adverse outcome. If an exposure alters one or more normal biological pathways to an extent that leads to an adverse toxicity outcome, a significant correlation must exist between the exposure, the extent of pathway alteration, and the degree of adverse outcome. Biological pathways are regulated at multiple levels, including transcriptional, post-transcriptional, post-translational, and targeted degradation, each of which can affect the levels and extents of modification of proteins involved in the pathways. Significant alterations of toxicity pathways resulting from changes in regulation at any of these levels therefore are likely to be detectable as alterations in the proteome. We hypothesize that significant correlations between exposures, adverse outcomes, and changes in the proteome have the potential to identify putative toxicity pathways, facilitating selection of candidate targets for high throughput screening, even in the absence of a priori knowledge of either the specific pathways involved or the specific agents inducing the pathway alterations. We explored this hypothesis in vitro in BEAS-2B human airway epithelial cells exposed to different concentrations of Ni2+, Cd2+, and Cr6+, alone and in defined mixtures. Levels and phosphorylation status of a variety of signaling pathway proteins and cytokines were

Exposure matrix development for the Libby cohort.

PubMed

Noonan, C W

2006-11-01

The Libby, MT, cohort includes current and former residents with potential historical exposure to asbestos-contaminated vermiculite. This cohort includes individuals with a broad range of exposure experiences and work histories. While both occupational and nonoccupational exposure pathways were found to be relevant in recent investigations of health effects among this cohort, there has not been a comprehensive approach to characterizing these varied exposure pathways. Any approach toward assessing historical exposures among this population must account for three general categories: (1) occupational exposures, (2) residential exposures, and (3) exposures related to a variety of nonoccupational activities thought to be associated with vermiculite/asbestos exposure in this community. First, a job exposure matrix is commonly used in occupational epidemiology to assess historical worker exposures, allowing for the incorporation of numerous occupational categories and weighting factors applied to specific jobs for different time periods. Second, residential exposures can best be quantified by integrating individuals' residential histories with data on environmental asbestos contamination in the community. Previous soil or sediment sampling as well as air modeling could inform estimates of time- and spatial-dependent exposure concentrations for a residential exposure matrix. Finally, exposure opportunities due to nonoccupational activities could be weighted by factors such as time, geography, environmental sampling, and an assessment of the relative importance for each pathway. These three matrices for occupational, residential, and activity exposure pathways could be combined or used separately to provide a more comprehensive and quantitative, or semiquantitative, assessment of individual exposure in future epidemiological studies of this cohort.

Organic UV filters exposure induces the production of inflammatory cytokines in human macrophages.

PubMed

Ao, Junjie; Yuan, Tao; Gao, Li; Yu, Xiaodan; Zhao, Xiaodong; Tian, Ying; Ding, Wenjin; Ma, Yuning; Shen, Zhemin

2018-09-01

Organic ultraviolet (UV) filters, found in many personal care products, are considered emerging contaminants due to growing concerns about potential long-term deleterious effects. We investigated the immunomodulatory effects of four commonly used organic UV filters (2-hydroxy-4-methoxybenzophenone, BP-3; 4-methylbenzylidene camphor, 4-MBC; 2-ethylhexyl 4-methoxycinnamate, EHMC; and butyl-methoxydibenzoylmethane, BDM) on human macrophages. Our results indicated that exposure to these four UV filters significantly increased the production of various inflammatory cytokines in macrophages, particular tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). After exposure to the UV filters, a significant 1.1-1.5 fold increase were found in TNF-α and IL-6 mRNA expression. In addition, both the p38 MAPK and the NF-κB signaling pathways were enhanced 2 to 10 times in terms of phosphorylation after exposure to the UV filters, suggesting that these pathways are involved in the release of TNF-α and IL-6. Molecular docking analysis predicted that all four UV filter molecules would efficiently bind transforming growth factor beta-activated kinase 1 (TAK1), which is responsible for the activation of the p38 MAPK and NF-κB pathways. Our results therefore demonstrate that exposure to the four organic UV filters investigated may alter human immune system function. It provides new clue for the development of asthma or allergic diseases in terms of the environmental pollutants. Copyright © 2018 Elsevier B.V. All rights reserved.

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

USGS Publications Warehouse

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 are the locally endemic Tusayan flameflower Phemeranthus validulus, the long-legged bat Myotis volans, and the Arizona bat Myotis occultus. The most common vertebrate species identified at the mine site included the Mexican spadefoot toad Spea multiplicata, plateau fence lizard Sceloporus tristichus, violetgreen swallow Tachycineta thalassina, pygmy nuthatch Sitta pygmaea, purple martin Progne subis, western bluebird Sialia mexicana, deermouse Peromyscus maniculatus, valley pocket gopher Thomomys bottae, cliff chipmunk Tamias dorsalis, black-tailed jackrabbit Lepus californicus, mule deer Odocoileus hemionus, and elk Cervus canadensis. A limited number of the most common species were collected for contaminant analysis to establish baseline contaminant and radiological concentrations prior to ore extraction. These empirical baseline data will help validate contaminant exposure pathways and potential threats from contaminant exposures to ecological receptors. Resource managers will also be able to use these data to determine the extent to which local species are exposed to chemical and radiation contamination once the mine is operational and producing ore. More broadly, these data could inform resource management decisions on mitigating chemical and radiation exposure of biota at high-grade uranium breccia pipes throughout the Grand Canyon watershed.

Fully Bayesian Analysis of High-throughput Targeted Metabolomics Assays

EPA Science Inventory

High-throughput metabolomic assays that allow simultaneous targeted screening of hundreds of metabolites have recently become available in kit form. Such assays provide a window into understanding changes to biochemical pathways due to chemical exposure or disease, and are usefu...

Peripheral Blood Signatures of Lead Exposure

PubMed Central

LaBreche, Heather G.; Meadows, Sarah K.; Nevins, Joseph R.; Chute, John P.

2011-01-01

Background Current evidence indicates that even low-level lead (Pb) exposure can have detrimental effects, especially in children. We tested the hypothesis that Pb exposure alters gene expression patterns in peripheral blood cells and that these changes reflect dose-specific alterations in the activity of particular pathways. Methodology/Principal Finding Using Affymetrix Mouse Genome 430 2.0 arrays, we examined gene expression changes in the peripheral blood of female Balb/c mice following exposure to per os lead acetate trihydrate or plain drinking water for two weeks and after a two-week recovery period. Data sets were RMA-normalized and dose-specific signatures were generated using established methods of supervised classification and binary regression. Pathway activity was analyzed using the ScoreSignatures module from GenePattern. Conclusions/Significance The low-level Pb signature was 93% sensitive and 100% specific in classifying samples a leave-one-out crossvalidation. The high-level Pb signature demonstrated 100% sensitivity and specificity in the leave-one-out crossvalidation. These two signatures exhibited dose-specificity in their ability to predict Pb exposure and had little overlap in terms of constituent genes. The signatures also seemed to reflect current levels of Pb exposure rather than past exposure. Finally, the two doses showed differential activation of cellular pathways. Low-level Pb exposure increased activity of the interferon-gamma pathway, whereas high-level Pb exposure increased activity of the E2F1 pathway. PMID:21829687

A FUGACITY-BASED INDOOR RESIDENTIAL PESTICIDE FATE MODEL

EPA Science Inventory

Dermal and non-dietary pathways are potentially significant exposure pathways to pesticides used in the home. Exposure pathways include dermal contact of pesticide residues with the hands and skin, ingestion from hand-to-mouth activities, ingestion through contact with toys an...

The injury of fine particulate matter from cooking oil fumes on umbilical cord blood vessels in vitro.

PubMed

Hou, Lijuan; Zhang, Jian; Zhang, Chao; Xu, Yachun; Zhu, Xiaoxia; Yao, Cijiang; Liu, Ying; Li, Tao; Cao, Jiyu

2017-01-01

Cooking oil fumes (COFs) derived PM 2.5 is the major source of indoor air pollution in Asia. For this, a pregnant rat model within different doses of cooking oil fumes (COFs) derived PM 2.5 was established in pregnancy in our research. Our previous studies have showed that exposure to COFs-derived PM 2.5 was related to adverse pregnancy outcomes. However, the mechanisms of signaling pathways remain unknown. Therefore, this study aimed to investigate the underlying mechanisms induced by COFs-derived PM2.5 injury on umbilical cord blood vessels (UCs) in vitro. Exposure to COFs-derived PM 2.5 resulted in changing the expression of eNOS, ET-1, ETRA, and ETRB. In additions, western blot analysis indicated that the HIF-1α/iNOS/NO signaling pathway and VEGF/VEGFR1/iNOS signaling pathway were involved in UCs injury triggered by COFs-derived PM 2.5 . In conclusion, our data suggested that exposure to COFs-derived PM 2.5 resulted in increasing of oxidative stress and inflammation, as well as dysfunction of UCs. Copyright © 2016 Elsevier B.V. All rights reserved.

Metagenomic insights into the effect of oxytetracycline on microbial structures, functions and functional genes in sediment denitrification.

PubMed

Zou, Yong; Lin, Manxia; Xiong, Wenguang; Wang, Mei; Zhang, Jiaxuan; Wang, Mianzhi; Sun, Yongxue

2018-06-02

Denitrification is an indispensable pathway of nitrogen removal in aquatic ecosystems, and plays an important role in decreasing eutrophication induced by excessive reactive nitrogen pollution. Aquatic environments also suffer from antibiotic pollution due to runoff from farms and sewage systems. The aim of this study was to investigate the effect of oxytetracycline stress on denitrifying functional genes, the microbial community and metabolic pathways in sediments using high-throughput sequencing and metagenomic analysis. The oxytetracycline was observed to significantly inhibit the abundance of nirK and nosZ genes (P < 0.001). KEGG pathway annotation indicated that oxytetracycline treatment decreased the abundance of nitrate reductase, nitrite reductase and N 2 O reductase. Functional annotations revealed that oxytetracycline exposure decreased the abundance of the protein metabolism subsystem in the bacterial community. Metagenomic sequencing demonstrated that the abundance of Proteobacteria and Firmicutes increased with oxytetracycline exposure while the Actinobacteria decreased. In sediments, Pseudomonas and Bradyrhizobium were major contributors to denitrification and oxytetracycline exposure resulted in a decreased abundance of Bradyrhizobium. These results indicated that oxytetracycline residues influences the denitrifier community and may heighten occurrence of reactive nitrogen in aquatic ecosystems. Copyright © 2018. Published by Elsevier Inc.

Divergent Effects of Arsenic on NF-κB Signaling in Different Cells or Tissues: A Systematic Review and Meta-Analysis.

PubMed

Wei, Meng; Liu, Jiaming; Xu, Mengchuan; Rui, Dongsheng; Xu, Shangzhi; Feng, Gangling; Ding, Yusong; Li, Shugang; Guo, Shuxia

2016-01-26

Arsenic is ubiquitously present in human lives, including in the environment and organisms, and has divergent effects between different cells and tissues and between different exposure times and doses. These observed effects have been attributed to the nuclear transcription factor kappa B(NF-κB) signaling pathway. Herein, a meta-analysis was performed by independently searching databases including the Cochrane Library, PubMed, Springer, Embase, and China National Knowledge Infrastructure, to analyze effects of arsenic exposure on NF-κB signaling. Compared to controls, in the exposed group, p-IκB levels were found to be 8.13-fold higher (95% CI, 2.40-13.85; Z = 2.78; p = 0.005), IκB levels were 16.19-fold lower (95% CI, -27.44--4.94; Z = 2.78; p = 0.005), and NF-κBp65 levels were 0.77-fold higher (95% CI, 0.13-1.42; Z = 2.34; p = 0.02) for normal cells and tissue, while NF-κBp65 levels were 4.90-fold lower (95% CI, -8.49-1.31; Z = 2.62; p = 0.009), NF-κB activity was 2.45-fold lower (95% CI, -3.66-1.25; Z = 4.00; p < 0.0001), and DNA-binding activity of NF-κB was 9.75-fold lower (95% CI, -18.66-4.54; Z = 2.15; p = 0.03) for abnormal cells and tissue. Short exposure to high arsenic doses activated the NF-κB signaling pathway, while long exposure to low arsenic doses suppressed NF-κB signaling pathway activation. These findings may provide a theoretical basis for injurious and therapeutic mechanisms of divergent effects of arsenic.

Effects of Acute Prenatal Exposure to Ethanol on microRNA Expression are Ameliorated by Social Enrichment

PubMed Central

Ignacio, Cherry; Mooney, Sandra M.; Middleton, Frank A.

2014-01-01

Fetal alcohol spectrum disorders (FASDs) are associated with abnormal social behavior. These behavioral changes may resemble those seen in autism. Rats acutely exposed to ethanol on gestational day 12 show decreased social motivation at postnatal day 42. We previously showed that housing these ethanol-exposed rats with non-exposed controls normalized this deficit. The amygdala is critical for social behavior and regulates it, in part, through connections with the basal ganglia, particularly the ventral striatum. MicroRNAs (miRNAs) are short, hairpin-derived RNAs that repress mRNA expression. Many brain disorders, including FASD, show dysregulation of miRNAs. In this study, we tested if miRNA and mRNA networks are altered in the amygdala and ventral striatum as a consequence of prenatal ethanol exposure and show any evidence of reversal as a result of social enrichment. RNA samples from two different brain regions in 72 male and female adolescent rats were analyzed by RNA-Seq and microarray analysis. Several miRNAs showed significant changes due to prenatal ethanol exposure and/or social enrichment in one or both brain regions. The top predicted gene targets of these miRNAs were mapped and subjected to pathway enrichment analysis. Several miRNA changes caused by ethanol were reversed by social enrichment, including mir-204, mir-299a, miR-384-5p, miR-222-3p, miR-301b-3p, and mir-6239. Moreover, enriched gene networks incorporating the targets of these miRNAs also showed reversal. We also extended our previously published mRNA expression analysis by directly examining all annotated brain-related canonical pathways. The additional pathways that were most strongly affected at the mRNA level included p53, CREB, glutamate, and GABA signaling. Together, our data suggest a number of novel epigenetic mechanisms for social enrichment to reverse the effects of ethanol exposure through widespread influences on gene expression. PMID:25309888

Prenatal arsenic exposure and the epigenome: altered microRNAs associated with innate and adaptive immune signaling in newborn cord blood

PubMed Central

Rager, Julia E.; Bailey, Kathryn A.; Smeester, Lisa; Miller, Sloane K.; Parker, Joel S.; Laine, Jessica E.; Drobná, Zuzana; Currier, Jenna; Douillet, Christelle; Olshan, Andrew F.; Rubio-Andrade, Marisela; Stýblo, Miroslav; García-Vargas, Gonzalo; Fry, Rebecca C.

2014-01-01

The Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Gómez Palacio, Mexico was recently established to better understand the impacts of prenatal exposure to inorganic arsenic (iAs). In the present study, we examined a subset (n=40) of newborn cord blood samples for microRNA (miRNA) expression changes associated with in utero arsenic exposure. Levels of iAs in maternal drinking water (DW-iAs) and maternal urine were assessed. Levels of DW-iAs ranged from below detectable values to 236 μg/L (mean=51.7 μg/L). Total arsenic in maternal urine (U-tAs) was defined as the sum of iAs and its monomethylated and dimethylated metabolites (MMAs and DMAs, respectively) and ranged from 6.2 to 319.7 μg/L (mean=64.5 μg/L). Genome-wide miRNA expression analysis of cord blood revealed 12 miRNAs with increasing expression associated with U-tAs. Transcriptional targets of the miRNAs were computationally predicted and subsequently assessed using transcriptional profiling. Pathway analysis demonstrated that the U-tAs-associated miRNAs are involved in signaling pathways related to known health outcomes of iAs exposure including cancer and diabetes mellitus. Immune response-related mRNAs were also identified with decreased expression levels associated with U-tAs, and predicted to be mediated in part by the arsenic-responsive miRNAs. Results of this study highlight miRNAs as novel responders to prenatal arsenic exposure that may contribute to associated immune response perturbations. PMID:24327377

Exposure to nicotine increases nicotinic acetylcholine receptor density in the reward pathway and binge ethanol consumption in C57BL/6J adolescent female mice.

PubMed

Locker, Alicia R; Marks, Michael J; Kamens, Helen M; Klein, Laura Cousino

2016-05-01

Nearly 80% of adult smokers begin smoking during adolescence. Binge alcohol consumption is also common during adolescence. Past studies report that nicotine and ethanol activate dopamine neurons in the reward pathway and may increase synaptic levels of dopamine in the nucleus accumbens through nicotinic acetylcholine receptor (nAChR) stimulation. Activation of the reward pathway during adolescence through drug use may produce neural alterations affecting subsequent drug consumption. Consequently, the effect of nicotine exposure on binge alcohol consumption was examined along with an assessment of the neurobiological underpinnings that drive adolescent use of these drugs. Adolescent C57BL/6J mice (postnatal days 35-44) were exposed to either water or nicotine (200μg/ml) for ten days. On the final four days, ethanol intake was examined using the drinking-in-the-dark paradigm. Nicotine-exposed mice consumed significantly more ethanol and displayed higher blood ethanol concentrations than did control mice. Autoradiographic analysis of nAChR density revealed higher epibatidine binding in frontal cortical regions in mice exposed to nicotine and ethanol compared to mice exposed to ethanol only. These data show that nicotine exposure during adolescence increases subsequent binge ethanol consumption, and may affect the number of nAChRs in regions of the brain reward pathway, specifically the frontal cortex. Published by Elsevier Inc.

20171015 - Predicting Exposure Pathways with Machine Learning (ISES)

EPA Science Inventory

Prioritizing the risk posed to human health from the thousands of chemicals in the environment requires tools that can estimate exposure rates from limited information. High throughput models exist to make predictions of exposure via specific, important pathways such as residenti...

Children’s Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making

PubMed Central

Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

2017-01-01

Background: Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)’s National Drinking Water Advisory Council (NDWAC) recommended establishment of a “health-based, household action level” for lead in drinking water based on children’s exposure. Objectives: The primary objective was to develop a coupled exposure–dose modeling approach that can be used to determine what drinking water lead concentrations keep children’s blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. Methods: A modeling approach using the EPA’s Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Results: Modeled BLLs compared well with nationally representative BLLs (0–23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. Conclusions: This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605 PMID:28934096

Monoethylhexyl Phthalate Elicits an Inflammatory Response in Adipocytes Characterized by Alterations in Lipid and Cytokine Pathways

PubMed Central

Manteiga, Sara; Lee, Kyongbum

2016-01-01

Background: A growing body of evidence links endocrine-disrupting chemicals (EDCs) with obesity-related metabolic diseases. While it has been shown that EDCs can predispose individuals toward adiposity by affecting developmental processes, little is known about the chemicals’ effects on adult adipose tissue. Objectives: Our aim was to study the effects of low, physiologically relevant doses of EDCs on differentiated murine adipocytes. Methods: We combined metabolomics, proteomics, and gene expression analysis to characterize the effects of mono-ethylhexyl phthalate (MEHP) in differentiated adipocytes. Results: Repeated exposure to MEHP over several days led to changes in metabolite and enzyme levels indicating elevated lipogenesis and lipid oxidation. The chemical exposure also increased expression of major inflammatory cytokines, including chemotactic factors. Proteomic and gene expression analysis revealed significant alterations in pathways regulated by peroxisome proliferator activated receptor-γ (PPARγ). Inhibiting the nuclear receptor’s activity using a chemical antagonist abrogated not only the alterations in PPARγ-regulated metabolic pathways, but also the increases in cytokine expression. Conclusions: Our results show that MEHP can induce a pro-inflammatory state in differentiated adipocytes. This effect is at least partially mediated PPARγ. Citation: Manteiga S, Lee K. 2017. Monoethylhexyl phthalate elicits an inflammatory response in adipocytes characterized by alterations in lipid and cytokine pathways. Environ Health Perspect 125:615–622; http://dx.doi.org/10.1289/EHP464 PMID:27384973

Central insulin signaling is attenuated by long-term insulin exposure via insulin receptor substrate-1 serine phosphorylation, proteasomal degradation, and lysosomal insulin receptor degradation.

PubMed

Mayer, Christopher M; Belsham, Denise D

2010-01-01

Central insulin signaling is critical for the prevention of insulin resistance. Hyperinsulinemia contributes to insulin resistance, but it is not yet clear whether neurons are subject to cellular insulin resistance. We used an immortalized, hypothalamic, clonal cell line, mHypoE-46, which exemplifies neuronal function and expresses the components of the insulin signaling pathway, to determine how hyperinsulinemia modifies neuronal function. Western blot analysis indicated that prolonged insulin treatment of mHypoE-46 cells attenuated insulin signaling through phospho-Akt. To understand the mechanisms involved, time-course analysis was performed. Insulin exposure for 4 and 8 h phosphorylated Akt and p70-S6 kinase (S6K1), whereas 8 and 24 h treatment decreased insulin receptor (IR) and IR substrate 1 (IRS-1) protein levels. Insulin phosphorylation of S6K1 correlated with IRS-1 ser1101 phosphorylation and the mTOR-S6K1 pathway inhibitor rapamycin prevented IRS-1 serine phosphorylation. The proteasomal inhibitor epoxomicin and the lysosomal pathway inhibitor 3-methyladenine prevented the degradation of IRS-1 and IR by insulin, respectively, and pretreatment with rapamycin, epoxomicin, or 3-methyladenine prevented attenuation of insulin signaling by long-term insulin exposure. Thus, a sustained elevation of insulin levels diminishes neuronal insulin signaling through mTOR-S6K1-mediated IRS-1 serine phosphorylation, proteasomal degradation of IRS-1 and lysosomal degradation of the IR.

10 CFR 50.47 - Emergency plans.

Code of Federal Regulations, 2014 CFR

2014-01-01

... to the populace within the plume exposure pathway Emergency Planning Zone have been established. (6... has been developed for the plume exposure pathway EPZ for emergency workers and the public. In... pathway EPZ appropriate to the locale have been developed. (11) Means for controlling radiological...

10 CFR 50.47 - Emergency plans.

Code of Federal Regulations, 2013 CFR

2013-01-01

... to the populace within the plume exposure pathway Emergency Planning Zone have been established. (6... has been developed for the plume exposure pathway EPZ for emergency workers and the public. In... pathway EPZ appropriate to the locale have been developed. (11) Means for controlling radiological...

10 CFR 50.47 - Emergency plans.

Code of Federal Regulations, 2012 CFR

2012-01-01

... to the populace within the plume exposure pathway Emergency Planning Zone have been established. (6... has been developed for the plume exposure pathway EPZ for emergency workers and the public. In... pathway EPZ appropriate to the locale have been developed. (11) Means for controlling radiological...

Semi-quantitative proteomics of mammalian cells upon short-term exposure to non-ionizing electromagnetic fields.

PubMed

Kuzniar, Arnold; Laffeber, Charlie; Eppink, Berina; Bezstarosti, Karel; Dekkers, Dick; Woelders, Henri; Zwamborn, A Peter M; Demmers, Jeroen; Lebbink, Joyce H G; Kanaar, Roland

2017-01-01

The potential effects of non-ionizing electromagnetic fields (EMFs), such as those emitted by power-lines (in extremely low frequency range), mobile cellular systems and wireless networking devices (in radio frequency range) on human health have been intensively researched and debated. However, how exposure to these EMFs may lead to biological changes underlying possible health effects is still unclear. To reveal EMF-induced molecular changes, unbiased experiments (without a priori focusing on specific biological processes) with sensitive readouts are required. We present the first proteome-wide semi-quantitative mass spectrometry analysis of human fibroblasts, osteosarcomas and mouse embryonic stem cells exposed to three types of non-ionizing EMFs (ELF 50 Hz, UMTS 2.1 GHz and WiFi 5.8 GHz). We performed controlled in vitro EMF exposures of metabolically labeled mammalian cells followed by reliable statistical analyses of differential protein- and pathway-level regulations using an array of established bioinformatics methods. Our results indicate that less than 1% of the quantitated human or mouse proteome responds to the EMFs by small changes in protein abundance. Further network-based analysis of the differentially regulated proteins did not detect significantly perturbed cellular processes or pathways in human and mouse cells in response to ELF, UMTS or WiFi exposure. In conclusion, our extensive bioinformatics analyses of semi-quantitative mass spectrometry data do not support the notion that the short-time exposures to non-ionizing EMFs have a consistent biologically significant bearing on mammalian cells in culture.

Semi-quantitative proteomics of mammalian cells upon short-term exposure to non-ionizing electromagnetic fields

PubMed Central

Laffeber, Charlie; Eppink, Berina; Bezstarosti, Karel; Dekkers, Dick; Woelders, Henri; Zwamborn, A. Peter M.; Demmers, Jeroen; Lebbink, Joyce H. G.; Kanaar, Roland

2017-01-01

The potential effects of non-ionizing electromagnetic fields (EMFs), such as those emitted by power-lines (in extremely low frequency range), mobile cellular systems and wireless networking devices (in radio frequency range) on human health have been intensively researched and debated. However, how exposure to these EMFs may lead to biological changes underlying possible health effects is still unclear. To reveal EMF-induced molecular changes, unbiased experiments (without a priori focusing on specific biological processes) with sensitive readouts are required. We present the first proteome-wide semi-quantitative mass spectrometry analysis of human fibroblasts, osteosarcomas and mouse embryonic stem cells exposed to three types of non-ionizing EMFs (ELF 50 Hz, UMTS 2.1 GHz and WiFi 5.8 GHz). We performed controlled in vitro EMF exposures of metabolically labeled mammalian cells followed by reliable statistical analyses of differential protein- and pathway-level regulations using an array of established bioinformatics methods. Our results indicate that less than 1% of the quantitated human or mouse proteome responds to the EMFs by small changes in protein abundance. Further network-based analysis of the differentially regulated proteins did not detect significantly perturbed cellular processes or pathways in human and mouse cells in response to ELF, UMTS or WiFi exposure. In conclusion, our extensive bioinformatics analyses of semi-quantitative mass spectrometry data do not support the notion that the short-time exposures to non-ionizing EMFs have a consistent biologically significant bearing on mammalian cells in culture. PMID:28234898

Hepatic expression of the GH/JAK/STAT/IGF pathway, acute-phase response signalling and complement system are affected in mouse offspring by prenatal and early postnatal exposure to maternal high-protein diet.

PubMed

Vanselow, Jens; Kucia, Marzena; Langhammer, Martina; Koczan, Dirk; Rehfeldt, Charlotte; Metges, Cornelia C

2011-12-01

Effects of pre- and early postnatal exposure to maternal high-protein diets are not well understood. Transcription profiling was performed in male mouse offspring exposed to maternal high-protein diet during pregnancy and/or lactation to identify affected hepatic molecular pathways. Dams were fed isoenergetic diets with control (20% w/w) or high protein levels (40%). The hepatic expression profiles were evaluated by differential microarray analysis 3 days (d3) and 3 weeks (d21) after birth. Offspring from three different high-protein dietary groups, HP (d3, high-protein diet during pregnancy), HPHP (d21, high-protein diet during pregnancy and lactation) and CHP (d21, control diet during pregnancy and high-protein diet during lactation), were compared with age-matched offspring from dams fed control diet. Offspring body and liver mass of all high-protein groups were decreased. Prenatal high-protein diet affected hepatic expression of genes mapping to the acute response/complement system and the GH/JAK/STAT/IGF signalling pathways. Maternal exposure to high-protein diet during lactation affected hepatic gene expression of the same pathways but additionally affected genes mapping to protein, fatty acid, hexose and pyruvate metabolism. (1) Genes of the acute response/complement system and GH/JAK/STAT/IGF pathways were down-regulated in offspring of dams exposed to high-protein diets during pregnancy and/or lactation. (2) Genes related to nutrient and energy metabolism, however, were only affected when high-protein diet was administered during lactation. (3) Modulation of the GH/JAK/STAT/IGF pathway might be responsible for reduced body and liver masses by maternal high-protein diet.

Endocrine-disrupting chemicals-Mechanisms of action on male reproductive system.

PubMed

Sidorkiewicz, Iwona; Zaręba, Kamil; Wołczyński, Sławomir; Czerniecki, Jan

2017-07-01

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that can cause disturbances in the endocrine system and have multiple harmful effects on health by targeting different organs and systems in the human body. Mass industrial production and widespread use of EDCs have resulted in worldwide contamination. Accumulating evidence suggest that human exposure to EDCs is related to the impairment of male reproductive function and can interrupt other hormonally regulated metabolic processes, particularly if exposure occurs during early development. Investigation of studies absent in previous reviews and meta-analysis of adverse effects of EDCs on functioning of the male reproductive system is the core of this work. Four main modes of action of EDCs on male fertility have been summarized in this review. First, studies describing estrogen- pathway disturbing chemicals are investigated. Second, androgen-signaling pathway alterations and influence on androgen sensitive tissues are examined. Third, evaluation of steroidogenesis dysfunction is discussed by focusing on the steroid hormone biosynthesis pathway, which is targeted by EDCs. Last, the reportedly destructive role of reactive oxygen species (ROS) on sperm function is discussed. Spermatogenesis is a remarkably complex process, hence multiple studies point out various dysfunctions depending on the development state at which the exposure occurred. Collected data show the need to account for critical windows of exposure such as fetal, perinatal and pubertal periods as well as effects of mixtures of several compounds in future research.

Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure

PubMed Central

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 four airborne concentration ranges (from <1 ppm to >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. PMID:24786086

Approaches to Children’s Exposure Assessment: Case Study with Diethylhexylphthalate (DEHP)

PubMed Central

Ginsberg, Gary; Ginsberg, Justine; Foos, Brenda

2016-01-01

Children’s exposure assessment is a key input into epidemiology studies, risk assessment and source apportionment. The goals of this article are to describe a methodology for children’s exposure assessment that can be used for these purposes and to apply the methodology to source apportionment for the case study chemical, diethylhexylphthalate (DEHP). A key feature is the comparison of total (aggregate) exposure calculated via a pathways approach to that derived from a biomonitoring approach. The 4-step methodology and its results for DEHP are: (1) Prioritization of life stages and exposure pathways, with pregnancy, breast-fed infants, and toddlers the focus of the case study and pathways selected that are relevant to these groups; (2) Estimation of pathway-specific exposures by life stage wherein diet was found to be the largest contributor for pregnant women, breast milk and mouthing behavior for the nursing infant and diet, house dust, and mouthing for toddlers; (3) Comparison of aggregate exposure by pathways vs biomonitoring-based approaches wherein good concordance was found for toddlers and pregnant women providing confidence in the exposure assessment; (4) Source apportionment in which DEHP presence in foods, children’s products, consumer products and the built environment are discussed with respect to early life mouthing, house dust and dietary exposure. A potential fifth step of the method involves the calculation of exposure doses for risk assessment which is described but outside the scope for the current case study. In summary, the methodology has been used to synthesize the available information to identify key sources of early life exposure to DEHP. PMID:27376320

Pathways to Aggression in Urban Elementary School Youth

ERIC Educational Resources Information Center

Ozkol, Hivren; Zucker, Marla; Spinazzola, Joseph

2011-01-01

This study examined the pathways from violence exposure to aggressive behaviors in urban, elementary school youth. We utilized structural equation modeling to examine putative causal pathways between children's exposure to violence, development of posttraumatic stress symptoms, permissive attitudes towards violence, and engagement in aggressive…

The Screening of Genes Sensitive to Long-Term, Low-Level Microwave Exposure and Bioinformatic Analysis of Potential Correlations to Learning and Memory.

PubMed

Zhao, Ya Li; Li, Ying Xian; Ma, Hong Bo; Li, Dong; Li, Hai Liang; Jiang, Rui; Kan, Guang Han; Yang, Zhen Zhong; Huang, Zeng Xin

2015-08-01

To gain a better understanding of gene expression changes in the brain following microwave exposure in mice. This study hopes to reveal mechanisms contributing to microwave-induced learning and memory dysfunction. Mice were exposed to whole body 2100 MHz microwaves with specific absorption rates (SARs) of 0.45 W/kg, 1.8 W/kg, and 3.6 W/kg for 1 hour daily for 8 weeks. Differentially expressing genes in the brains were screened using high-density oligonucleotide arrays, with genes showing more significant differences further confirmed by RT-PCR. The gene chip results demonstrated that 41 genes (0.45 W/kg group), 29 genes (1.8 W/kg group), and 219 genes (3.6 W/kg group) were differentially expressed. GO analysis revealed that these differentially expressed genes were primarily involved in metabolic processes, cellular metabolic processes, regulation of biological processes, macromolecular metabolic processes, biosynthetic processes, cellular protein metabolic processes, transport, developmental processes, cellular component organization, etc. KEGG pathway analysis showed that these genes are mainly involved in pathways related to ribosome, Alzheimer's disease, Parkinson's disease, long-term potentiation, Huntington's disease, and Neurotrophin signaling. Construction of a protein interaction network identified several important regulatory genes including synbindin (sbdn), Crystallin (CryaB), PPP1CA, Ywhaq, Psap, Psmb1, Pcbp2, etc., which play important roles in the processes of learning and memorye. Long-term, low-level microwave exposure may inhibit learning and memory by affecting protein and energy metabolic processes and signaling pathways relating to neurological functions or diseases. Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Pathways of inhalation exposure to manganese in children ...

EPA Pesticide Factsheets

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

Exposure and Dosimetry Considerations for Adverse Outcome Pathways (AOPs) (NIH-AOP)

EPA Science Inventory

Risk is a function of both of hazard and exposure. Toxicokinetic (TK) models can determine whether chemical exposures produce potentially hazardous tissue concentrations. Whether or not the initial molecular event (MIE) in an Adverse Outcome Pathway (AOP) occurs depends on both e...

Transcriptomic profiling of chemical exposure reveals roles of Yap1 in protecting yeast cells from oxidative and other types of stresses.

PubMed

Zhang, Chao; Li, Zhouquan; Zhang, Xiaohua; Yuan, Li; Dai, Heping; Xiao, Wei

2016-01-01

Transcriptomic profiles are generated by comparing wild-type and the yeast yap1 mutant to various chemicals in an attempt to establish a correlation between this gene mutation and chemical exposure. Test chemicals include ClonNAT as a non-genotoxic agent, methyl methanesulphonate (MMS) as an alkylating agent, tert-butyl hydroperoxide (t-BHP) as an oxidative agent and the mixture of t-BHP and MMS to reflect complex natural exposure. Differentially expressed genes (DEGs) were identified and specific DEGs were obtained by excluding overlapping DEGs with the control group. In the MMS exposure group, deoxyribonucleotide biosynthetic processes were upregulated, while oxidation-reduction processes were downregulated. In the t-BHP exposure group, metabolic processes were upregulated while peroxisome and ion transport pathways were downregulated. In the mixture exposure group, the proteasome pathway was upregulated, while the aerobic respiration was downregulated. Homologue analysis of DEGs related to human diseases showed that many of DEGs were linked to cancer, ageing and neuronal degeneration. These observations confirm that the yap1 mutant is more sensitive to chemicals than wild-type cells and that the susceptible individuals carrying the YAP1-like gene defect may enhance risk to chemical exposure. Hence, this study offers a novel approach to environmental risk assessment, based on the genetic backgrounds of susceptible individuals. Copyright © 2015 John Wiley & Sons, Ltd.

INDIRECT EXPOSURE ASSESSMENT AT THE UNITED STATES ENRONMENTAL PROTECTION AGENCY

EPA Science Inventory

In the early 1980s, expousres and subsequent health impact assessments from contaminants emitted into the air from stationary sources focused on the inhalation pathway. This 'direct' pathway of exposure was thought to be the most critical pathway, as it is for many contaminants. ...

Transplacental exposure to environmental carcinogens: Association with childhood cancer risks and the role of modulating factors.

PubMed

Fucic, A; Guszak, V; Mantovani, A

2017-09-01

Biological responses to carcinogens from environmental exposure during adulthood are modulated over years or decades. Conversely, during transplacental exposure, the effects on the human foetus change within weeks, intertwining with developmental mechanisms: even short periods of transplacental exposure may be imprinted in the organism for a lifetime. The pathways leading to childhood and juvenile cancers, such as leukaemias, neuroblastoma/brain tumours, hepatoblastoma, and Willm's tumour involve prenatally-induced genomic, epigenomic and/or non-genomic effects caused by xenobiotics. Pregnant women most often live in complex environmental settings that cause transplacental exposure of the foetus to xenobiotic mixtures. Mother-child biomonitoring should integrate the analysis of chemicals/radiation present in the living and workplace environment with relevant risk modulators related to life style. The interdisciplinary approach for transplacental cancer risk assessment in high-pressure areas should be based on an integrated model for mother-child exposure estimation via profiling the exposure level by water quality analysis, usage of emission grids, and land use maps. Copyright © 2017. Published by Elsevier Inc.

Transcriptome sequencing reveals e-cigarette vapor and mainstream-smoke from tobacco cigarettes activate different gene expression profiles in human bronchial epithelial cells

PubMed Central

Shen, Yifei; Wolkowicz, Michael J.; Kotova, Tatyana; Fan, Lonjiang; Timko, Michael P.

2016-01-01

Electronic cigarettes (e-cigarettes) generate an aerosol vapor (e-vapor) thought to represent a less risky alternative to main stream smoke (MSS) of conventional tobacco cigarettes. RNA-seq analysis was used to examine the transcriptomes of differentiated human bronchial epithelial (HBE) cells exposed to air, MSS from 1R5F tobacco reference cigarettes, and e-vapor with and without added nicotine in an in vitro air-liquid interface model for cellular exposure. Our results indicate that while e-vapor does not elicit many of the cell toxicity responses observed in MSS-exposed HBE cells, e-vapor exposure is not benign, but elicits discrete transcriptomic signatures with and without added nicotine. Among the cellular pathways with the most significantly enriched gene expression following e-vapor exposure are the phospholipid and fatty acid triacylglycerol metabolism pathways. Our data suggest that alterations in cellular glycerophopholipid biosynthesis are an important consequences of e-vapor exposure. Moreover, the presence of nicotine in e-vapor elicits a cellular response distinct from e-vapor alone including alterations of cytochrome P450 function, retinoid metabolism, and nicotine catabolism. These studies establish a baseline for future analysis of e-vapor and e-vapor additives that will better inform the FDA and other governmental bodies in discussions of the risks and future regulation of these products. PMID:27041137

Genetic variants in endotoxin signalling pathway, domestic endotoxin exposure and asthma exacerbations.

PubMed

Kljaic-Bukvic, Blazenka; Blekic, Mario; Aberle, Neda; Curtin, John A; Hankinson, Jenny; Semic-Jusufagic, Aida; Belgrave, Danielle; Simpson, Angela; Custovic, Adnan

2014-10-01

We investigated the interaction between genetic variants in endotoxin signalling pathway and domestic endotoxin exposure in relation to asthma presence, and amongst children with asthma, we explored the association of these genetic variants and endotoxin exposure with hospital admissions due to asthma exacerbations. In a case-control study, we analysed data from 824 children (417 asthmatics, 407 controls; age 5-18 yr). Amongst asthmatics, we extracted data on hospitalization for asthma exacerbation from medical records. Endotoxin exposure was measured in dust samples collected from homes. We included 26 single-nucleotide polymorphisms (SNPs) in the final analysis (5 CD14, 7LY96 and 14 TLR4). Two variants remained significantly associated with hospital admissions with asthma exacerbations after correction for multiple testing: for CD14 SNP rs5744455, carriers of T allele had decreased risk of repeated hospital admissions compared with homozygotes for C allele [OR (95% CI), 0.42 (0.25-0.88), p = 0.01, False Discovery Rate (FDR) p = 0.02]; for LY96 SNP rs17226566, C-allele carriers were at a lower risk of hospital admissions compared with T-allele homozygotes [0.59 (0.38-0.90), p = 0.01, FDR p = 0.04]. We observed two interactions between SNPs in CD14 and LY96 with environmental endotoxin exposure in relation to hospital admissions due to asthma exacerbation which remained significant after correction for multiple testing (CD14 SNPs rs2915863 and LY96 SNP rs17226566). Amongst children with asthma, genetic variants in CD14 and LY96 may increase the risk of hospital admissions with acute exacerbations. Polymorphisms in endotoxin pathway interact with domestic endotoxin exposure in further modification of the risk of hospitalization. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Gene expression profile in circulating mononuclear cells after exposure to ultrafine carbon particles

PubMed Central

Huang, Yuh-Chin T.; Schmitt, Michael; Yang, Zhonghui; Que, Loretta G.; Stewart, Judith C.; Frampton, Mark W.; Devlin, Robert B.

2013-01-01

Context Exposure to particulate matter (PM) is associated with systemic health effects, but the cellular and molecular mechanisms are unclear. Objective We hypothesized that, if circulating mononuclear cells play an important role in mediating systemic effects of PM, they would show gene expression changes following exposure. Materials and methods Peripheral blood samples were collected before (0 hour) and at 24 hours after exposure from healthy subjects who participated in previous controlled exposures to ultrafine carbon particles (UFP, 50 μg/m3) or filtered air (FA)(n = 3 each). RNA from mononuclear cell fraction (>85% lymphocytes) was extracted, amplified and hybridized to Affymetrix HU133 plus 2 microarrays. Results We identified 1713 genes (UFP 24 hours vs. FA 0 and 24 hours, p < 0.05, FDR 0.01). The top 10 upregulated genes (fold) were CDKN1C (1.86), ZNF12 (1.83), SRGAP2 (1.82), FYB (1.79), LSM14B (1.79), CD93 (1.76), NCSTN (1.70), DUSP6 (1.69), TACC1 (1.68) and H2AFY (1.68). Upregulation of CDKN1C and SRGAP2 was confirmed by RT-PCR using samples from additional 5 subjects exposed to FA and UFP. We entered 1020 genes with a ratio >1.1 or <−1.1 into the Ingenuity Pathway Analysis and identified many canonical pathways related to inflammation, tissue growth and host defense against environmental insults, including IGF-1 signaling, insulin receptor signaling and NRF2-mediated oxidative stress response pathway. Discussion and conclusions Two-hour exposures to UFP produced gene expression changes in circulating mononuclear cells. These gene changes provide biologically plausible links to PM-induced systemic health effects, especially those in the cardiovascular system and glucose metabolism. PMID:20507211

Global Metabolomic Profiling Reveals an Association of Metal Fume Exposure and Plasma Unsaturated Fatty Acids

PubMed Central

Chang, Chiung-yu; Fan, Tianteng; Su, Li; Chen, Feng; Christiani, David C.

2013-01-01

Background Welding-associated air pollutants negatively affect the health of exposed workers; however, their molecular mechanisms in causing disease remain largely unclear. Few studies have systematically investigated the systemic toxic effects of welding fumes on humans. Objectives To explore the effects of welding fumes on the plasma metabolome, and to identify biomarkers for risk assessment of welding fume exposure. Methods The two-stage, self-controlled exploratory study included 11 boilermakers from a 2011 discovery panel and 8 boilermakers from a 2012 validation panel. Plasma samples were collected pre- and post-welding fume exposure and analyzed by chromatography/mass spectrometry. Results Eicosapentaenoic or docosapentaenoic acid metabolic changes post-welding were significantly associated with particulate (PM2.5) exposure (p<0.05). The combined analysis by linear mixed-effects model showed that exposure was associated with a statistically significant decline in metabolite change of eicosapentaenoic acid [(95% CI) = −0.013(−0.022∼−0.004); p = 0.005], docosapentaenoic acid n3 [(95% CI) = −0.010(−0.018∼−0.002); p = 0.017], and docosapentaenoic acid n6 [(95% CI) = −0.007(−0.013∼−0.001); p = 0.021]. Pathway analysis identified an association of the unsaturated fatty acid pathway with exposure (p Study−2011 = 0.025; p Study−2012 = 0.021; p Combined = 0.009). The functional network built by these fatty acids and their interactive genes contained significant enrichment of genes associated with various diseases, including neoplasms, cardiovascular diseases, and lipid metabolism disorders. Conclusions High-dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. This alteration in fatty acids is a potential biological mediator and biomarker for exposure-related health disorders. PMID:24143234

The Global Food System as a Transport Pathway for Hazardous Chemicals: The Missing Link between Emissions and Exposure

PubMed Central

Ng, Carla A.; von Goetz, Natalie

2016-01-01

Background: Food is a major pathway for human exposure to hazardous chemicals. The modern food system is becoming increasingly complex and globalized, but models for food-borne exposure typically assume locally derived diets or use concentrations directly measured in foods without accounting for food origin. Such approaches may not reflect actual chemical intakes because concentrations depend on food origin, and representative analysis is seldom available. Processing, packaging, storage, and transportation also impart different chemicals to food and are not yet adequately addressed. Thus, the link between environmental emissions and realistic human exposure is effectively broken. Objectives: We discuss the need for a fully integrated treatment of the modern industrialized food system, and we propose strategies for using existing models and relevant supporting data sources to track chemicals during production, processing, packaging, storage, and transport. Discussion: Fate and bioaccumulation models describe how chemicals distribute in the environment and accumulate through local food webs. Human exposure models can use concentrations in food to determine body burdens based on individual or population characteristics. New models now include the impacts of processing and packaging but are far from comprehensive. We propose to close the gap between emissions and exposure by utilizing a wider variety of models and data sources, including global food trade data, processing, and packaging models. Conclusions: A comprehensive approach that takes into account the complexity of the modern global food system is essential to enable better prediction of human exposure to chemicals in food, sound risk assessments, and more focused risk abatement strategies. Citation: Ng CA, von Goetz N. 2017. The global food system as a transport pathway for hazardous chemicals: the missing link between emissions and exposure. Environ Health Perspect 125:1–7; http://dx.doi.org/10.1289/EHP168 PMID:27384039

Proteome analysis of Arabidopsis seedlings exposed to bacterial volatiles.

PubMed

Kwon, Young Sang; Ryu, Choong-Min; Lee, Soohyun; Park, Hyo Bee; Han, Ki Soo; Lee, Jung Han; Lee, Kyunghee; Chung, Woo Sik; Jeong, Mi-Jeong; Kim, Hee Kyu; Bae, Dong-Won

2010-11-01

Plant root-associated bacteria (rhizobacteria) elicit plant basal immunity referred to as induced systemic resistance (ISR) against multiple pathogens. Among multi-bacterial determinants involving such ISR, the induction of ISR and promotion of growth by bacterial volatile compounds was previously reported. To exploit global de novo expression of plant proteins by bacterial volatiles, proteomic analysis was performed after exposure of Arabidopsis plants to the rhizobacterium Bacillus subtilis GB03. Ethylene biosynthesis enzymes were significantly up-regulated. Analysis by quantitative reverse transcriptase polymerase chain reaction confirmed that ethylene biosynthesis-related genes SAM-2, ACS4, ACS12, and ACO2 as well as ethylene response genes, ERF1, GST2, and CHIB were up-regulated by the exposure to bacterial volatiles. More interestingly, the emission of bacterial volatiles significantly up-regulated both key defense mechanisms mediated by jasmonic acid and salicylic acid signaling pathways. In addition, high accumulation of antioxidant proteins also provided evidence of decreased sensitivity to reactive oxygen species during the elicitation of ISR by bacterial volatiles. The present results suggest that the proteomic analysis of plant defense responses in bacterial volatile-mediated ISR can reveal the mechanisms of plant basal defenses orchestrated by endogenous ethylene production pathways and the generation of reactive oxygen species.

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

EPA Science Inventory

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...

Human Health Risk Assessment Calculator. In: SMARTe20ll, EPA/600/C-10/007

EPA Science Inventory

This calculator is aimed at supporting a human health risk assessment. Risk scenarios can be built by combining various health effects, exposure pathways, exposure parameters, and analytes. Scenario risk are calculated for each exposure pathway and analyte combination. The out...

NMR-based Metabolomics Analysis of Liver from C57BL/6 Mouse Exposed to Ionizing Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xiao, Xiongjie; Hu, Mary; Zhang, Xu

The health effects of exposing to ionizing radiation are attracting great interest in the space exploration community and patients considering radiotherapy. However, the impact to metabolism after exposure to high dose radiation has not yet been clearly defined in livers. In the present study, 1H nuclear magnetic resonance (NMR) based metabolomics combined with multivariate data analysis are applied to study the changes of metabolism in the liver of C57BL/6 mouse after whole body exposure to either gamma (3.0 and 7.8 Gy) or proton (3.0 Gy) radiation. Principal component analysis (PCA) and orthogonal projection to latent structures analysis (OPLS) are employedmore » for classification and identification of potential biomarkers associated with gamma and proton irradiation. The results show that the radiation exposed groups can be well separated from the control group. At the same radiation dosage, the group exposed to proton radiation is well separated from the group exposed to gamma radiation, indicating different radiation sources induce different alterations based on metabolic profiling. Common to both gamma and proton radiation at the high radiation doses studied in this work, compared with the control groups the concentrations of choline, O-phosphocholine and trimethylamine N-oxide are decreased statistically, while those of glutamine, glutathione, malate, creatinine, phosphate, betaine and 4-hydroxyphenylacetate are statistically and significantly elevated after exposure to radiation. Since these altered metabolites are associated with multiple biological pathways, the changes suggest that the exposure to radiation induce abnormality in multiple biological pathways. In particular, metabolites such as 4-hydroxyphenylacetate, betaine, glutamine, choline and trimethylamine N-oxide may be good candidates of pre-diagnose biomarkers for ionizing radiation in liver.« less

Gene expression profiles following exposure to a developmental neurotoxicant, Aroclor 1254: Pathway analysis for possible mode(s) of action

DOE Office of Scientific and Technical Information (OSTI.GOV)

Royland, Joyce E.; Kodavanti, Prasada Rao S.

2008-09-01

Epidemiological studies indicate that low levels of polychlorinated biphenyl (PCB) exposure can adversely affect neurocognitive development. In animal models, perturbations in calcium signaling, neurotransmitters, and thyroid hormones have been postulated as potential mechanisms for PCB-induced developmental neurotoxicity. In order to understand the role of these proposed mechanisms and to identify other mechanisms in PCB-induced neurotoxicity, we have chosen a global approach utilizing oligonucleotide microarrays to examine gene expression profiles in the brain following developmental exposure to Aroclor 1254 (0 or 6 mg/kg/day from gestation day 6 through postnatal day (PND) 21) in Long-Evans rats. Gene expression levels in the cerebellummore » and hippocampus from PNDs 7 and 14 animals were determined on Affymetrix rat 230A{sub 2}.0 chips. In the cerebellum, 87 transcripts were altered at PND7 compared to 27 transcripts at PND14 by Aroclor 1254 exposure, with only one transcript affected at both ages. In hippocampus, 175 transcripts and 50 transcripts were altered at PND7 and PND14, respectively, by Aroclor 1254 exposure with five genes commonly affected. Functional analysis suggests that pathways related to calcium homeostasis (Gng3, Ryr2, Trdn, Cacna1a), intracellular signaling (Camk2d, Stk17b, Pacsin2, Ryr2, Trio, Fert2, Ptk2b), axonal guidance (Lum, Mxd3, Akap11, Gucy1b3), aryl hydrocarbon receptor signaling (Nfia, Col1a2), and transcripts involved in cell proliferation (Gspt2, Cdkn1c, Ptk2b) and differentiation (Ifitm31, Hpca, Zfp260, Igsf4a, Hes5) leading to the development of nervous system were significantly altered by Aroclor 1254 exposure. Of the two brain regions examined, Aroclor 1254-induced genomic changes were greater in the hippocampus than the cerebellum. The genomic data suggests that PCB-induced neurotoxic effects were due to disruption of normal ontogenetic pattern of nervous system growth and development by altering intracellular signaling pathways but not by endocrine disruption.« less

Frameworks for organizing exposure and toxicity data - the Aggregate Exposure Pathway (AEP) and the Adverse Outcome Pathway (AOP)

EPA Science Inventory

The Adverse Outcome Pathway (AOP) framework organizes existing knowledge regarding a series of biological events, starting with a molecular initiating event (MIE) and ending at an adverse outcome. The AOP framework provides a biological context to interpret in vitro toxicity dat...

Analysis of Total Food Intake and Composition of Individual's ...

EPA Pesticide Factsheets

EPA released the final report, Analysis of Total Food Intake and Composition of Individual’s Diet Based on USDA’s 1994-1996, 98 Continuing Survey of Food Intakes by Individuals (CSFII). The consumption of food by the general population is a significant route of potential exposure to hazardous substances that are present in the environment. For this reason, a thorough analysis of the dietary habits of the American public would aid in the identification of potential exposure pathways. To that end, the EPA developed per capita food intake rates for various food items and food categories using databases developed by the United States Department of Agriculture (USDA). These intake rates were incorporated into EPA's 1997 Exposure Factors Handbook. Since that time, EPA has recommended that the food intake study be updated and expanded to include a more comprehensive analysis of food intake. That analysis is presented in this document. The purpose of this study is to characterize the consumption of food by the people of the United States.

Education, fish consumption, well water, chicken coops, and cooking fires: Using biogeochemistry and ethnography to study exposure of children from Yucatan, Mexico to metals and arsenic.

PubMed

Arcega-Cabrera, Flor; Fargher, Lane F

2016-10-15

Around the world, the nocuous health effects of exposure to environmental contaminants, especially metals and Arsenic, are a growing health concern. This is especially the case in Mexico, where corruption and ineffective political administration are contributing to increasing deterioration in the environment. Importantly, shallow soils and the karstic nature of bedrock in Yucatan, Mexico make the subterranean aquifer especially susceptible to contamination because contaminates are carried to it with little resistance. Given these environmental conditions, we developed a multi/interdisciplinary project to evaluate the impact of metal and Arsenic pollution on a sample of 107 children, ages 6 to 9years, living in the urban areas of Progreso, Merida, and Ticul, in the State of Yucatan using urine and blood samples. In addition, ethnographic research was carried out in the homes of the children that participated in the study to identify potential exposure pathways. This research proved invaluable because the complexity of human social organization, lifestyles, and geographical patterning create an intricate array of exposure pathways that vary across social sectors and geographic space. In the following article, we use nonparametric univariate statistical analysis to reveal potential exposure pathways among sub-populations included in our sample. These analyses show that children from poor/marginal families tend to be exposed to Copper, Lead, and Nickel; whereas, children, from wealthier families, tend to be exposed to Cadmium, Arsenic, and inorganic Copper (Copper Sulfate). Copyright © 2016 Elsevier B.V. All rights reserved.

The Cardiopulmonary Effects of Ambient Air Pollution and Mechanistic Pathways: A Comparative Hierarchical Pathway Analysis

PubMed Central

Thomas, Duncan C.; Zhang, Junfeng; Kipen, Howard M.; Rich, David Q.; Zhu, Tong; Huang, Wei; Hu, Min; Wang, Guangfa; Wang, Yuedan; Zhu, Ping; Lu, Shou-En; Ohman-Strickland, Pamela; Diehl, Scott R.; Eckel, Sandrah P.

2014-01-01

Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2–3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system. PMID:25502951

Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts.

PubMed

Mahemuti, Laziyan; Chen, Qixuan; Coughlan, Melanie C; Qiao, Cunye; Chepelev, Nikolai L; Florian, Maria; Dong, Dillon; Woodworth, Robert G; Yan, Jin; Cao, Xu-Liang; Scoggan, Kylie A; Jin, Xiaolei; Willmore, William G

2018-04-01

Experimental and/or epidemiological studies suggest that prenatal exposure to bisphenol A (BPA) may delay fetal lung development and maturation and increase the susceptibility to childhood respiratory disease. However, the underlying mechanisms remain to be elucidated. In our previous study with cultured human fetal lung fibroblasts (HFLF), we demonstrated that 24-h exposure to 1 and 100 µM BPA increased GPR30 protein in the nuclear fraction. Exposure to 100 μM BPA had no effects on cell viability, but increased cytoplasmic expression of ERβ and release of GDF-15, as well as decreased release of IL-6, ET-1, and IP-10 through suppression of NFκB phosphorylation. By performing global gene expression and pathway analysis in this study, we identified molecular pathways, gene networks, and key molecules that were affected by 100, but not 0.01 and 1 µM BPA in HFLF. Using multiple genomic and proteomic tools, we confirmed these changes at both gene and protein levels. Our data suggest that 100 μM BPA increased CYP1B1 and HSD17B14 gene and protein expression and release of endogenous estradiol, which was associated with increased ROS production and DNA double-strand breaks, upregulation of genes and/or proteins in steroid synthesis and metabolism, and activation of Nrf2-regulated stress response pathways. In addition, BPA activated ATM-p53 signaling pathway, resulting in increased cell cycle arrest at G1 phase, senescence and autophagy, and decreased cell proliferation in HFLF. The results suggest that prenatal exposure to BPA at certain concentrations may affect fetal lung development and maturation, and thereby affecting susceptibility to childhood respiratory diseases.

A Review of Non-occupational Pathways for Pesticide Exposure in Women Living in Agricultural Areas

EPA Science Inventory

Women living in agricultural areas may experience relatively high pesticide exposures compared to women in urban or suburban areas due to their proximity to farm activities. However, exposure pathways in these women are not well-characterized. We reviewed the evidence for the con...

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data

EPA Science Inventory

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified rel...

Metal-induced Dysregulation of the NF-kB Pathway in a Detroit Michigan's Children Cohort

EPA Science Inventory

Heavy metal exposure can have adverse effects on childhood development, and early life exposures have been shown to modify key biological pathways. We set out to evaluate the genome-wide effects of metals exposure in the Mechanistic Indicators of Childhood Asthma (MICA) study, wh...

Transcriptional pathway and de novo network-based approaches to effects-based monitoring in the Great Lakes

EPA Science Inventory

Transcriptomics provides unique solutions for understanding the impact of complex mixtures and their components on aquatic systems. Here we describe the application of transcriptomics analysis of in situ fathead minnow exposures for assessing biological impacts of wastewater trea...

40 CFR 300.420 - Remedial site evaluation.

Code of Federal Regulations, 2010 CFR

2010-07-01

... existing information about a release such as information on the pathways of exposure, exposure targets, and... known contaminants; (iii) A description of pathways of migration of contaminants; (iv) An identification...

40 CFR 300.420 - Remedial site evaluation.

Code of Federal Regulations, 2011 CFR

2011-07-01

... existing information about a release such as information on the pathways of exposure, exposure targets, and... known contaminants; (iii) A description of pathways of migration of contaminants; (iv) An identification...

40 CFR 300.420 - Remedial site evaluation.

Code of Federal Regulations, 2012 CFR

2012-07-01

... existing information about a release such as information on the pathways of exposure, exposure targets, and... known contaminants; (iii) A description of pathways of migration of contaminants; (iv) An identification...

Prenatal arsenic exposure and the epigenome: altered microRNAs associated with innate and adaptive immune signaling in newborn cord blood.

PubMed

Rager, Julia E; Bailey, Kathryn A; Smeester, Lisa; Miller, Sloane K; Parker, Joel S; Laine, Jessica E; Drobná, Zuzana; Currier, Jenna; Douillet, Christelle; Olshan, Andrew F; Rubio-Andrade, Marisela; Stýblo, Miroslav; García-Vargas, Gonzalo; Fry, Rebecca C

2014-04-01

The Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Gómez Palacio, Mexico was recently established to better understand the impacts of prenatal exposure to inorganic arsenic (iAs). In this study, we examined a subset (n = 40) of newborn cord blood samples for microRNA (miRNA) expression changes associated with in utero arsenic exposure. Levels of iAs in maternal drinking water (DW-iAs) and maternal urine were assessed. Levels of DW-iAs ranged from below detectable values to 236 µg/L (mean = 51.7 µg/L). Total arsenic in maternal urine (U-tAs) was defined as the sum of iAs and its monomethylated and dimethylated metabolites (MMAs and DMAs, respectively) and ranged from 6.2 to 319.7 µg/L (mean = 64.5 µg/L). Genome-wide miRNA expression analysis of cord blood revealed 12 miRNAs with increasing expression associated with U-tAs. Transcriptional targets of the miRNAs were computationally predicted and subsequently assessed using transcriptional profiling. Pathway analysis demonstrated that the U-tAs-associated miRNAs are involved in signaling pathways related to known health outcomes of iAs exposure including cancer and diabetes mellitus. Immune response-related mRNAs were also identified with decreased expression levels associated with U-tAs, and predicted to be mediated in part by the arsenic-responsive miRNAs. Results of this study highlight miRNAs as novel responders to prenatal arsenic exposure that may contribute to associated immune response perturbations. Copyright © 2013 Wiley Periodicals, Inc.

Untargeted Metabolomics Reveals Predominant Alterations in Lipid Metabolism Following Light Exposure in Broccoli Sprouts

PubMed Central

Maldini, Mariateresa; Natella, Fausta; Baima, Simona; Morelli, Giorgio; Scaccini, Cristina; Langridge, James; Astarita, Giuseppe

2015-01-01

The consumption of vegetables belonging to the family Brassicaceae (e.g., broccoli and cauliflower) is linked to a reduced incidence of cancer and cardiovascular diseases. The molecular composition of such plants is strongly affected by growing conditions. Here we developed an unbiased metabolomics approach to investigate the effect of light and dark exposure on the metabolome of broccoli sprouts and we applied such an approach to provide a bird’s-eye view of the overall metabolic response after light exposure. Broccoli seeds were germinated and grown hydroponically for five days in total darkness or with a light/dark photoperiod (16 h light/8 h dark cycle). We used an ultra-performance liquid-chromatography system coupled to an ion-mobility, time-of-flight mass spectrometer to profile the large array of metabolites present in the sprouts. Differences at the metabolite level between groups were analyzed using multivariate statistical analyses, including principal component analysis and correlation analysis. Altered metabolites were identified by searching publicly available and in-house databases. Metabolite pathway analyses were used to support the identification of subtle but significant changes among groups of related metabolites that may have gone unnoticed with conventional approaches. Besides the chlorophyll pathway, light exposure activated the biosynthesis and metabolism of sterol lipids, prenol lipids, and polyunsaturated lipids, which are essential for the photosynthetic machinery. Our results also revealed that light exposure increased the levels of polyketides, including flavonoids, and oxylipins, which play essential roles in the plant’s developmental processes and defense mechanism against herbivores. This study highlights the significant contribution of light exposure to the ultimate metabolic phenotype, which might affect the cellular physiology and nutritional value of broccoli sprouts. Furthermore, this study highlights the potential of an unbiased omics approach for the comprehensive study of the metabolism. PMID:26084047

10 CFR 50.33 - Contents of applications; general information.

Code of Federal Regulations, 2013 CFR

2013-01-01

... within the plume exposure pathway emergency planning zone (EPZ), 4 as well as the plans of State governments wholly or partially within the ingestion pathway EPZ. 5 If the application is for an early site... plume exposure pathway EPZ for nuclear power reactors shall consist of an area about 10 miles (16 km) in...

10 CFR 50.33 - Contents of applications; general information.

Code of Federal Regulations, 2014 CFR

2014-01-01

... within the plume exposure pathway emergency planning zone (EPZ), 4 as well as the plans of State governments wholly or partially within the ingestion pathway EPZ. 5 If the application is for an early site... plume exposure pathway EPZ for nuclear power reactors shall consist of an area about 10 miles (16 km) in...

10 CFR 50.33 - Contents of applications; general information.

Code of Federal Regulations, 2012 CFR

2012-01-01

... within the plume exposure pathway emergency planning zone (EPZ), 4 as well as the plans of State governments wholly or partially within the ingestion pathway EPZ. 5 If the application is for an early site... plume exposure pathway EPZ for nuclear power reactors shall consist of an area about 10 miles (16 km) in...

10 CFR 50.33 - Contents of applications; general information.

Code of Federal Regulations, 2011 CFR

2011-01-01

... within the plume exposure pathway emergency planning zone (EPZ), 4 as well as the plans of State governments wholly or partially within the ingestion pathway EPZ. 5 If the application is for an early site... plume exposure pathway EPZ for nuclear power reactors shall consist of an area about 10 miles (16 km) in...

Global gene expression and Ingenuity biological functions analysis on PCBs 153 and 138 induced human PBMC in vitro reveals differential mode(s) of action in developing toxicities.

PubMed

Ghosh, Somiranjan; Zang, Shizhu; Mitra, Partha S; Ghimbovschi, Svetlana; Hoffman, Eric P; Dutta, Sisir K

2011-07-01

Several reports have indicated that low level of polychlorinated biphenyl (PCB) exposure can adversely affect a multitude of physiological disorders and diseases in in vitro, in vivo, and as reported in epidemiological studies. This investigation is focused on the possible contribution of two most prevalent PCB congeners in vitro in developing toxicities. We used PCBs 138 and 153 at the human equivalence level as model agents to test their specificity in developing toxicities. We chose a global approach using oligonucleotide microarray technology to investigate modulated gene expression for biological effects, upon exposure of PCBs, followed by Ingenuity Pathway Analysis (IPA), to understand the underlying consequence in developing disease and disorders. We performed in vitro studies with human peripheral blood mononuclear cells (PBMC), where PBMC cells were exposed to respective PCBs for 48 h. Overall, our observation on gene expression indicated that PCB produces a unique signature affecting different pathways, specific for each congener. While analyzing these data through IPA, the prominent and interesting disease and disorders were neurological disease, cancer, cardiovascular disease, respiratory disease, as well as endocrine system disorders, genetic disorders, and reproductive system disease. They showed strong resemblances with in vitro, in vivo, and in the epidemiological studies. A distinct difference was observed in renal and urological diseases, organisimal injury and abnormalities, dental disease, ophthalmic disease, and psychological disorders, which are only revealed by PCB 138 exposure, but not in PCB 153. The present study emphasizes the challenges of global gene expression in vitro and was correlated with the results of exposed human population. The microarray results give a molecular mechanistic insight and functional effects, following PCB exposure. The extent of changes in genes related to several possible mode(s) of action highlights the changes in cellular functions and signaling pathways that play major roles. In addition to understanding the pathways related to mode of action for chemicals, these data could lead to the identification of genomic signatures that could be used for screening of chemicals for their potential to cause disease and developmental disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

The effect of tributyltin chloride on Caenorhabditis elegans germline is mediated by a conserved DNA damage checkpoint pathway.

PubMed

Cheng, Zhe; Tian, Huimin; Chu, Hongran; Wu, Jianjian; Li, Yingying; Wang, Yanhai

2014-03-21

Tributyltin (TBT), one of the environmental pollutants, has been shown to impact the reproduction of animals. However, due to the lack of appropriate animal model, analysis of the affected molecular pathways in germ cells is lagging and has been particularly challenging. In the present study, we investigated the effects of tributyltin chloride (TBTCL) on the nematode Caenorhabditis elegans germline. We show that exposure of C. elegans to TBTCL causes significantly elevated level of sterility and embryonic lethality. TBTCL exposure results in an increased number of meiotic DNA double-strand breaks in germ cells, subsequently leading to activated DNA damage checkpoint. Exposing C. elegans to TBTCL causes dose- and time-dependent germline apoptosis. This apoptotic response was blocked in loss-of-function mutants of hus-1 (op241), mrt-2 (e2663) and p53/cep-1 (gk138), indicating that checkpoints and p53 are essential for mediating TBTCL-induced germ cell apoptosis. Moreover, TBTCL exposure can inhibit germ cell proliferation, which is also mediated by the conserved checkpoint pathway. We thereby propose that TBT exhibits its effects on the germline by inducing DNA damage and impaired maintenance of genomic integrity. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Differential DNA methylation at conserved non-genic elements and evidence for transgenerational inheritance following developmental exposure to mono(2-ethylhexyl) phthalate and 5-azacytidine in zebrafish.

PubMed

Kamstra, Jorke H; Sales, Liana Bastos; Aleström, Peter; Legler, Juliette

2017-01-01

Exposure to environmental stressors during development may lead to latent and transgenerational adverse health effects. To understand the role of DNA methylation in these effects, we used zebrafish as a vertebrate model to investigate heritable changes in DNA methylation following chemical-induced stress during early development. We exposed zebrafish embryos to non-embryotoxic concentrations of the biologically active phthalate metabolite mono(2-ethylhexyl) phthalate (MEHP, 30 µM) and the DNA methyltransferase 1 inhibitor 5-azacytidine (5AC, 10 µM). Direct, latent and transgenerational effects on DNA methylation were assessed using global, genome-wide and locus-specific DNA methylation analyses. Following direct exposure in zebrafish embryos from 0 to 6 days post-fertilization, genome-wide analysis revealed a multitude of differentially methylated regions, strongly enriched at conserved non-genic elements for both compounds. Pathways involved in adipogenesis were enriched with the putative obesogenic compound MEHP. Exposure to 5AC resulted in enrichment of pathways involved in embryonic development and transgenerational effects on larval body length. Locus-specific methylation analysis of 10 differentially methylated sites revealed six of these loci differentially methylated in sperm sampled from adult zebrafish exposed during development to 5AC, and in first and second generation larvae. With MEHP, consistent changes were found at 2 specific loci in first and second generation larvae. Our results suggest a functional role for DNA methylation on cis-regulatory conserved elements following developmental exposure to compounds. Effects on these regions are potentially transferred to subsequent generations.

Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a High-throughput Targeted Metabolomics Approach

NASA Astrophysics Data System (ADS)

Yu, Nanyang; Wei, Si; Li, Meiying; Yang, Jingping; Li, Kan; Jin, Ling; Xie, Yuwei; Giesy, John P.; Zhang, Xiaowei; Yu, Hongxia

2016-04-01

Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.

40 CFR 270.10 - General application requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... associated with transportation to or from the unit; (ii) The potential pathways of human exposure to... resulting from both direct and indirect exposure pathways. The Director may also require a permittee or...

Investigating Rare Risk Factors for Nipah Virus in Bangladesh: 2001-2012.

PubMed

Hegde, Sonia T; Sazzad, Hossain M S; Hossain, M Jahangir; Alam, Mahbub-Ul; Kenah, Eben; Daszak, Peter; Rollin, Pierre; Rahman, Mahmudur; Luby, Stephen P; Gurley, Emily S

2016-12-01

Human Nipah encephalitis outbreaks have been identified almost yearly in Bangladesh since 2001. Though raw date palm sap consumption and person-to-person contact are recognized as major transmission pathways, alternative pathways of transmission are plausible and may not have been identified due to limited statistical power in each outbreak. We conducted a risk factor analysis using all 157 cases and 632 controls surveyed in previous investigations during 2004-2012 to identify exposures independently associated with Nipah, since date palm sap was first asked about as an exposure in 2004. To further explore possible rare exposures, we also conducted in-depth interviews with all cases, or proxies, since 2001 that reported no exposure to date palm sap or contact with another case. Cases were 4.9 (95% 3.2-7.7) times more likely to consume raw date palm sap and 7.3 (95% 4.0-13.4) times more likely to have contact with a Nipah case than controls. In-depth interviews revealed that 39/182 (21%) of Nipah cases reporting neither date palm sap consumption nor contact with another case were misclassified. Prevention efforts should be focused on interventions to interrupt transmission through date palm sap consumption and person-to-person contact. Furthermore, pooling outbreak investigation data is a good method for assessing rare exposures.

Applying Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks to link toxicity testing data to exposure-relevant and biologically-relevant responses

EPA Science Inventory

Hazard assessment for nanomaterials often involves applying in vitro dose-response data to estimate potential health risks that arise from exposure to products that contain nanomaterials. However, much uncertainty is inherent in relating bioactivities observed in an in vitro syst...

MEASUREMENT OF MULTI-POLLUTANT AND MULTI-PATHWAY EXPOSURES IN A PROBABILITY-BASED SAMPLE OF CHILDREN: PRACTICAL STRATEGIES FOR EFFECTIVE FIELD STUDIES

EPA Science Inventory

The purpose of this manuscript is to describe the practical strategies developed for the implementation of the Minnesota Children's Pesticide Exposure Study (MNCPES), which is one of the first probability-based samples of multi-pathway and multi-pesticide exposures in children....

Cross-species integration of human health and ecological endpoints into risk assessment using the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks

EPA Science Inventory

Exposure to environmental contaminants can influence both human health and ecological endpoints. Chemical risk assessments combine exposure and toxicity data to estimate the likelihood of adverse outcomes for these endpoints, but are rarely conducted in a manner that integrates ...

Parsing the Effects Violence Exposure in Early Childhood: Modeling Developmental Pathways

PubMed Central

Carter, Alice S.; Ford, Julian D.

2012-01-01

Objective To prospectively examine pathways from early childhood violence exposure and trauma-related symptoms to school-age emotional health. Methods A longitudinal, birth cohort (N = 437) was assessed with parent reports of lifetime violence exposure and trauma-related symptoms at 3 years of age and later, internalizing and externalizing symptoms, and social competence at school age. Results Early family and neighborhood violence correlated significantly with early trauma-related symptoms and also significantly predicted school-age internalizing and externalizing symptoms and poorer competence, independent of sociodemographic risk and past-year violence exposure. Longitudinal pathways were significantly mediated by arousal and avoidance symptoms at 3 years of age, which increased risk for clinically significant emotional problems and lower competence at school age (adjusted odds ratios = 3.1–6.1, p < 0.01). Conclusions Trauma-related symptoms may mediate developmental pathways from early violence exposure to later emotional health. Interventions that prevent or reduce early trauma-related symptoms may ameliorate the long-term deleterious impact of violence exposure. PMID:21903730

Applicability of western chemical dietary exposure models to the Chinese population.

PubMed

Zhao, Shizhen; Price, Oliver; Liu, Zhengtao; Jones, Kevin C; Sweetman, Andrew J

2015-07-01

A range of exposure models, which have been developed in Europe and North America, are playing an increasingly important role in priority setting and the risk assessment of chemicals. However, the applicability of these tools, which are based on Western dietary exposure pathways, to estimate chemical exposure to the Chinese population to support the development of a risk-based environment and exposure assessment, is unclear. Three frequently used modelling tools, EUSES, RAIDAR and ACC-HUMANsteady, have been evaluated in terms of human dietary exposure estimation by application to a range of chemicals with different physicochemical properties under both model default and Chinese dietary scenarios. Hence, the modelling approaches were assessed by considering dietary pattern differences only. The predicted dietary exposure pathways were compared under both scenarios using a range of hypothetical and current emerging contaminants. Although the differences across models are greater than those between dietary scenarios, model predictions indicated that dietary preference can have a significant impact on human exposure, with the relatively high consumption of vegetables and cereals resulting in higher exposure via plants-based foodstuffs under Chinese consumption patterns compared to Western diets. The selected models demonstrated a good ability to identify key dietary exposure pathways which can be used for screening purposes and an evaluative risk assessment. However, some model adaptations will be required to cover a number of important Chinese exposure pathways, such as freshwater farmed-fish, grains and pork. Copyright © 2015 Elsevier Inc. All rights reserved.

Genomic analysis of the interaction between pesticide exposure and nutrition in honey bees (Apis mellifera)

USDA-ARS?s Scientific Manuscript database

Populations of pollinators are in decline worldwide. These declines are best documented in honey bees and are due to a combination of stressors. In particular, pesticides have been linked to decreased longevity and performance in honey bees; however, the molecular and physiological pathways mediatin...

Metabolic Profiling as Well as Stable Isotope Assisted Metabolic and Proteomic Analysis of RAW 264.7 Macrophages Exposed to Ship Engine Aerosol Emissions: Different Effects of Heavy Fuel Oil and Refined Diesel Fuel

PubMed Central

Sapcariu, Sean C.; Kanashova, Tamara; Dilger, Marco; Diabaté, Silvia; Oeder, Sebastian; Passig, Johannes; Radischat, Christian; Buters, Jeroen; Sippula, Olli; Streibel, Thorsten; Paur, Hanns-Rudolf; Schlager, Christoph; Mülhopt, Sonja; Stengel, Benjamin; Rabe, Rom; Harndorf, Horst; Krebs, Tobias; Karg, Erwin; Gröger, Thomas; Weiss, Carsten; Dittmar, Gunnar; Hiller, Karsten; Zimmermann, Ralf

2016-01-01

Exposure to air pollution resulting from fossil fuel combustion has been linked to multiple short-term and long term health effects. In a previous study, exposure of lung epithelial cells to engine exhaust from heavy fuel oil (HFO) and diesel fuel (DF), two of the main fuels used in marine engines, led to an increased regulation of several pathways associated with adverse cellular effects, including pro-inflammatory pathways. In addition, DF exhaust exposure was shown to have a wider response on multiple cellular regulatory levels compared to HFO emissions, suggesting a potentially higher toxicity of DF emissions over HFO. In order to further understand these effects, as well as to validate these findings in another cell line, we investigated macrophages under the same conditions as a more inflammation-relevant model. An air-liquid interface aerosol exposure system was used to provide a more biologically relevant exposure system compared to submerged experiments, with cells exposed to either the complete aerosol (particle and gas phase), or the gas phase only (with particles filtered out). Data from cytotoxicity assays were integrated with metabolomics and proteomics analyses, including stable isotope-assisted metabolomics, in order to uncover pathways affected by combustion aerosol exposure in macrophages. Through this approach, we determined differing phenotypic effects associated with the different components of aerosol. The particle phase of diluted combustion aerosols was found to induce increased cell death in macrophages, while the gas phase was found more to affect the metabolic profile. In particular, a higher cytotoxicity of DF aerosol emission was observed in relation to the HFO aerosol. Furthermore, macrophage exposure to the gas phase of HFO leads to an induction of a pro-inflammatory metabolic and proteomic phenotype. These results validate the effects found in lung epithelial cells, confirming the role of inflammation and cellular stress in the response to combustion aerosols. PMID:27348622

DOE Office of Scientific and Technical Information (OSTI.GOV)

Evans, M.V., E-mail: evans.marina@epa.go; Caldwell, J.C.

Dichloromethane (DCM, methylene chloride) is a lipophilic volatile compound readily absorbed and then metabolized to several metabolites that may lead to chronic toxicity in different target organs. Physiologically based pharmacokinetic (PBPK) models are useful tools for calculation of internal and target organ doses of parent compound and metabolites. PBPK models, coupled with in vivo inhalation gas-uptake data, can be useful to estimate total metabolism. Previously, such an approach was used to make predictions regarding the metabolism and to make subsequent inferences of DCM's mode of action for toxicity. However, current evidence warrants re-examination of this approach. The goal of thismore » work was to examine two different hypotheses for DCM metabolism in mice. One hypothesis describes two metabolic pathways: one involving cytochrome P450 2E1 (CYP2E1) and a second glutathione (GSH). The second metabolic hypothesis describes only one pathway mediated by CYP2E1 that includes multiple binding sites. The results of our analysis show that the in vivo gas-uptake data fit both hypotheses well and the traditional analysis of the chamber concentration data is not sufficient to distinguish between them. Gas-uptake data were re-analyzed by construction of a velocity plot as a function of increasing DCM initial concentration. The velocity (slope) analysis revealed that there are two substantially different phases in velocity, one rate for lower exposures and a different rate for higher exposures. The concept of a 'metabolic switch,' namely that due to conformational changes in the enzyme after one site is occupied - a different metabolic rate is seen - is also consistent with the experimental data. Our analyses raise questions concerning the importance of GSH metabolism for DCM. Recent research results also question the importance of this pathway in the toxicity of DCM. GSH-related DNA adducts were not formed after in vivo DCM exposure in mice and DCM-induced DNA damage has been detected in human lung cultures without GSH metabolism. In summary, a revised/updated metabolic hypothesis for DCM has been examined using in vivo inhalation data in mice combined with PBPK modeling that is consistent with up-to-date models of the active site for CYP2E1 and suggests that this pathway is the major metabolizing pathway for DCM metabolism.« less

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

PubMed

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.

Transcriptomic Analysis of Ciguatoxin-Induced Changes in Gene Expression in Primary Cultures of Mice Cortical Neurons.

PubMed

Rubiolo, Juan Andrés; Vale, Carmen; Boente-Juncal, Andrea; Hirama, Masahiro; Yamashita, Shuji; Camiña, Mercedes; Vieytes, Mercedes R; Botana, Luis M

2018-05-10

Ciguatoxins are polyether marine toxins that act as sodium channel activators. These toxins cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents several symptoms in humans including long-term neurological alterations. Earlier work has shown that both acute and chronic exposure of primary cortical neurons to synthetic ciguatoxin CTX3C have profound impacts on neuronal function. Thus, the present work aimed to identify relevant neuronal genes and metabolic pathways that could be altered by ciguatoxin exposure. To study the effect of ciguatoxins in primary neurons in culture, we performed a transcriptomic analysis using whole mouse genome microarrays, for primary cortical neurons exposed during 6, 24, or 72 h in culture to CTX3C. Here, we have shown that the effects of the toxin on gene expression differ with the exposure time. The results presented here have identified several relevant genes and pathways related to the effect of ciguatoxins on neurons and may assist in future research or even treatment of ciguatera. Moreover, we demonstrated that the effects of the toxin on gene expression were exclusively consequential of its action as a voltage-gated sodium channel activator, since all the effects of CTX3C were avoided by preincubation of the neurons with the sodium channel blocker tetrodotoxin.

Exposure to Cell Phone Radiation Up-Regulates Apoptosis Genes in Primary Cultures of Neurons and Astrocytes

PubMed Central

Zhao, Tian-Yong; Zou, Shi-Ping; Knapp, Pamela E.

2007-01-01

The health effects of cell phone radiation exposure are a growing public concern. This study investigated whether expression of genes related to cell death pathways are dysregulated in primary cultured neurons and astrocytes by exposure to a working GSM (Global System for Mobile Communication) cell phone rated at a frequency of 1900 MHz. Primary cultures were exposed to cell phone emissions for 2 hrs. We used array analysis and real-time RT-PCR to show up-regulation of caspase-2, caspase-6 and Asc (apoptosis associated speck-like protein containing a card) gene expression in neurons and astrocytes. Upregulation occurred in both “on” and “stand-by” modes in neurons, but only in “on” mode in astrocytes. Additionally, astrocytes showed up-regulation of the Bax gene. The effects are specific since up-regulation was not seen for other genes associated with apoptosis, such as caspase-9 in either neurons and astrocytes, or Bax in neurons. The results show that even relatively short-term exposure to cell phone radiofrequency emissions can up-regulate elements of apoptotic pathways in cells derived from the brain, and that neurons appear to be more sensitive to this effect than astrocytes. PMID:17187929

Editor's Highlight: Application of Gene Set Enrichment Analysis for Identification of Chemically Induced, Biologically Relevant Transcriptomic Networks and Potential Utilization in Human Health Risk Assessment.

PubMed

Dean, Jeffry L; Zhao, Q Jay; Lambert, Jason C; Hawkins, Belinda S; Thomas, Russell S; Wesselkamper, Scott C

2017-05-01

The rate of new chemical development in commerce combined with a paucity of toxicity data for legacy chemicals presents a unique challenge for human health risk assessment. There is a clear need to develop new technologies and incorporate novel data streams to more efficiently inform derivation of toxicity values. One avenue of exploitation lies in the field of transcriptomics and the application of gene expression analysis to characterize biological responses to chemical exposures. In this context, gene set enrichment analysis (GSEA) was employed to evaluate tissue-specific, dose-response gene expression data generated following exposure to multiple chemicals for various durations. Patterns of transcriptional enrichment were evident across time and with increasing dose, and coordinated enrichment plausibly linked to the etiology of the biological responses was observed. GSEA was able to capture both transient and sustained transcriptional enrichment events facilitating differentiation between adaptive versus longer term molecular responses. When combined with benchmark dose (BMD) modeling of gene expression data from key drivers of biological enrichment, GSEA facilitated characterization of dose ranges required for enrichment of biologically relevant molecular signaling pathways, and promoted comparison of the activation dose ranges required for individual pathways. Median transcriptional BMD values were calculated for the most sensitive enriched pathway as well as the overall median BMD value for key gene members of significantly enriched pathways, and both were observed to be good estimates of the most sensitive apical endpoint BMD value. Together, these efforts support the application of GSEA to qualitative and quantitative human health risk assessment. Published by Oxford University Press on behalf of the Society of Toxicology 2017. This work is written by US Government employees and is in the public domain in the US.

Waveband specific transcriptional control of select genetic pathways in vertebrate skin (Xiphophorus maculatus).

PubMed

Walter, Ronald B; Boswell, Mikki; Chang, Jordan; Boswell, William T; Lu, Yuan; Navarro, Kaela; Walter, Sean M; Walter, Dylan J; Salinas, Raquel; Savage, Markita

2018-05-10

Evolution occurred exclusively under the full spectrum of sunlight. Conscription of narrow regions of the solar spectrum by specific photoreceptors suggests a common strategy for regulation of genetic pathways. Fluorescent light (FL) does not possess the complexity of the solar spectrum and has only been in service for about 60 years. If vertebrates evolved specific genetic responses regulated by light wavelengths representing the entire solar spectrum, there may be genetic consequences to reducing the spectral complexity of light. We utilized RNA-Seq to assess changes in the transcriptional profiles of Xiphophorus maculatus skin after exposure to FL ("cool white"), or narrow wavelength regions of light between 350 and 600 nm (i.e., 50 nm or 10 nm regions, herein termed "wavebands"). Exposure to each 50 nm waveband identified sets of genes representing discrete pathways that showed waveband specific transcriptional modulation. For example, 350-400 or 450-500 nm waveband exposures resulted in opposite regulation of gene sets marking necrosis and apoptosis (i.e., 350-400 nm; necrosis suppression, apoptosis activation, while 450-500 nm; apoptosis suppression, necrosis activation). Further investigation of specific transcriptional modulation employing successive 10 nm waveband exposures between 500 and 550 nm showed; (a) greater numbers of genes may be transcriptionally modulated after 10 nm exposures, than observed for 50 nm or FL exposures, (b) the 10 nm wavebands induced gene sets showing greater functional specificity than 50 nm or FL exposures, and (c) the genetic effects of FL are primarily due to 30 nm between 500 and 530 nm. Interestingly, many genetic pathways exhibited completely opposite transcriptional effects after different waveband exposures. For example, the epidermal growth factor (EGF) pathway exhibits transcriptional suppression after FL exposure, becomes highly active after 450-500 nm waveband exposure, and again, exhibits strong transcriptional suppression after exposure to the 520-530 nm waveband. Collectively, these results suggest one may manipulate transcription of specific genetic pathways in skin by exposure of the intact animal to specific wavebands of light. In addition, we identify genes transcriptionally modulated in a predictable manner by specific waveband exposures. Such genes, and their regulatory elements, may represent valuable tools for genetic engineering and gene therapy protocols.

Coupled near-field and far-field exposure assessment framework for chemicals in consumer products.

PubMed

Fantke, Peter; Ernstoff, Alexi S; Huang, Lei; Csiszar, Susan A; Jolliet, Olivier

2016-09-01

Humans can be exposed to chemicals in consumer products through product use and environmental emissions over the product life cycle. Exposure pathways are often complex, where chemicals can transfer directly from products to humans during use or exchange between various indoor and outdoor compartments until sub-fractions reach humans. To consistently evaluate exposure pathways along product life cycles, a flexible mass balance-based assessment framework is presented structuring multimedia chemical transfers in a matrix of direct inter-compartmental transfer fractions. By matrix inversion, we quantify cumulative multimedia transfer fractions and exposure pathway-specific product intake fractions defined as chemical mass taken in by humans per unit mass of chemical in a product. Combining product intake fractions with chemical mass in the product yields intake estimates for use in life cycle impact assessment and chemical alternatives assessment, or daily intake doses for use in risk-based assessment and high-throughput screening. Two illustrative examples of chemicals used in personal care products and flooring materials demonstrate how this matrix-based framework offers a consistent and efficient way to rapidly compare exposure pathways for adult and child users and for the general population. This framework constitutes a user-friendly approach to develop, compare and interpret multiple human exposure scenarios in a coupled system of near-field ('user' environment), far-field and human intake compartments, and helps understand the contribution of individual pathways to overall human exposure in various product application contexts to inform decisions in different science-policy fields for which exposure quantification is relevant. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Transcriptomic analysis of liver from grass carp (Ctenopharyngodon idellus) exposed to high environmental ammonia reveals the activation of antioxidant and apoptosis pathways.

PubMed

Jin, Jiali; Wang, Yao; Wu, Zhixin; Hergazy, Abeer; Lan, Jiangfeng; Zhao, Lijuan; Liu, Xiaoling; Chen, Nan; Lin, Li

2017-04-01

High concentration of ammonia in aquatic system leads to detrimental effects on the health of aquatic animals. However, the mechanism underlying ammonia-induced toxicity is still not clear. To better understand the mechanism of ammonia toxicity effects on fish, juvenile grass carp was employed in the present study. RNA high-throughput sequencing technique was applied to analyze the total RNAs extracted from the liver of fish after 8 h post exposure to the water containing 2 mM NH 4 HCO 3 which experimentally mimicked the high environmental ammonia (HEA). A total of 49,971,114 and 53,826,986 clean reads were obtained in control and 2 mM HEA group, respectively, in which there were 911 differently expressed genes (DEGs) including 563 up-regulated and 348 down-regulated genes. In addition, 10 DEGs were validated by quantitative PCR. These DEGs were involved in several pathways related with oxidative stress or apoptosis. Further analysis on oxidative stress, histopathology and cellular apoptosis in grass carp liver after HEA exposure revealed interesting findings. Increased reactive oxygen species (ROS) content and superoxide dismutase (SOD) activity together with the decreased catalase (CAT) activity were detected, which may be effected by DEGs and related pathways such as FOXO signaling pathway. The histopathology and TUNEL assays results confirmed that apoptosis was induced in liver when fish had suffered HEA. Combined with the results of transcriptomic experiments, c-Myc-Bax-Caspase9 apoptosis pathway could be involved in grass carp liver apoptosis induced by ammonia stress. Copyright © 2017 Elsevier Ltd. All rights reserved.

Saccharomyces cerevisiae Boulardii Reduces the Deoxynivalenol-Induced Alteration of the Intestinal Transcriptome.

PubMed

Alassane-Kpembi, Imourana; Pinton, Philippe; Hupé, Jean-François; Neves, Manon; Lippi, Yannick; Combes, Sylvie; Castex, Mathieu; Oswald, Isabelle P

2018-05-15

Type B trichothecene mycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. By inducing trans-activation of a number of pro-inflammatory cytokines and increasing the stability of their mRNA, trichothecene can impair intestinal health. Several yeast products, especially Saccharomyces cerevisiae , have the potential for improving the enteric health of piglets, but little is known about the mechanisms by which the administration of yeast counteracts the DON-induced intestinal alterations. Using a pig jejunum explant model, a whole-transcriptome analysis was performed to decipher the early response of the small intestine to the deleterious effects of DON after administration of S. cerevisiae boulardii strain CNCM I-1079. Compared to the control condition, no differentially expressed gene (DE) was observed after treatment by yeast only. By contrast, 3619 probes-corresponding to 2771 genes-were differentially expressed following exposure to DON, and 32 signaling pathways were identified from the IPA software functional analysis of the set of DE genes. When the intestinal explants were treated with S. cerevisiae boulardii prior to DON exposure, the number of DE genes decreased by half (1718 probes corresponding to 1384 genes). Prototypical inflammation signaling pathways triggered by DON, including NF-κB and p38 MAPK, were reversed, although the yeast demonstrated limited efficacy toward some other pathways. S. cerevisiae boulardii also restored the lipid metabolism signaling pathway, and reversed the down-regulation of the antioxidant action of vitamin C signaling pathway. The latter effect could reduce the burden of DON-induced oxidative stress. Altogether, the results show that S. cerevisiae boulardii reduces the DON-induced alteration of intestinal transcriptome, and point to new mechanisms for the healing of tissue injury by yeast.

Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia.

PubMed

Sethy, Niroj Kumar; Singh, Manjulata; Kumar, Rajesh; Ilavazhagan, Govindasamy; Bhargava, Kalpana

2011-03-01

Exposure to high altitude (and thus hypobaric hypoxia) induces electrophysiological, metabolic, and morphological modifications in the brain leading to several neurological clinical syndromes. Despite the known fact that hypoxia episodes in brain are a common factor for many neuropathologies, limited information is available on the underlying cellular and molecular mechanisms. In this study, we investigated the temporal effect of short-term (0-12 h) chronic hypobaric hypoxia on global gene expression of rat brain followed by detailed canonical pathway analysis and regulatory network identification. Our analysis revealed significant alteration of 33, 17, 53, 81, and 296 genes (p < 0.05, <1.5-fold) after 0.5, 1, 3, 6, and 12 h of hypoxia, respectively. Biological processes like regulation, metabolic, and transport pathways are temporally activated along with anti- and proinflammatory signaling networks like PI3K/AKT, NF-κB, ERK/MAPK, IL-6 and IL-8 signaling. Irrespective of exposure durations, nuclear factor (erythroid-derived 2)-like 2 (NRF2)-mediated oxidative stress response pathway and genes were detected at all time points suggesting activation of NRF2-ARE antioxidant defense system. The results were further validated by assessing the expression levels of selected genes in temporal as well as brain regions with quantitative RT-PCR and western blot. In conclusion, our whole brain approach with temporal monitoring of gene expression patterns during hypobaric hypoxia has resulted in (1) deciphering sequence of pathways and signaling networks activated during onset of hypoxia, and (2) elucidation of NRF2-orchestrated antioxidant response as a major intrinsic defense mechanism. The results of this study will aid in better understanding and management of hypoxia-induced brain pathologies.

Saccharomyces cerevisiae boulardii Reduces the Deoxynivalenol-Induced Alteration of the Intestinal Transcriptome

PubMed Central

Alassane-Kpembi, Imourana; Hupé, Jean-François; Neves, Manon; Lippi, Yannick; Combes, Sylvie; Castex, Mathieu

2018-01-01

Type B trichothecene mycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. By inducing trans-activation of a number of pro-inflammatory cytokines and increasing the stability of their mRNA, trichothecene can impair intestinal health. Several yeast products, especially Saccharomyces cerevisiae, have the potential for improving the enteric health of piglets, but little is known about the mechanisms by which the administration of yeast counteracts the DON-induced intestinal alterations. Using a pig jejunum explant model, a whole-transcriptome analysis was performed to decipher the early response of the small intestine to the deleterious effects of DON after administration of S. cerevisiae boulardii strain CNCM I-1079. Compared to the control condition, no differentially expressed gene (DE) was observed after treatment by yeast only. By contrast, 3619 probes—corresponding to 2771 genes—were differentially expressed following exposure to DON, and 32 signaling pathways were identified from the IPA software functional analysis of the set of DE genes. When the intestinal explants were treated with S. cerevisiae boulardii prior to DON exposure, the number of DE genes decreased by half (1718 probes corresponding to 1384 genes). Prototypical inflammation signaling pathways triggered by DON, including NF-κB and p38 MAPK, were reversed, although the yeast demonstrated limited efficacy toward some other pathways. S. cerevisiae boulardii also restored the lipid metabolism signaling pathway, and reversed the down-regulation of the antioxidant action of vitamin C signaling pathway. The latter effect could reduce the burden of DON-induced oxidative stress. Altogether, the results show that S. cerevisiae boulardii reduces the DON-induced alteration of intestinal transcriptome, and point to new mechanisms for the healing of tissue injury by yeast. PMID:29762474

Relative contributions of four exposure pathways to influenza infection risk.

PubMed

Nicas, Mark; Jones, Rachael M

2009-09-01

The relative contribution of four influenza virus exposure pathways-(1) virus-contaminated hand contact with facial membranes, (2) inhalation of respirable cough particles, (3) inhalation of inspirable cough particles, and (4) spray of cough droplets onto facial membranes-must be quantified to determine the potential efficacy of nonpharmaceutical interventions of transmission. We used a mathematical model to estimate the relative contributions of the four pathways to infection risk in the context of a person attending a bed-ridden family member ill with influenza. Considering the uncertainties in the sparse human subject influenza dose-response data, we assumed alternative ratios of 3,200:1 and 1:1 for the infectivity of inhaled respirable virus to intranasally instilled virus. For the 3,200:1 ratio, pathways (1), (2), and (4) contribute substantially to influenza risk: at a virus saliva concentration of 10(6) mL(-1), pathways (1), (2), (3), and (4) contribute, respectively, 31%, 17%, 0.52%, and 52% of the infection risk. With increasing virus concentrations, pathway (2) increases in importance, while pathway (4) decreases in importance. In contrast, for the 1:1 infectivity ratio, pathway (1) is the most important overall: at a virus saliva concentration of 10(6) mL(-1), pathways (1), (2), (3), and (4) contribute, respectively, 93%, 0.037%, 3.3%, and 3.7% of the infection risk. With increasing virus concentrations, pathway (3) increases in importance, while pathway (4) decreases in importance. Given the sparse knowledge concerning influenza dose and infectivity via different exposure pathways, nonpharmaceutical interventions for influenza should simultaneously address potential exposure via hand contact to the face, inhalation, and droplet spray.

Olfactory Transcriptional Analysis of Salmon Exposed to Mixtures of Chlorpyrifos and Malathion Reveal Novel Molecular Pathways of Neurobehavioral Injury

PubMed Central

Wang, Lu; Espinoza, Herbert M.; MacDonald, James W.; Bammler, Theo K.; Williams, Chase R.; Yeh, Andrew; Louie, Ke’ale W.; Marcinek, David J.; Gallagher, Evan P.

2016-01-01

Pacific salmon exposed to sublethal concentrations of organophosphate pesticides (OP) have impaired olfactory function that can lead to loss of behaviors that are essential for survival. These exposures often involve mixtures and can occur at levels below those which inhibit acetylcholinesterase (AChE). In this study, juvenile Coho salmon were exposed for 24 h to either 0.1, 0.5, or 2.5 ppb chlorpyrifos (CPF), 2, 10, or 50 ppb malathion (MAL), or binary mixtures of 0.1 CPF:2 ppb MAL, 0.5 CPF:10 ppb MAL, or 2.5 CPF:10 ppb MAL to mimic single and binary environmental exposures. Microarray analysis of olfactory rosettes from pesticide-exposed salmon revealed differentially expressed genes involved in nervous system function and signaling, aryl hydrocarbon receptor signaling, xenobiotic metabolism, and mitochondrial dysfunction. Coho exposed to OP mixtures exhibited a more pronounced loss in detection of a predatory olfactory cue relative to those exposed to single compounds, whereas respirometry experiments demonstrated that exposure to OPs, individually and in mixtures, reduced maximum respiratory capacity of olfactory rosette mitochondria. The observed molecular, biochemical, and behavioral effects occurred largely in the absence of effects on brain AChE. In summary, our results provide new insights associated with the sublethal neurotoxic effects of OP mixtures relevant to environmental exposures involving molecular and cellular pathways of injury to the salmon olfactory system that underlie neurobehavioral injury. PMID:26494550

Metabolome Integrated Analysis of High-Temperature Response in Pinus radiata.

PubMed

Escandón, Mónica; Meijón, Mónica; Valledor, Luis; Pascual, Jesús; Pinto, Gloria; Cañal, María Jesús

2018-01-01

The integrative omics approach is crucial to identify the molecular mechanisms underlying high-temperature response in non-model species. Based on future scenarios of heat increase, Pinus radiata plants were exposed to a temperature of 40°C for a period of 5 days, including recovered plants (30 days after last exposure to 40°C) in the analysis. The analysis of the metabolome using complementary mass spectrometry techniques (GC-MS and LC-Orbitrap-MS) allowed the reliable quantification of 2,287 metabolites. The analysis of identified metabolites and highlighter metabolic pathways across heat time exposure reveal the dynamism of the metabolome in relation to high-temperature response in P. radiata , identifying the existence of a turning point (on day 3) at which P. radiata plants changed from an initial stress response program (shorter-term response) to an acclimation one (longer-term response). Furthermore, the integration of metabolome and physiological measurements, which cover from the photosynthetic state to hormonal profile, suggests a complex metabolic pathway interaction network related to heat-stress response. Cytokinins (CKs), fatty acid metabolism and flavonoid and terpenoid biosynthesis were revealed as the most important pathways involved in heat-stress response in P. radiata , with zeatin riboside (ZR) and isopentenyl adenosine (iPA) as the key hormones coordinating these multiple and complex interactions. On the other hand, the integrative approach allowed elucidation of crucial metabolic mechanisms involved in heat response in P. radiata , as well as the identification of thermotolerance metabolic biomarkers (L-phenylalanine, hexadecanoic acid, and dihydromyricetin), crucial metabolites which can reschedule the metabolic strategy to adapt to high temperature.

Metabolome Integrated Analysis of High-Temperature Response in Pinus radiata

PubMed Central

Escandón, Mónica; Meijón, Mónica; Valledor, Luis; Pascual, Jesús; Pinto, Gloria; Cañal, María Jesús

2018-01-01

The integrative omics approach is crucial to identify the molecular mechanisms underlying high-temperature response in non-model species. Based on future scenarios of heat increase, Pinus radiata plants were exposed to a temperature of 40°C for a period of 5 days, including recovered plants (30 days after last exposure to 40°C) in the analysis. The analysis of the metabolome using complementary mass spectrometry techniques (GC-MS and LC-Orbitrap-MS) allowed the reliable quantification of 2,287 metabolites. The analysis of identified metabolites and highlighter metabolic pathways across heat time exposure reveal the dynamism of the metabolome in relation to high-temperature response in P. radiata, identifying the existence of a turning point (on day 3) at which P. radiata plants changed from an initial stress response program (shorter-term response) to an acclimation one (longer-term response). Furthermore, the integration of metabolome and physiological measurements, which cover from the photosynthetic state to hormonal profile, suggests a complex metabolic pathway interaction network related to heat-stress response. Cytokinins (CKs), fatty acid metabolism and flavonoid and terpenoid biosynthesis were revealed as the most important pathways involved in heat-stress response in P. radiata, with zeatin riboside (ZR) and isopentenyl adenosine (iPA) as the key hormones coordinating these multiple and complex interactions. On the other hand, the integrative approach allowed elucidation of crucial metabolic mechanisms involved in heat response in P. radiata, as well as the identification of thermotolerance metabolic biomarkers (L-phenylalanine, hexadecanoic acid, and dihydromyricetin), crucial metabolites which can reschedule the metabolic strategy to adapt to high temperature. PMID:29719546

In silico epigenetics of metal exposure and subclinical atherosclerosis in middle aged men: pilot results from the Aragon Workers Health Study.

PubMed

Riffo-Campos, Angela L; Fuentes-Trillo, Azahara; Tang, Wan Y; Soriano, Zoraida; De Marco, Griselda; Rentero-Garrido, Pilar; Adam-Felici, Victoria; Lendinez-Tortajada, Veronica; Francesconi, Kevin; Goessler, Walter; Ladd-Acosta, Christine; Leon-Latre, Montse; Casasnovas, Jose A; Chaves, F Javier; Navas-Acien, Ana; Guallar, Eliseo; Tellez-Plaza, Maria

2018-06-05

We explored the association of metal levels with subclinical atherosclerosis and epigenetic changes in relevant biological pathways. Whole blood DNA Infinium Methylation 450 K data were obtained from 23 of 73 middle age men without clinically evident cardiovascular disease (CVD) who participated in the Aragon Workers Health Study in 2009 (baseline visit) and had available baseline urinary metals and subclinical atherosclerosis measures obtained in 2010-2013 (follow-up visit). The median metal levels were 7.36 µg g -1 , 0.33 µg g -1 , 0.11 µg g -1 and 0.07 µg g -1 , for arsenic (sum of inorganic and methylated species), cadmium, antimony and tungsten, respectively. Urine cadmium and tungsten were associated with femoral and carotid intima-media thickness, respectively (Pearson's r = 0.27; p = 0.03 in both cases). Among nearest genes to identified differentially methylated regions (DMRs), 46% of metal-DMR genes overlapped with atherosclerosis-DMR genes ( p < 0.001). Pathway enrichment analysis of atherosclerosis-DMR genes showed a role in inflammatory, metabolic and transport pathways. In in silico protein-to-protein interaction networks among proteins encoded by 162 and 108 genes attributed to atherosclerosis- and metal-DMRs, respectively, with proteins known to have a role in atherosclerosis pathways, we observed hub proteins in the network associated with both atherosclerosis and metal-DMRs (e.g. SMAD3 and NOP56 ), and also hub proteins associated with metal-DMRs only but with relevant connections with atherosclerosis effectors (e.g. SSTR5 , HDAC4 , AP2A2 , CXCL12 and SSTR4 ). Our integrative in silico analysis demonstrates the feasibility of identifying epigenomic regions linked to environmental exposures and potentially involved in relevant pathways for human diseases. While our results support the hypothesis that metal exposures can influence health due to epigenetic changes, larger studies are needed to confirm our pilot results.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'. © 2018 The Author(s).

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

PubMed

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

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. 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. 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.

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

PubMed Central

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

1H NMR spectroscopic analysis detects metabolic disturbances in rat urine on acute exposure to heavy metal tungsten alloy based metals salt.

PubMed

Tyagi, Ritu; Rana, Poonam; Gupta, Mamta; Bhatnagar, Deepak; Srivastava, Shatakshi; Roy, Raja; Khushu, Subash

2014-03-25

Heavy metal tungsten alloys (HMTAs) have been found to be safer alternatives for making military munitions. Recently, some studies demonstrating the toxic potential of HMTAs have raised concern over the safety issues, and further propose that HMTAs exposure may lead to physiological disturbances as well. To look for the systemic effect of acute toxicity of HMTA based metals salt, (1)H nuclear magnetic resonance ((1)H NMR) spectroscopic profiling of rat urine was carried out. Male Sprague Dawley rats were administered (intraperitoneal) low and high dose of mixture of HMTA based metals salt and NMR spectroscopy was carried out in urine samples collected at 8, 24, 72 and 120 h post dosing (p.d.). Serum biochemical parameters and liver histopathology were also conducted. The (1)H NMR spectra were analysed using multivariate analysis techniques to show the time- and dose-dependent biochemical variations in post HMTA based metals salt exposure. Urine metabolomic analysis showed changes associated with energy metabolism, amino acids, N-methyl nicotinamide, membrane and gut flora metabolites. Multivariate analysis showed maximum variation with best classification of control and treated groups at 24h p.d. At the end of the study, for the low dose group most of the changes at metabolite level reverted to control except for the energy metabolites; whereas, in the high dose group some of the changes still persisted. The observations were well correlated with histopathological and serum biochemical parameters. Further, metabolic pathway analysis clarified that amongst all the metabolic pathways analysed, tricarboxylic acid cycle was most affected at all the time points indicating a switchover in energy metabolism from aerobic to anaerobic. These results suggest that exposure of rats to acute doses of HMTA based metals salt disrupts physiological metabolism with moderate injury to the liver, which might indirectly result from heavy metals induced oxidative stress. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Effects of acute dieldrin exposure on neurotransmitters and global gene transcription in largemouth bass (Micropterus salmoides) hypothalamus

PubMed Central

Martyniuk, Christopher J.; Feswick, April; Spade, Daniel J.; Kroll, Kevin J.; Barber, David S.; Denslow, Nancy D.

2010-01-01

Exposure to dieldrin induces neurotoxic effects in the vertebrate CNS and disrupts reproductive processes in teleost fish. Reproductive impairment observed in fish by dieldrin is likely the result of multiple effects along the hypothalamic-pituitary-gonadal axis but the molecular signaling cascades are not well characterized. To better elucidate the mode of action of dieldrin in the hypothalamus, this study measured neurotransmitter levels and examined the transcriptomic response in female largemouth bass (LMB) to an acute treatment of dieldrin. Male and female LMB were injected with either vehicle or 10 mg dieldrin/kg and sacrificed after seven days. There were no significant changes in dopamine or DOPAC concentrations in the neuroendocrine brain of males and females after treatment but GABA levels in females were moderately increased 20–30% in the hypothalamus and cerebellum. In the female hypothalamus, there were 227 transcripts (p<0.001) identified as being differentially regulated by dieldrin. Functional enrichment analysis revealed transcription, DNA repair, ubiquitin-proteasome pathway, and cell communication, as biological processes over-represented in the microarray analysis. Pathway analysis identified DNA damage, inflammation, regeneration, and Alzheimer’s disease as major cell processes and diseases affected by dieldrin. Using multiple bioinformatics approaches, this study demonstrates that the teleostean hypothalamus is a target for dieldrin-induced neurotoxicity and provides mechanistic evidence that dieldrin activates similar cell pathways and biological processes that are also associated with the etiology of human neurological disorders. PMID:20438755

Conditioning protects C. elegans from lethal effects of enteropathogenic E. coli through activation of genes that regulate lifespan and innate immunity

PubMed Central

Anyanful, Akwasi; Easley, Kirk A.; Benian, Guy M.; Kalman, Daniel

2010-01-01

SUMMARY Caenorhabditis elegans exhibit avoidance behavior when presented with diverse bacterial pathogens. We hypothesized that exposure to pathogens might not only cause worms to move away but also simultaneously activate pathways that promote resistance to the pathogen. We show that brief exposure to the virulent or avirulent strains of the bacterial pathogen enteropathogenic E. coli (EPEC) “conditions” or “immunizes” C. elegans to survive a subsequent exposure that would otherwise prove lethal. Conditioning requires dopaminergic neurons. Conditioning also requires the p38 MAP Kinase pathway, which regulates innate immunity, and the insulin/IGFR pathway, which regulates lifespan. Our findings suggest that the molecular pathways that regulate innate immunity and lifespan and provide protection may, in nature, be regulated or “conditioned” by exposure to pathogens, and perhaps allow survival in noxious environments. PMID:19454349

Activation of AhR-mediated toxicity pathway by emerging ...

EPA Pesticide Factsheets

Polychlorinated diphenyl sulfides (PCDPSs) are a group of environmental pollutants for which limited toxicological information is available. This study tested the hypothesis that PCDPSs could activate the mammalian aryl hydrocarbon receptor (AhR) mediated toxicity pathways. Eighteen PCDPSs were tested in the H4IIE-luc transactivation assay, with 13/18 causing concentration-dependent AhR activation. Potencies of several congeners were similar to those of mono-ortho substituted polychlorinated biphenyls. A RNA sequencing (RNA-seq)-based transcriptomic analysis was performed on H4IIE cells treated with two PCDPS congeners, 2,2',3,3',4,5,6-hepta-CDPS, and 2,4,4',5-tetra-CDPS. Results of RNA-seq revealed a remarkable modulation on a relatively short gene list by exposure to the tested concentrations of PCDPSs, among which, Cyp1 responded with the greatest fold up-regulation. Both the identities of the modulated transcripts and the associated pathways were consistent with targets and pathways known to be modulated by other types of AhR agonists and there was little evidence for significant off-target effects within the cellular context of the H4IIE bioassay. The results suggest AhR activation as a toxicologically relevant mode of action for PCDPSs suggests the utility of AhR-related toxicity pathways for predicting potential hazards associated with PCDPS exposure in mammals and potentially other vertebrates. Polychlorinated diphenyl sulfides (PCDPSs) are a group of en

Prenatal Exposure to Arsenic and Cadmium Impacts Infectious Disease-Related Genes within the Glucocorticoid Receptor Signal Transduction Pathway

PubMed Central

Rager, Julia E.; Yosim, Andrew; Fry, Rebecca C.

2014-01-01

There is increasing evidence that environmental agents mediate susceptibility to infectious disease. Studies support the impact of prenatal/early life exposure to the environmental metals inorganic arsenic (iAs) and cadmium (Cd) on increased risk for susceptibility to infection. The specific biological mechanisms that underlie such exposure-mediated effects remain understudied. This research aimed to identify key genes/signal transduction pathways that associate prenatal exposure to these toxic metals with changes in infectious disease susceptibility using a Comparative Genomic Enrichment Method (CGEM). Using CGEM an infectious disease gene (IDG) database was developed comprising 1085 genes with known roles in viral, bacterial, and parasitic disease pathways. Subsequently, datasets collected from human pregnancy cohorts exposed to iAs or Cd were examined in relationship to the IDGs, specifically focusing on data representing epigenetic modifications (5-methyl cytosine), genomic perturbations (mRNA expression), and proteomic shifts (protein expression). A set of 82 infection and exposure-related genes was identified and found to be enriched for their role in the glucocorticoid receptor signal transduction pathway. Given their common identification across numerous human cohorts and their known toxicological role in disease, the identified genes within the glucocorticoid signal transduction pathway may underlie altered infectious disease susceptibility associated with prenatal exposures to the toxic metals iAs and Cd in humans. PMID:25479081

Effects of chronic dietary exposure of zinc oxide nanoparticles on the serum protein profile of juvenile common carp (Cyprinus carpio L.).

PubMed

Chupani, Latifeh; Zusková, Eliška; Niksirat, Hamid; Panáček, Aleš; Lünsmann, Vanessa; Haange, Sven-Bastiaan; von Bergen, Martin; Jehmlich, Nico

2017-02-01

Zinc oxide (ZnO) nanoparticles (NPs) have been dramatically used in industry, biology, and medicine. Despite their interesting physico-chemical properties for application in various industrial, medical, and consumer products, safe use of ZnO NPs are under challenges due to the inadequate information related to their toxicological endpoints. Proteomics was applied to evaluate the sub-lethal effects of dietary exposure to ZnO NPs on serum proteome profile of juvenile common carp, (Cyprinus carpio). Therefore, ZnO NPs solution (500mgkg -1 of feed) was added to a commercial carp feed for six weeks. We compared the serum proteome profile from 7 controls and 7 treated fish. In addition, zinc accumulation were measured in intestine, liver, gill and brain. In total, we were able to identify 326 proteins from 6845 distinct peptides. As a result of the data analysis, the abundance levels of four proteins were significantly altered (fold change (fc) ≥2 and p<0.05) after dietary exposure to ZnO NPs. The protein levels of the complement component C4-2 (fc 2.5) and the uncharacterised protein encoded by kng1 (fc 5.8) were increased and major histocompatibility class I (fc 4.9) and the uncharacterised protein encoded by lum (fc 3.5) were decreased (fc 2.5). Molecular pathway analysis revealed four canonical pathways including acute-phase response signalling, liver and retinoid X receptors activation, and intrinsic and extrinsic prothrombin activation pathways as significantly regulated in the treated fish. No significant difference was observed for zinc accumulation in exposed fish compared to controls. In summary, despite no apparent accumulation, ZnO NPs exposure to common carp probably disturbs the fish homeostasis by affecting proteins of the haematological and the immune systems. Copyright © 2016 Elsevier B.V. All rights reserved.

Caffeine exposure alters cardiac gene expression in embryonic cardiomyocytes

PubMed Central

Fang, Xiefan; Mei, Wenbin; Barbazuk, William B.; Rivkees, Scott A.

2014-01-01

Previous studies demonstrated that in utero caffeine treatment at embryonic day (E) 8.5 alters DNA methylation patterns, gene expression, and cardiac function in adult mice. To provide insight into the mechanisms, we examined cardiac gene and microRNA (miRNA) expression in cardiomyocytes shortly after exposure to physiologically relevant doses of caffeine. In HL-1 and primary embryonic cardiomyocytes, caffeine treatment for 48 h significantly altered the expression of cardiac structural genes (Myh6, Myh7, Myh7b, Tnni3), hormonal genes (Anp and BnP), cardiac transcription factors (Gata4, Mef2c, Mef2d, Nfatc1), and microRNAs (miRNAs; miR208a, miR208b, miR499). In addition, expressions of these genes were significantly altered in embryonic hearts exposed to in utero caffeine. For in utero experiments, pregnant CD-1 dams were treated with 20–60 mg/kg of caffeine, which resulted in maternal circulation levels of 37.3–65.3 μM 2 h after treatment. RNA sequencing was performed on embryonic ventricles treated with vehicle or 20 mg/kg of caffeine daily from E6.5-9.5. Differential expression (DE) analysis revealed that 124 genes and 849 transcripts were significantly altered, and differential exon usage (DEU) analysis identified 597 exons that were changed in response to prenatal caffeine exposure. Among the DE genes identified by RNA sequencing were several cardiac structural genes and genes that control DNA methylation and histone modification. Pathway analysis revealed that pathways related to cardiovascular development and diseases were significantly affected by caffeine. In addition, global cardiac DNA methylation was reduced in caffeine-treated cardiomyocytes. Collectively, these data demonstrate that caffeine exposure alters gene expression and DNA methylation in embryonic cardiomyocytes. PMID:25354728

Applied mediation analyses: a review and tutorial.

PubMed

Lange, Theis; Hansen, Kim Wadt; Sørensen, Rikke; Galatius, Søren

2017-01-01

In recent years, mediation analysis has emerged as a powerful tool to disentangle causal pathways from an exposure/treatment to clinically relevant outcomes. Mediation analysis has been applied in scientific fields as diverse as labour market relations and randomized clinical trials of heart disease treatments. In parallel to these applications, the underlying mathematical theory and computer tools have been refined. This combined review and tutorial will introduce the reader to modern mediation analysis including: the mathematical framework; required assumptions; and software implementation in the R package medflex. All results are illustrated using a recent study on the causal pathways stemming from the early invasive treatment of acute coronary syndrome, for which the rich Danish population registers allow us to follow patients' medication use and more after being discharged from hospital.

Integrating Aggregate Exposure Pathway (AEP) and Adverse ...

EPA Pesticide Factsheets

High throughput toxicity testing (HTT) holds the promise of providing data for tens of thousands of chemicals that currently have no data due to the cost and time required for animal testing. Interpretation of these results require information linking the perturbations seen in vitro with adverse outcomes in vivo and requires knowledge of how estimated exposure to the chemicals compare to the in vitro concentrations that show an effect. This abstract discusses how Adverse Outcome Pathways (AOPs) can be used to link HTT with adverse outcomes of regulatory significance and how Aggregate Exposure Pathways (AEPs) can connect concentrations of environment stressors at a source with an expected target site concentration designed to provide exposure estimates that are comparable to concentrations identified in HTT. Presentation at the ICCA-LRI and JRC Workshop: Fit-For-Purpose Exposure Assessment For Risk-Based Decision Making

Predicting Residential Exposure to Phthalate Plasticizer Emitted from Vinyl Flooring: Sensitivity, Uncertainty, and Implications for Biomonitoring

PubMed Central

Xu, Ying; Cohen Hubal, Elaine A.; Little, John C.

2010-01-01

Background Because of the ubiquitous nature of phthalates in the environment and the potential for adverse human health effects, an urgent need exists to identify the most important sources and pathways of exposure. Objectives Using emissions of di(2-ethylhexyl) phthalate (DEHP) from vinyl flooring (VF) as an illustrative example, we describe a fundamental approach that can be used to identify the important sources and pathways of exposure associated with phthalates in indoor material. Methods We used a three-compartment model to estimate the emission rate of DEHP from VF and the evolving exposures via inhalation, dermal absorption, and oral ingestion of dust in a realistic indoor setting. Results A sensitivity analysis indicates that the VF source characteristics (surface area and material-phase concentration of DEHP), as well as the external mass-transfer coefficient and ventilation rate, are important variables that influence the steady-state DEHP concentration and the resulting exposure. In addition, DEHP is sorbed by interior surfaces, and the associated surface area and surface/air partition coefficients strongly influence the time to steady state. The roughly 40-fold range in predicted exposure reveals the inherent difficulty in using biomonitoring to identify specific sources of exposure to phthalates in the general population. Conclusions The relatively simple dependence on source and chemical-specific transport parameters suggests that the mechanistic modeling approach could be extended to predict exposures arising from other sources of phthalates as well as additional sources of other semivolatile organic compounds (SVOCs) such as biocides and flame retardants. This modeling approach could also provide a relatively inexpensive way to quantify exposure to many of the SVOCs used in indoor materials and consumer products. PMID:20123613

Predicting residential exposure to phthalate plasticizer emitted from vinyl flooring: sensitivity, uncertainty, and implications for biomonitoring.

PubMed

Xu, Ying; Cohen Hubal, Elaine A; Little, John C

2010-02-01

Because of the ubiquitous nature of phthalates in the environment and the potential for adverse human health effects, an urgent need exists to identify the most important sources and pathways of exposure. Using emissions of di(2-ethylhexyl) phthalate (DEHP) from vinyl flooring (VF) as an illustrative example, we describe a fundamental approach that can be used to identify the important sources and pathways of exposure associated with phthalates in indoor material. We used a three-compartment model to estimate the emission rate of DEHP from VF and the evolving exposures via inhalation, dermal absorption, and oral ingestion of dust in a realistic indoor setting. A sensitivity analysis indicates that the VF source characteristics (surface area and material-phase concentration of DEHP), as well as the external mass-transfer coefficient and ventilation rate, are important variables that influence the steady-state DEHP concentration and the resulting exposure. In addition, DEHP is sorbed by interior surfaces, and the associated surface area and surface/air partition coefficients strongly influence the time to steady state. The roughly 40-fold range in predicted exposure reveals the inherent difficulty in using biomonitoring to identify specific sources of exposure to phthalates in the general population. The relatively simple dependence on source and chemical-specific transport parameters suggests that the mechanistic modeling approach could be extended to predict exposures arising from other sources of phthalates as well as additional sources of other semivolatile organic compounds (SVOCs) such as biocides and flame retardants. This modeling approach could also provide a relatively inexpensive way to quantify exposure to many of the SVOCs used in indoor materials and consumer products.

Health risk assessment and source study of PAHs from roadside soil dust of a heavy mining area in India.

PubMed

Tarafdar, Abhrajyoti; Sinha, Alok

2018-02-26

The total concentrations of 13 detected polycyclic aromatic hydrocarbons (PAHs) in different traffic soil samples of Dhanbad heavy mining area, India, were between 8.256 and 12.562 µg/g and were dominated by four ring PAHs (44%). Diagnostic ratio study revealed that fossil fuel burning and vehicular pollution are the most prominent sources of the PAHs in roadside soil even at a heavy coal mining area. The 90th percentiles cancer risks determined by probabilistic health risk assessment (Monte Carlo simulations) for both the age groups (children and adults) were above tolerable limit (>1.00E-06) according to USEPA. The simulated mean cancer risk was 1.854E-05 for children and 1.823E-05 for adults. For different exposure pathways, dermal contact was observed to be the major pathway with an exposure load of 74% for children and 85% for adults. Sensitivity analysis demonstrated relative skin adherence factor for soil (AF) is the most influential parameter of the simulation, followed by exposure duration (ED).

Analysis of aromatic catabolic pathways in Pseudomonas putida KT 2440 using a combined proteomic approach: 2-DE/MS and cleavable isotope-coded affinity tag analysis.

PubMed

Kim, Young Hwan; Cho, Kun; Yun, Sung-Ho; Kim, Jin Young; Kwon, Kyung-Hoon; Yoo, Jong Shin; Kim, Seung Il

2006-02-01

Proteomic analysis of Pseudomonas putida KT2440 cultured in monocyclic aromatic compounds was performed using 2-DE/MS and cleavable isotope-coded affinity tag (ICAT) to determine whether proteins involved in aromatic compound degradation pathways were altered as predicted by genomic analysis (Jiménez et al., Environ Microbiol. 2002, 4, 824-841). Eighty unique proteins were identified by 2-DE/MS or MS/MS analysis from P. putida KT2440 cultured in the presence of six different organic compounds. Benzoate dioxygenase (BenA, BenD) and catechol 1,2-dioxygenase (CatA) were induced by benzoate. Protocatechuate 3,4-dixoygenase (PcaGH) was induced by p-hydroxybenzoate and vanilline. beta-Ketoadipyl CoA thiolase (PcaF) and 3-oxoadipate enol-lactone hydrolase (PcaD) were induced by benzoate, p-hydroxybenzoate and vanilline, suggesting that benzoate, p-hydroxybenzoate and vanilline were degraded by different dioxygenases and then converged in the same beta-ketoadipate degradation pathway. An additional 110 proteins, including 19 proteins from 2-DE analysis, were identified by cleavable ICAT analysis for benzoate-induced proteomes, which complemented the 2-DE results. Phenylethylamine exposure induced beta-ketoacyl CoA thiolase (PhaD) and ring-opening enzyme (PhaL), both enzymes of the phenylacetate (pha) biodegradation pathway. Phenylalanine induced 4-hydroxyphenyl-pyruvate dioxygenase (Hpd) and homogentisate 1,2-dioxygenase (HmgA), key enzymes in the homogentisate degradation pathway. Alkyl hydroperoxide reductase (AphC) was induced under all aromatic compounds conditions. These results suggest that proteome analysis complements and supports predictive information obtained by genomic sequence analysis.

Cold-Induced Changes in Gene Expression in Brown Adipose Tissue, White Adipose Tissue and Liver

PubMed Central

Shore, Andrew M.; Karamitri, Angeliki; Kemp, Paul; Speakman, John R.; Graham, Neil S.; Lomax, Michael A.

2013-01-01

Cold exposure imposes a metabolic challenge to mammals that is met by a coordinated response in different tissues to prevent hypothermia. This study reports a transcriptomic analysis in brown adipose tissue (BAT), white adipose (WAT) and liver of mice in response to 24 h cold exposure at 8°C. Expression of 1895 genes were significantly (P<0.05) up- or down-regulated more than two fold by cold exposure in all tissues but only 5 of these genes were shared by all three tissues, and only 19, 14 and 134 genes were common between WAT and BAT, WAT and liver, and BAT and liver, respectively. We confirmed using qRT-PCR, the increased expression of a number of characteristic BAT genes during cold exposure. In both BAT and the liver, the most common direction of change in gene expression was suppression (496 genes in BAT and 590 genes in liver). Gene ontology analysis revealed for the first time significant (P<0.05) down regulation in response to cold, of genes involved in oxidoreductase activity, lipid metabolic processes and protease inhibitor activity, in both BAT and liver, but not WAT. The results reveal an unexpected importance of down regulation of cytochrome P450 gene expression and apolipoprotein, in both BAT and liver, but not WAT, in response to cold exposure. Pathway analysis suggests a model in which down regulation of the nuclear transcription factors HNF4α and PPARα in both BAT and liver may orchestrate the down regulation of genes involved in lipoprotein and steroid metabolism as well as Phase I enzymes belonging to the cytochrome P450 group in response to cold stress in mice. We propose that the response to cold stress involves decreased gene expression in a range of cellular processes in order to maximise pathways involved in heat production. PMID:23894377

Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weng, Yu-I; Hsu, Pei-Yin; Liyanarachchi, Sandya

Substantial evidence indicates that exposure to bisphenol A (BPA) during early development may increase breast cancer risk later in life. The changes may persist into puberty and adulthood, suggesting an epigenetic process being imposed in differentiated breast epithelial cells. The molecular mechanisms by which early memory of BPA exposure is imprinted in breast progenitor cells and then passed onto their epithelial progeny are not well understood. The aim of this study was to examine epigenetic changes in breast epithelial cells treated with low-dose BPA. We also investigated the effect of BPA on the ER{alpha} signaling pathway and global gene expressionmore » profiles. Compared to control cells, nuclear internalization of ER{alpha} was observed in epithelial cells preexposed to BPA. We identified 170 genes with similar expression changes in response to BPA. Functional analysis confirms that gene suppression was mediated in part through an ER{alpha}-dependent pathway. As a result of exposure to BPA or other estrogen-like chemicals, the expression of lysosomal-associated membrane protein 3 (LAMP3) became epigenetically silenced in breast epithelial cells. Furthermore, increased DNA methylation in the LAMP3 CpG island was this repressive mark preferentially occurred in ER{alpha}-positive breast tumors. These results suggest that the in vitro system developed in our laboratory is a valuable tool for exposure studies of BPA and other xenoestrogens in human cells. Individual and geographical differences may contribute to altered patterns of gene expression and DNA methylation in susceptible loci. Combination of our exposure model with epigenetic analysis and other biochemical assays can give insight into the heritable effect of low-dose BPA in human cells.« less

Movie Exposure to Alcohol Cues and Adolescent Alcohol Problems: A Longitudinal Analysis in a National Sample

PubMed Central

Wills, Thomas A.; Sargent, James D.; Gibbons, Frederick X.; Gerrard, Meg; Stoolmiller, Mike

2009-01-01

The authors tested a theoretical model of how exposure to alcohol cues in movies predicts level of alcohol use (ever use plus ever and recent binge drinking) and alcohol-related problems. A national sample of younger adolescents was interviewed by telephone with 4 repeated assessments spaced at 8-month intervals. A structural equation modeling analysis performed for ever-drinkers at Time 3 (N = 961) indicated that, controlling for a number of covariates, movie alcohol exposure at Time 1 was related to increases in peer alcohol use and adolescent alcohol use at Time 2. Movie exposure had indirect effects to alcohol use and problems at Times 3 and 4 through these pathways, with direct effects to problems from Time 1 rebelliousness and Time 2 movie exposure also found. Prospective risk-promoting effects were also found for alcohol expectancies, peer alcohol use, and availability of alcohol in the home; protective effects were found for mother’s responsiveness and for adolescent’s school performance and self-control. Theoretical and practical implications are discussed. PMID:19290687

Movie exposure to alcohol cues and adolescent alcohol problems: a longitudinal analysis in a national sample.

PubMed

Wills, Thomas A; Sargent, James D; Gibbons, Frederick X; Gerrard, Meg; Stoolmiller, Mike

2009-03-01

The authors tested a theoretical model of how exposure to alcohol cues in movies predicts level of alcohol use (ever use plus ever and recent binge drinking) and alcohol-related problems. A national sample of younger adolescents was interviewed by telephone with 4 repeated assessments spaced at 8-month intervals. A structural equation modeling analysis performed for ever-drinkers at Time 3 (N = 961) indicated that, controlling for a number of covariates, movie alcohol exposure at Time 1 was related to increases in peer alcohol use and adolescent alcohol use at Time 2. Movie exposure had indirect effects to alcohol use and problems at Times 3 and 4 through these pathways, with direct effects to problems from Time 1 rebelliousness and Time 2 movie exposure also found. Prospective risk-promoting effects were also found for alcohol expectancies, peer alcohol use, and availability of alcohol in the home; protective effects were found for mother's responsiveness and for adolescent's school performance and self-control. Theoretical and practical implications are discussed. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Conceptualizing adverse outcome pathways for ...

EPA Pesticide Factsheets

Cyclooxygenase (COX) inhibition is of concern in fish because COX inhibitors (e.g., ibuprofen) are ubiquitous in aquatic systems/fish tissues, and can disrupt synthesis of prostaglandins that modulate a variety of essential biological functions (e.g., reproduction). This study utilized newly generated high content (transcriptomic and metabolomic) empirical data in combination with existing high throughput (ACTOR, epa.gov) toxicity data to facilitate development of adverse outcome pathways (AOPs) for molecular initiating event (MIE) of COX inhibition. We examined effects of a waterborne, 96h exposure to three COX inhibitors (indomethacin (IN; 100 µg/L), ibuprofen (IB; 200 µg/L) and celecoxib (CX; 20 µg/L) on the liver metabolome and ovarian gene expression (using oligonucleotide microarray 4 x15K platform) in sexually mature fathead minnows (n=8). Differentially expressed genes were identified (t-test, p < 0.01), and functional analyses performed to determine enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (p < 0.05). Principal component analysis indicated that liver metabolomics profiles of IN, IB and CX were not significantly different from control or one another. When compared to control, exposure to IB and CX resulted in differential expression of comparable numbers of genes (IB = 433, CX= 545). In contrast, 2558 genes were differentially expressed in IN-treated fish. KEGG pathway analyses show that IN had extensive effects on oocyte meios

Region-specific effects of developmental exposure to cocaine on fibroblast growth factor-2 expression in the rat brain.

PubMed

Giannotti, Giuseppe; Caffino, Lucia; Mottarlini, Francesca; Racagni, Giorgio; Fumagalli, Fabio

2016-07-01

Adolescence is a period of high vulnerability to drugs of abuse and alterations of the proper developmental trajectory via psychostimulant exposure might change the physiological brain homeostasis. By microdissection of brain areas via punching, we investigated whether repeated exposure to cocaine during adolescence (from postnatal day 28 [PND28] to PND42) has altered fibroblast growth factor-2 (FGF-2) messenger RNA (mRNA) levels in selected brain subregions critical for the action of cocaine. We found a reduction of FGF-2 mRNA levels in ventral tegmental area (VTA), where mesocortical and mesolimbic pathways originate. The analysis of the trophic factor levels in the distal projecting regions revealed a selective reduction of FGF-2 mRNA levels in infralimbic (IL) subregion of the medial prefrontal cortex (the terminal region of the mesocortical pathway) and in the nucleus accumbens core (cNAc) (the terminal region of the mesolimbic pathway). Last, we found reduced FGF-2 mRNA levels also in brain regions which, although in a different manner, contribute to the reward system, i.e., the central nucleus of amygdala (cAmy) and the ventral portion of hippocampus (vHip). The widespread and coordinated reduction of FGF-2 mRNA levels across the brain's reward neurocircuitry might represent a defensive strategy set in motion to oppose to the psychostimulant properties of cocaine. Moreover, given the role of FGF-2 in modulating mood disorders, the reduced trophic support here observed might sustain the negative emotional state set in motion by repeated exposure to cocaine.

Alteration of peripheral blood monocyte gene expression in humans following diesel exhaust inhalation

PubMed Central

Pettit, Ashley P.; Brooks, Andrew; Laumbach, Robert; Fiedler, Nancy; Wang, Qi; Strickland, Pamela Ohman; Madura, Kiran; Zhang, Junfeng; Kipen, Howard M.

2013-01-01

Context Epidemiologic associations between acutely increased cardiorespiratory morbidity and mortality and particulate air pollution are well established, but the effects of acute pollution exposure on human gene expression changes are not well understood. Objective In order to identify potential mechanisms underlying epidemiologic associations between air pollution and morbidity, we explored changes in gene expression in humans following inhalation of fresh diesel exhaust (DE), a model for particulate air pollution. Materials and methods Fourteen ethnically homogeneous (white males), young, healthy subjects underwent 60-min inhalation exposures on 2 separate days with clean filtered air (CA) or freshly generated and diluted DE at a concentration of 300 μg/m3 PM2.5. Prior to and 24 h following each session, whole blood was sampled and fractionated for peripheral blood mononuclear cell (PBMC) isolation, RNA extraction, and generation of cDNA, followed by hybridization with Agilent Whole Human Genome (4X44K) arrays. Results Oxidative stress and the ubiquitin proteasome pathway, as well as the coagulation system, were among hypothesized pathways identified by analysis of differentially expressed genes. Nine genes from these pathways were validated using real-time polymerase chain reaction (PCR) to compare fold change in expression between DE exposed and CA days. Quantitative gene fold changes generated by real-time PCR were directionally consistent with the fold changes from the microarray analysis. Discussion and conclusion Changes in gene expression connected with key oxidative stress, protein degradation, and coagulation pathways are likely to underlie observed physiologic and clinical outcomes and suggest specific avenues and sensitive time points for further physiologic exploration. PMID:22369193

Middle Latency Auditory Evoked Potential (MLAEP) in Workers with and without Tinnitus who are Exposed to Occupational Noise.

PubMed

dos Santos Filha, Valdete Alves Valentins; Samelli, Alessandra Giannella; Matas, Carla Gentile

2015-09-11

Tinnitus is an important occupational health concern, but few studies have focused on the central auditory pathways of workers with a history of occupational noise exposure. Thus, we analyzed the central auditory pathways of workers with a history of occupational noise exposure who had normal hearing threshold, and compared middle latency auditory evoked potential in those with and without noise-induced tinnitus. Sixty individuals (30 with and 30 without tinnitus) underwent the following procedures: anamnesis, immittance measures, pure-tone air conduction thresholds at all frequencies between 0.25-8 kHz, and middle latency auditory evoked potentials. Quantitative analysis of latencies and amplitudes of middle latency auditory evoked potential showed no significant differences between the groups with and without tinnitus. In the qualitative analysis, we found that both groups showed increased middle latency auditory evoked potential latencies. The study group had more alterations of the "both" type regarding the Na-Pa amplitude, while the control group had more "electrode effect" alterations, but these alterations were not significantly different when compared to controls. Individuals with normal hearing with or without tinnitus who are exposed to occupational noise have altered middle latency auditory evoked potential, suggesting impairment of the auditory pathways in cortical and subcortical regions. Although differences did not reach significance, individuals with tinnitus seemed to have more abnormalities in components of the middle latency auditory evoked potential when compared to individuals without tinnitus, suggesting alterations in the generation and transmission of neuroelectrical impulses along the auditory pathway.

High concentrations of atmospheric ammonia induce alterations of gene expression in the breast muscle of broilers (Gallus gallus) based on RNA-Seq.

PubMed

Yi, Bao; Chen, Liang; Sa, Renna; Zhong, Ruqing; Xing, Huan; Zhang, Hongfu

2016-08-11

High concentrations of atmospheric ammonia are one of the key environmental stressors affecting broiler production performance, which causes remarkable economic losses as well as potential welfare problems of the broiler industry. Previous reports demonstrated that high levels of ammonia altered body fat distribution and meat quality of broilers. However, the molecular mechanisms and metabolic pathways in breast muscle altered by high concentrations of ambient ammonia exposure on broilers are still unknown. This study utilized RNA-Seq to compare the transcriptomes of breast muscles to identify differentially enriched genes in broilers exposed to high and low concentrations of atmospheric ammonia. A total of 267 promising candidate genes were identified by differential expression analysis, among which 67 genes were up-regulated and 189 genes were down-regulated. Bioinformatics analysis suggested that the up and down-regulation of these genes were involved in the following two categories of cellular pathways and metabolisms: Steroid biosynthesis (gga00100) and peroxisome proliferator-activated receptor (PPAR) signaling pathway (gga03320), which both participated in the lipid metabolism processes. This study suggests that longtime exposure to high concentrations of aerial ammonia can change fat content in breast muscle, meat quality and palatability via altering expression level of genes participating in important lipid metabolism pathways. These findings have provided novel insights into our understanding of molecular mechanisms of breast muscles exposed to ammonia in broilers. This study provides new information that could be used for genetic breeding and nutritional intervention in production practice of broilers industry in the future.

Non-thermal plasma inhibits human cervical cancer HeLa cells invasiveness by suppressing the MAPK pathway and decreasing matrix metalloproteinase-9 expression

NASA Astrophysics Data System (ADS)

Li, Wei; Yu, K. N.; Bao, Lingzhi; Shen, Jie; Cheng, Cheng; Han, Wei

2016-01-01

Non-thermal plasma (NTP) has been proposed as a novel therapeutic method for anticancer treatment. However, the mechanism underlying its biological effects remains unclear. In this study, we investigated the inhibitory effect of NTP on the invasion of HeLa cells, and explored the possible mechanism. Our results showed that NTP exposure for 20 or 40 s significantly suppressed the migration and invasion of HeLa cells on the basis of matrigel invasion assay and wound healing assay, respectively. Moreover, NTP reduced the activity and protein expression of the matrix metalloproteinase (MMP)-9 enzyme. Western blot analysis indicated that NTP exposure effectively decreased phosphorylation level of both ERK1/2 and JNK, but not p38 MAPK. Furthermore, treatment with MAPK signal pathway inhibitors or NTP all exhibited significant depression of HeLa cells migration and MMP-9 expression. The result showed that NTP synergistically suppressed migration and MMP-9 expression in the presence of ERK1/2 inhibitor and JNK inhibitor, but not p38 MAPK inhibitor. Taken together, these findings suggested that NTP exposure inhibited the migration and invasion of HeLa cells via down-regulating MMP-9 expression in ERK1/2 and JNK signaling pathways dependent manner. These findings provide hints to the potential clinical research and therapy of NTP on cervical cancer metastasis.

Metabolomics evaluation of the impact of smokeless tobacco exposure on the oral bacterium Capnocytophaga sputigena

PubMed Central

Sun, Jinchun; Jin, Jinshan; Beger, Richard D.; Cerniglia, Carl E.; Yang, Maocheng; Chen, Huizhong

2017-01-01

The association between exposure to smokeless tobacco products (STP) and oral diseases is partially due to the physiological and pathological changes in the composition of the oral microbiome and its metabolic profile. However, it is not clear how STPs affect the physiology and ecology of oral microbiota. A UPLC/QTof-MS-based metabolomics study was employed to analyze metabolic alterations in oral bacterium, Capnocytophaga sputigena as a result of smokeless tobacco exposure and to assess the capability of the bacterium to metabolize nicotine. Pathway analysis of the metabolome profiles indicated that smokeless tobacco extracts caused oxidative stress in the bacterium. The metabolomics data also showed that the argininenitric oxide pathway was perturbed by the smokeless tobacco treatment. Results also showed that LC/MS was useful in identifying STP constituents and additives, including caffeine and many flavoring compounds. No significant changes in levels of nicotine and its major metabolites were found when C. sputigena was cultured in a nutrient rich medium, although hydroxylnicotine and cotinine N-oxide were detected in the bacterial metabolites suggesting that nicotine metabolism might be present as a minor degradation pathway in the bacterium. Study results provide new insights regarding the physiological and toxicological effects of smokeless tobacco on oral bacterium C. sputigena and associated oral health as well as measuring the ability of the oral bacterium to metabolize nicotine. PMID:27480511

Metabolomics evaluation of the impact of smokeless tobacco exposure on the oral bacterium Capnocytophaga sputigena.

PubMed

Sun, Jinchun; Jin, Jinshan; Beger, Richard D; Cerniglia, Carl E; Yang, Maocheng; Chen, Huizhong

2016-10-01

The association between exposure to smokeless tobacco products (STP) and oral diseases is partially due to the physiological and pathological changes in the composition of the oral microbiome and its metabolic profile. However, it is not clear how STPs affect the physiology and ecology of oral microbiota. A UPLC/QTof-MS-based metabolomics study was employed to analyze metabolic alterations in oral bacterium, Capnocytophaga sputigena as a result of smokeless tobacco exposure and to assess the capability of the bacterium to metabolize nicotine. Pathway analysis of the metabolome profiles indicated that smokeless tobacco extracts caused oxidative stress in the bacterium. The metabolomics data also showed that the arginine-nitric oxide pathway was perturbed by the smokeless tobacco treatment. Results also showed that LC/MS was useful in identifying STP constituents and additives, including caffeine and many flavoring compounds. No significant changes in levels of nicotine and its major metabolites were found when C. sputigena was cultured in a nutrient rich medium, although hydroxylnicotine and cotinine N-oxide were detected in the bacterial metabolites suggesting that nicotine metabolism might be present as a minor degradation pathway in the bacterium. Study results provide new insights regarding the physiological and toxicological effects of smokeless tobacco on oral bacterium C. sputigena and associated oral health as well as measuring the ability of the oral bacterium to metabolize nicotine. Published by Elsevier Ltd.

The Effect of Microplastic on the Uptake of Chemicals by the Lugworm Arenicola marina (L.) under Environmentally Relevant Exposure Conditions

PubMed Central

2017-01-01

It has been hypothesized that ingestion of microplastic increases exposure of aquatic organisms to hydrophobic contaminants. To date, most laboratory studies investigated chemical transfer from ingested microplastic without taking other exposure pathways into account. Therefore, we studied the effect of polyethylene (PE) microplastic in sediment on PCB uptake by Arenicola marina as a model species, quantifying uptake fluxes from all natural exposure pathways. PCB concentrations in sediment, biota lipids (Clip) and porewater measured with passive samplers were used to derive lipid-normalized bioaccumulation metrics Clip, Biota sediment accumulation factor (BSAF), Bioaccumulation factor (BAF) and the Biota plastic accumulation factor (BPAF). Small effects of PE addition were detected suggesting slightly increased or decreased bioaccumulation. However, the differences decreased in magnitude dependent on the metric used to assess bioaccumulation, in the order: Clip > BSAF > BPAF > BAF, and were nonsignificant for BAF. The fact that BAF, that is, normalization of Clip on porewater concentration, largely removed all effects of PE, shows that PE did not act as a measurable vector of PCBs. Biodynamic model analysis confirmed that PE ingestion contributed marginally to bioaccumulation. This work confirmed model-based predictions on the limited relevance of microplastic for bioaccumulation under environmentally realistic conditions, and illustrated the importance of assessing exposure through all media in microplastic bioaccumulation studies. PMID:28682597

Investigating Rare Risk Factors for Nipah Virus in Bangladesh: 2001–2012

PubMed Central

Hegde, Sonia T.; Sazzad, Hossain M. S.; Hossain, M. Jahangir; Alam, Mahbub-Ul; Kenah, Eben; Daszak, Peter; Rollin, Pierre; Rahman, Mahmudur; Luby, Stephen P.; Gurley, Emily S.

2016-01-01

Human Nipah encephalitis outbreaks have been identified almost yearly in Bangladesh since 2001. Though raw date palm sap consumption and person-to-person contact are recognized as major transmission pathways, alternative pathways of transmission are plausible and may not have been identified due to limited statistical power in each outbreak. We conducted a risk factor analysis using all 157 cases and 632 controls surveyed in previous investigations during 2004–2012 to identify exposures independently associated with Nipah, since date palm sap was first asked about as an exposure in 2004. To further explore possible rare exposures, we also conducted in-depth interviews with all cases, or proxies, since 2001 that reported no exposure to date palm sap or contact with another case. Cases were 4.9 (95% 3.2–7.7) times more likely to consume raw date palm sap and 7.3 (95% 4.0–13.4) times more likely to have contact with a Nipah case than controls. In-depth interviews revealed that 39/182 (21%) of Nipah cases reporting neither date palm sap consumption nor contact with another case were misclassified. Prevention efforts should be focused on interventions to interrupt transmission through date palm sap consumption and person-to-person contact. Furthermore, pooling outbreak investigation data is a good method for assessing rare exposures. PMID:27738775

The Effect of Microplastic on the Uptake of Chemicals by the Lugworm Arenicola marina (L.) under Environmentally Relevant Exposure Conditions.

PubMed

Besseling, Ellen; Foekema, Edwin M; van den Heuvel-Greve, Martine J; Koelmans, Albert A

2017-08-01

It has been hypothesized that ingestion of microplastic increases exposure of aquatic organisms to hydrophobic contaminants. To date, most laboratory studies investigated chemical transfer from ingested microplastic without taking other exposure pathways into account. Therefore, we studied the effect of polyethylene (PE) microplastic in sediment on PCB uptake by Arenicola marina as a model species, quantifying uptake fluxes from all natural exposure pathways. PCB concentrations in sediment, biota lipids (C lip ) and porewater measured with passive samplers were used to derive lipid-normalized bioaccumulation metrics C lip , Biota sediment accumulation factor (BSAF), Bioaccumulation factor (BAF) and the Biota plastic accumulation factor (BPAF). Small effects of PE addition were detected suggesting slightly increased or decreased bioaccumulation. However, the differences decreased in magnitude dependent on the metric used to assess bioaccumulation, in the order: C lip > BSAF > BPAF > BAF, and were nonsignificant for BAF. The fact that BAF, that is, normalization of C lip on porewater concentration, largely removed all effects of PE, shows that PE did not act as a measurable vector of PCBs. Biodynamic model analysis confirmed that PE ingestion contributed marginally to bioaccumulation. This work confirmed model-based predictions on the limited relevance of microplastic for bioaccumulation under environmentally realistic conditions, and illustrated the importance of assessing exposure through all media in microplastic bioaccumulation studies.

Non-thermal plasma induces mitochondria-mediated apoptotic signaling pathway via ROS generation in HeLa cells.

PubMed

Li, Wei; Yu, K N; Ma, Jie; Shen, Jie; Cheng, Cheng; Zhou, Fangjian; Cai, Zhiming; Han, Wei

2017-11-01

Non-thermal plasma (NTP) has been proposed as a novel therapeutic method for anticancer treatment. Although increasing evidence suggests that NTP selectively induces apoptosis in some types of tumor cells, the molecular mechanisms underlying this phenomenon remain unclear. In this study, we further investigated possible molecular mechanisms for NTP-induced apoptosis of HeLa cells. The results showed that NTP exposure significantly inhibited the growth and viability of HeLa cells. Morphological observation and flow cytometry analysis demonstrated that NTP exposure induced HeLa cell apoptosis. NTP exposure also activated caspase-9 and caspase-3, which subsequently cleaved poly (ADP- ribose) polymerase. Furthermore, NTP exposure suppressed Bcl-2 expression, enhanced Bax expression and translocation to mitochondria, activated mitochondria-mediated apoptotic pathway, followed by the release of cytochrome c. Further studies showed that NTP treatment led to ROS generation, whereas blockade of ROS generation by N-acetyl-l-cysteine (NAC, ROS scavengers) significantly prevented NTP-induced mitochondrial alteration and subsequent apoptosis of HeLa cells via suppressing Bax translocation, cytochrome c and caspase-3 activation. Taken together, our results indicated that NTP exposure induced mitochondria-mediated intrinsic apoptosis of HeLa cells was activated by ROS generation. These findings provide insights to the therapeutic potential and clinical research of NTP as a novel tool in cervical cancer treatment. Copyright © 2017. Published by Elsevier Inc.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Simões, Maylla Ronacher, E-mail: yllars@hotmail.com; Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz; Aguado, Andrea

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 didmore » 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 MAPK in lead exposure • Relationship between vascular ROS and COX-2 products in lead exposure.« less

DEVELOPMENT OF NATIONAL BIOACCUMULATION FACTORS

EPA Science Inventory

The 2000 Human Health Methodology incorporates a number of specific advancements made over the past two decades, one of which is in the assessment of chemical exposure to humans through the food chain pathway. For certain chemicals, the food chain exposure pathway is more importa...

The use of aquatic bioconcentration factors in ecological risk assessments: Confounding issues, laboratory v/s modeled results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brandt, C.; Blanton, M.L.; Dirkes, R.

1995-12-31

Bioconcentration in aquatic systems is generally taken to refer to contaminant uptake through non-ingestion pathways (i.e., dermal and respiration uptake). Ecological risk assessments performed on aquatic systems often rely on published data on bioconcentration factors to calibrate models of exposure. However, many published BCFs, especially those from in situ studies, are confounded by uptake from ingestion of prey. As part of exposure assessment and risk analysis of the Columbia River`s Hanford Reach, the authors tested a methodology to estimate radionuclide BCFs for several aquatic species in the Hanford Reach of the Columbia River. The iterative methodology solves for BCFs frommore » known body burdens and environmental media concentrations. This paper provides BCF methodology description comparisons of BCF from literature and modeled values and how they were used in the exposure assessment and risk analysis of the Columbia River`s Hanford Reach.« less

Estimating human exposure to PFOS isomers and PFCA homologues: the relative importance of direct and indirect (precursor) exposure.

PubMed

Gebbink, Wouter A; Berger, Urs; Cousins, Ian T

2015-01-01

Contributions of direct and indirect (via precursors) pathways of human exposure to perfluorooctane sulfonic acid (PFOS) isomers and perfluoroalkyl carboxylic acids (PFCAs) are estimated using a Scenario-Based Risk Assessment (SceBRA) modelling approach. Monitoring data published since 2008 (including samples from 2007) are used. The estimated daily exposures (resulting from both direct and precursor intake) for the general adult population are highest for PFOS and perfluorooctanoic acid (PFOA), followed by perfluorohexanoic acid (PFHxA) and perfluorodecanoic acid (PFDA), while lower daily exposures are estimated for perfluorobutanoic acid (PFBA) and perfluorododecanoic acid (PFDoDA). The precursor contributions to the individual perfluoroalkyl acid (PFAA) daily exposures are estimated to be 11-33% for PFOS, 0.1-2.5% for PFBA, 3.7-34% for PFHxA, 13-64% for PFOA, 5.2-66% for PFDA, and 0.7-25% for PFDoDA (ranges represent estimated precursor contributions in a low- and high-exposure scenario). For PFOS, direct intake via diet is the major exposure pathway regardless of exposure scenario. For PFCAs, the dominant exposure pathway is dependent on perfluoroalkyl chain length and exposure scenario. Modelled PFOS and PFOA concentrations in human serum using the estimated intakes from an intermediate-exposure scenario are in agreement with measured concentrations in different populations. The isomer pattern of PFOS resulting from total intakes (direct and via precursors) is estimated to be enriched with linear PFOS (84%) relative to technical PFOS (70% linear). This finding appears to be contradictory to the observed enrichment of branched PFOS isomers in recent human serum monitoring studies and suggests that either external exposure is not fully understood (e.g. there are unknown precursors, missing or poorly quantified exposure pathways) and/or that there is an incomplete understanding of the isomer-specific human pharmacokinetic processes of PFOS, its precursors and intermediates. Copyright © 2014. Published by Elsevier Ltd.

Exposure to air pollution interacts with obesogenic nutrition to induce tissue-specific response patterns.

PubMed

Pardo, Michal; Kuperman, Yael; Levin, Liron; Rudich, Assaf; Haim, Yulia; Schauer, James J; Chen, Alon; Rudich, Yinon

2018-04-20

Obesity and exposure to particular matter (PM) have become two leading global threats to public health. However, the exact mechanisms and tissue-specificity of their health effects are largely unknown. Here we investigate whether a metabolic challenge (early nutritional obesity) synergistically interacts with an environmental challenge (PM exposure) to alter genes representing key response pathways, in a tissue-specific manner. Mice subjected to 7 weeks obesogenic nutrition were exposed every other day during the final week and a half to aqueous extracts of PM collected in the city of London (UK). The expression of 61 selected genes representing key response pathways were investigated in lung, liver, white and brown adipose tissues. Principal component analysis (PCA) revealed distinct patterns of expression changes between the 4 tissues, particularly in the lungs and the liver. Surprisingly, the lung responded to the nutrition challenge. The response of these organs to the PM challenge displayed opposite patterns for some key genes, in particular, those related to the Nrf2 pathway. While the contribution to the variance in gene expression changes in mice exposed to the combined challenge were largely similar among the tissues in PCA1, PCA2 exhibited predominant contribution of inflammatory and oxidative stress responses to the variance in the lungs, and a greater contribution of autophagy genes and MAP kinases in adipose tissues. Possible involvement of alterations in DNA methylation was demonstrated by cell-type-specific responses to a methylation inhibitor. Correspondingly, the DNA methyltransferase Dnmt3a2 increased in the lungs but decreased in the liver, demonstrating potential tissue-differential synergism between nutritional and PM exposure. The results suggest that urban PM, containing dissolved metals, interacts with obesogenic nutrition to regulate diverse response pathways including inflammation and oxidative stress, in a tissue-specific manner. Tissue-differential effects on DNA methylation may underlie tissue-specific responses to key stress-response genes such as catalase and Nrf2. Copyright © 2018 Elsevier Ltd. All rights reserved.

Transcriptomic Analysis of Ciguatoxin-Induced Changes in Gene Expression in Primary Cultures of Mice Cortical Neurons

PubMed Central

Rubiolo, Juan Andrés; Boente-Juncal, Andrea; Hirama, Masahiro; Yamashita, Shuji; Camiña, Mercedes; Vieytes, Mercedes R.

2018-01-01

Ciguatoxins are polyether marine toxins that act as sodium channel activators. These toxins cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents several symptoms in humans including long-term neurological alterations. Earlier work has shown that both acute and chronic exposure of primary cortical neurons to synthetic ciguatoxin CTX3C have profound impacts on neuronal function. Thus, the present work aimed to identify relevant neuronal genes and metabolic pathways that could be altered by ciguatoxin exposure. To study the effect of ciguatoxins in primary neurons in culture, we performed a transcriptomic analysis using whole mouse genome microarrays, for primary cortical neurons exposed during 6, 24, or 72 h in culture to CTX3C. Here, we have shown that the effects of the toxin on gene expression differ with the exposure time. The results presented here have identified several relevant genes and pathways related to the effect of ciguatoxins on neurons and may assist in future research or even treatment of ciguatera. Moreover, we demonstrated that the effects of the toxin on gene expression were exclusively consequential of its action as a voltage-gated sodium channel activator, since all the effects of CTX3C were avoided by preincubation of the neurons with the sodium channel blocker tetrodotoxin. PMID:29748486

Issue Paper on Metal Exposure Assessment

EPA Pesticide Factsheets

This paper explores the best approaches for characterizing exposure pathways and routes, estimating the most relevant exposure concentrations, linking exposure to dose, and coping with natural or background concentrations.

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

PubMed Central

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

Using exposomics to assess cumulative risks and promote health.

PubMed

Smith, Martyn T; de la Rosa, Rosemarie; Daniels, Sarah I

2015-12-01

Under the exposome paradigm all nongenetic factors contributing to disease are considered to be 'environmental' including chemicals, drugs, infectious agents, and psychosocial stress. We can consider these collectively as environmental stressors. Exposomics is the comprehensive analysis of exposure to all environmental stressors and should yield a more thorough understanding of chronic disease development. We can operationalize exposomics by studying all the small molecules in the body and their influence on biological pathways that lead to impaired health. Here, we describe methods by which this may be achieved and discuss the application of exposomics to cumulative risk assessment in vulnerable populations. Since the goal of cumulative risk assessment is to analyze, characterize, and quantify the combined risks to health from exposures to multiple agents or stressors, it seems that exposomics is perfectly poised to advance this important area of environmental health science. We should therefore support development of tools for exposomic analysis and begin to engage impacted communities in participatory exposome research. A first step may be to apply exposomics to vulnerable populations already studied by more conventional cumulative risk approaches. We further propose that recent migrants, low socioeconomic groups with high environmental chemical exposures, and pregnant women should be high priority populations for study by exposomics. Moreover, exposomics allows us to study interactions between chronic stress and environmental chemicals that disrupt stress response pathways (i.e., 'stressogens'). Exploring the impact of early life exposures and maternal stress may be an interesting and accessible topic for investigation by exposomics using biobanked samples. © 2015 Wiley Periodicals, Inc.

Assessment of two nonnative poeciliid fishes for monitoring selenium exposure in the endangered desert pupfish

USGS Publications Warehouse

Saiki, Michael K.; Martin, Barbara A.; May, Thomas W.; Brumbaugh, William G.

2012-01-01

We assessed the suitability of two nonnative poeciliid fishes—western mosquitofish (Gambusia affinis) and sailfin mollies (Poecilia latipinna)—for monitoring selenium exposure in desert pupfish (Cyprinodon macularius). Our investigation was prompted by a need to avoid lethal take of an endangered species (pupfish) when sampling fish for chemical analysis. Total selenium (SeTot) concentrations in both poeciliids were highly correlated with SeTot concentrations in pupfish. However, mean SeTot concentrations varied among fish species, with higher concentrations measured in mosquitofish than in mollies and pupfish from one of three sampled agricultural drains. Moreover, regression equations describing the relationship of selenomethionine to SeTot differed between mosquitofish and pupfish, but not between mollies and pupfish. Because selenium accumulates in animals primarily through dietary exposure, we examined fish trophic relationships by measuring stable isotopes (δ13C and δ15N) and gut contents. According to δ13C measurements, the trophic pathway leading to mosquitofish was more carbon-depleted than trophic pathways leading to mollies and pupfish, suggesting that energy flow to mosquitofish originated from allochthonous sources (terrestrial vegetation, emergent macrophytes, or both), whereas energy flow to mollies and pupfish originated from autochthonous sources (filamentous algae, submerged macrophytes, or both). The δ15N measurements indicated that mosquitofish and mollies occupied similar trophic levels, whereas pupfish occupied a slightly higher trophic level. Analysis of gut contents showed that mosquitofish consumed mostly winged insects (an indication of terrestrial taxa), whereas mollies and pupfish consumed mostly organic detritus. Judging from our results, only mollies (not mosquitofish) are suitable for monitoring selenium exposure in pupfish.

Transcriptomics analysis and hormonal changes of male and female neonatal rats treated chronically with a low dose of acrylamide in their drinking water.

PubMed

Collí-Dulá, Reyna Cristina; Friedman, Marvin A; Hansen, Benjamin; Denslow, Nancy D

2016-01-01

Acrylamide is known to produce follicular cell tumors of the thyroid in rats. RccHan Wistar rats were exposed in utero to a carcinogenic dose of acrylamide (3 mg/Kg bw/day) from gestation day 6 to delivery and then through their drinking water to postnatal day 35. In order to identify potential mechanisms of carcinogenesis in the thyroid glands, we used a transcriptomics approach. Thyroid glands were collected from male pups at 10 PM and female pups at 10 AM or 10 PM in order to establish whether active exposure to acrylamide influenced gene expression patterns or pathways that could be related to carcinogenesis. While all animals exposed to acrylamide showed changes in expected target pathways related to carcinogenesis such as DNA repair, DNA replication, chromosome segregation, among others; animals that were sacrificed while actively drinking acrylamide-laced water during their active period at night showed increased changes in pathways related to oxidative stress, detoxification pathways, metabolism, and activation of checkpoint pathways, among others. In addition, thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were increased in acrylamide-treated rats sampled at night, but not in quiescent animals when compared to controls. The data clearly indicate that time of day for sample collection is critical to identifying molecular pathways that are altered by the exposures. These results suggest that carcinogenesis in the thyroids of acrylamide treated rats may ensue from several different mechanisms such as hormonal changes and oxidative stress and not only from direct genotoxicity, as has been assumed to date.

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

PubMed

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.

Inorganic Arsenic–Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell–Conditioned Media Model

PubMed Central

Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

2015-01-01

Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal–epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs). Results: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure. Conclusions: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications. Citation: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL, Figueiredo ML. 2016. Inorganic arsenic–related changes in the stromal tumor microenvironment in a prostate cancer cell–conditioned media model. Environ Health Perspect 124:1009–1015; http://dx.doi.org/10.1289/ehp.1510090 PMID:26588813

The NRF2-KEAP1 Pathway Is an Early Responsive Gene Network in Arsenic Exposed Lymphoblastoid Cells

PubMed Central

Córdova, Emilio J.; Martínez-Hernández, Angélica; Uribe-Figueroa, Laura; Centeno, Federico; Morales-Marín, Mirna; Koneru, Harsha; Coleman, Matthew A.; Orozco, Lorena

2014-01-01

Inorganic arsenic (iAs), a major environmental contaminant, has risen as an important health problem worldwide. More detailed identification of the molecular mechanisms associated with iAs exposure would help to establish better strategies for prevention and treatment. Although chronic iAs exposures have been previously studied there is little to no information regarding the early events of exposure to iAs. To better characterize the early mechanisms of iAs exposure we conducted gene expression studies using sublethal doses of iAs at two different time-points. The major transcripts differentially regulated at 2 hrs of iAs exposure included antioxidants, detoxificants and chaperones. Moreover, after 12 hrs of exposure many of the down-regulated genes were associated with DNA replication and S phase cell cycle progression. Interestingly, the most affected biological pathway by both 2 or 12 hrs of iAs exposure were the Nrf2-Keap1 pathway, represented by the highly up-regulated HMOX1 transcript, which is transcriptionally regulated by the transcription factor Nrf2. Additional Nrf2 targets included SQSTM1 and ABCB6, which were not previously associated with acute iAs exposure. Signalling pathways such as interferon, B cell receptor and AhR route were also responsive to acute iAs exposure. Since HMOX1 expression increased early (20 min) and was responsive to low iAs concentrations (0.1 µM), this gene could be a suitable early biomarker for iAs exposure. In addition, the novel Nrf2 targets SQSTM1 and ABCB6 could play an important and previously unrecognized role in cellular protection against iAs. PMID:24516582

Whole genome expression analysis in primary bronchial epithelial cells after exposure to sulphur mustard.

PubMed

Jowsey, Paul A; Blain, Peter G

2014-11-04

Sulphur mustard (SM) is a highly toxic chemical agent and poses a current threat to both civilians and military personnel in the event of a deliberate malicious release. Acute SM toxicity develops over the course of several hours and mainly affects the skin and mucosal surfaces of the eyes and respiratory system. In cases of acute severe exposure, significant lung injury can result in respiratory failure and death. Systemic levels of SM can also be fatal, frequently due to immunodepletion and the subsequent development of secondary infections. Whilst the physical effects associated with SM exposure are well documented, the molecular mechanisms mediating these changes are poorly understood, hindering the development of an effective therapeutic strategy. To gain a better understanding of the mechanism of SM toxicity, this study investigated whole genome transcriptional changes after SM in primary human bronchial epithelial cells, as a model for inhalation exposure. The analysis revealed >400 transcriptional changes associated with SM exposure. Pathways analysis confirmed the findings of previous studies suggesting that DNA damage, cell cycle arrest, cell death and inflammation were important components of SM toxicity. In addition, several other interesting observations were made, suggesting that protein oxidation as well as effects on the mitotic apparatus may contribute to SM toxicity. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tilton, Susan C., E-mail: susan.tilton@pnnl.gov; Waters, Katrina M.; Karin, Norman J.

The co-occurrence of environmental factors is common in complex human diseases and, as such, understanding the molecular responses involved is essential to determine risk and susceptibility to disease. We have investigated the key biological pathways that define susceptibility for pulmonary infection during obesity in diet-induced obese (DIO) and regular weight (RW) C57BL/6 mice exposed to inhaled lipopolysaccharide (LPS). LPS induced a strong inflammatory response in all mice as indicated by elevated cell counts of macrophages and neutrophils and levels of proinflammatory cytokines (MDC, MIP-1γ, IL-12, RANTES) in the bronchoalveolar lavage fluid. Additionally, DIO mice exhibited 50% greater macrophage cell counts,more » but decreased levels of the cytokines, IL-6, TARC, TNF-α, and VEGF relative to RW mice. Microarray analysis of lung tissue showed over half of the LPS-induced expression in DIO mice consisted of genes unique for obese mice, suggesting that obesity reprograms how the lung responds to subsequent insult. In particular, we found that obese animals exposed to LPS have gene signatures showing increased inflammatory and oxidative stress response and decreased antioxidant capacity compared with RW. Because signaling pathways for these responses can be common to various sources of environmentally induced lung damage, we further identified biomarkers that are indicative of specific toxicant exposure by comparing gene signatures after LPS exposure to those from a parallel study with cigarette smoke. These data show obesity may increase sensitivity to further insult and that co-occurrence of environmental stressors result in complex biosignatures that are not predicted from analysis of individual exposures. - Highlights: ► Obesity modulates inflammatory markers in BAL fluid after LPS exposure. ► Obese animals have a unique transcriptional signature in lung after LPS exposure. ► Obesity elevates inflammatory stress and reduces antioxidant capacity in the lung. ► Toxicant-specific biomarkers predict exposure independent of systemic inflammation.« less

BRCA1 Mutation Status and Follicular Fluid Exposure Alters NFκB Signaling and ISGylation in Human Fallopian Tube Epithelial Cells.

PubMed

Hollingsworth, Julia; Lau, Angela; Tone, Alicia; Kollara, Alexandra; Allen, Lisa; Colgan, Terence J; Dube, Valerie; Rosen, Barry; Murphy, K Joan; Greenblatt, Ellen M; Feigenberg, Tomer; Virtanen, Carl; Brown, Theodore J

2018-05-28

Germline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed epithelial ovarian cancer histotype. Other identified risk factors for this cancer, which originates primarily in the distal fallopian tube epithelium (FTE), implicate ovulation, during which the FTE cells become transiently exposed to follicular fluid (FF). To test whether mtBRCA1 or mtBRCA2 nonmalignant FTE cells respond differently to periovulatory FF exposure than control patient FTE cells, gene expression profiles from primary FTE cultures derived from BRCA1 or BRCA2 mutation carriers or control patients were compared at baseline, 24 hours after FF exposure, and 24 hours after FF replacement with culture medium. Hierarchical clustering revealed both FF exposure and BRCA mutation status affect gene expression, with BRCA1 mutation having the greatest impact. Gene set enrichment analysis revealed increased NFκB and EGFR signaling at baseline in mtBRCA1 samples, with increased interferon target gene expression, including members of the ISGylation pathway, observed after recovery from FF exposure. Gene set enrichment analysis did not identify altered pathway signaling in mtBRCA2 samples. An inverse relationship between EGFR signaling and ISGylation with BRCA1 protein levels was verified in an immortalized FTE cell line, OE-E6/E7, stably transfected with BRCA1 cDNA. Suppression of ISG15 and ISGylated protein levels by increased BRCA1 expression was found to be mediated by decreased NFκB signaling. These studies indicate that increased NFκB signaling associated with decreased BRCA1 expression results in increased ISG15 and protein ISGylation following FF exposure, which may be involved in predisposition to HGSOC. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

High-resolution metabolomics of occupational exposure to trichloroethylene

PubMed Central

Walker, Douglas I; Uppal, Karan; Zhang, Luoping; Vermeulen, Roel; Smith, Martyn; Hu, Wei; Purdue, Mark P; Tang, Xiaojiang; Reiss, Boris; Kim, Sungkyoon; Li, Laiyu; Huang, Hanlin; Pennell, Kurt D; Jones, Dean P; Rothman, Nathaniel; Lan, Qing

2016-01-01

Background: Occupational exposure to trichloroethylene (TCE) has been linked to adverse health outcomes including non-Hodgkin’s lymphoma and kidney and liver cancer; however, TCE’s mode of action for development of these diseases in humans is not well understood. Methods: Non-targeted metabolomics analysis of plasma obtained from 80 TCE-exposed workers [full shift exposure range of 0.4 to 230 parts-per-million of air (ppma)] and 95 matched controls were completed by ultra-high resolution mass spectrometry. Biological response to TCE exposure was determined using a metabolome-wide association study (MWAS) framework, with metabolic changes and plasma TCE metabolites evaluated by dose-response and pathway enrichment. Biological perturbations were then linked to immunological, renal and exposure molecular markers measured in the same population. Results: Metabolic features associated with TCE exposure included known TCE metabolites, unidentifiable chlorinated compounds and endogenous metabolites. Exposure resulted in a systemic response in endogenous metabolism, including disruption in purine catabolism and decreases in sulphur amino acid and bile acid biosynthesis pathways. Metabolite associations with TCE exposure included uric acid (β = 0.13, P-value = 3.6 × 10−5), glutamine (β = 0.08, P-value = 0.0013), cystine (β = 0.75, P-value = 0.0022), methylthioadenosine (β = −1.6, P-value = 0.0043), taurine (β = −2.4, P-value = 0.0011) and chenodeoxycholic acid (β = −1.3, P-value = 0.0039), which are consistent with known toxic effects of TCE, including immunosuppression, hepatotoxicity and nephrotoxicity. Correlation with additional exposure markers and physiological endpoints supported known disease associations. Conclusions: High-resolution metabolomics correlates measured occupational exposure to internal dose and metabolic response, providing insight into molecular mechanisms of exposure-related disease aetiology. PMID:27707868

High-resolution metabolomics of occupational exposure to trichloroethylene.

PubMed

Walker, Douglas I; Uppal, Karan; Zhang, Luoping; Vermeulen, Roel; Smith, Martyn; Hu, Wei; Purdue, Mark P; Tang, Xiaojiang; Reiss, Boris; Kim, Sungkyoon; Li, Laiyu; Huang, Hanlin; Pennell, Kurt D; Jones, Dean P; Rothman, Nathaniel; Lan, Qing

2016-10-01

Occupational exposure to trichloroethylene (TCE) has been linked to adverse health outcomes including non-Hodgkin's lymphoma and kidney and liver cancer; however, TCE's mode of action for development of these diseases in humans is not well understood. Non-targeted metabolomics analysis of plasma obtained from 80 TCE-exposed workers [full shift exposure range of 0.4 to 230 parts-per-million of air (ppm a )] and 95 matched controls were completed by ultra-high resolution mass spectrometry. Biological response to TCE exposure was determined using a metabolome-wide association study (MWAS) framework, with metabolic changes and plasma TCE metabolites evaluated by dose-response and pathway enrichment. Biological perturbations were then linked to immunological, renal and exposure molecular markers measured in the same population. Metabolic features associated with TCE exposure included known TCE metabolites, unidentifiable chlorinated compounds and endogenous metabolites. Exposure resulted in a systemic response in endogenous metabolism, including disruption in purine catabolism and decreases in sulphur amino acid and bile acid biosynthesis pathways. Metabolite associations with TCE exposure included uric acid (β = 0.13, P-value = 3.6 × 10 -5 ), glutamine (β = 0.08, P-value = 0.0013), cystine (β = 0.75, P-value = 0.0022), methylthioadenosine (β = -1.6, P-value = 0.0043), taurine (β = -2.4, P-value = 0.0011) and chenodeoxycholic acid (β = -1.3, P-value = 0.0039), which are consistent with known toxic effects of TCE, including immunosuppression, hepatotoxicity and nephrotoxicity. Correlation with additional exposure markers and physiological endpoints supported known disease associations. High-resolution metabolomics correlates measured occupational exposure to internal dose and metabolic response, providing insight into molecular mechanisms of exposure-related disease aetiology. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data.

PubMed

Deziel, Nicole C; Freeman, Laura E Beane; Graubard, Barry I; Jones, Rena R; Hoppin, Jane A; Thomas, Kent; Hines, Cynthia J; Blair, Aaron; Sandler, Dale P; Chen, Honglei; Lubin, Jay H; Andreotti, Gabriella; Alavanja, Michael C R; Friesen, Melissa C

2017-03-01

Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and ≥ 20%, respectively (88 statistics, five studies). Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296-305; http://dx.doi.org/10.1289/EHP426.

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data

PubMed Central

Deziel, Nicole C.; Freeman, Laura E. Beane; Graubard, Barry I.; Jones, Rena R.; Hoppin, Jane A.; Thomas, Kent; Hines, Cynthia J.; Blair, Aaron; Sandler, Dale P.; Chen, Honglei; Lubin, Jay H.; Andreotti, Gabriella; Alavanja, Michael C. R.; Friesen, Melissa C.

2016-01-01

Background: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. Objective: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. Methods: From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). Results: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1–19% and ≥ 20%, respectively (88 statistics, five studies). Conclusion: Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296–305; http://dx.doi.org/10.1289/EHP426 PMID:27458779

Exploring consumer exposure pathways and patterns of use for chemicals in the environment through the Chemical/Product Categories Database

EPA Pesticide Factsheets

Exploring consumer exposure pathways and patterns of use for chemicals in the environment through the Chemical/Product Categories Database (CPCat) (Presented by: Kathie Dionisio, Sc.D., NERL, US EPA, Research Triangle Park, NC (1/23/2014).

A conceptual framework to advance exposure science research and complement the Adverse Outcome Pathway framework

EPA Science Inventory

A tremendous amount of data on environmental stressors has been accumulated in exposure science, epidemiology, and toxicology, yet most of these data reside in different silos. The Adverse Outcome Pathway (AOP) framework was developed as an organizing principle for toxicological ...

Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/beta-catenin signaling in the thymus resulting in altered thymocyte development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hanson, Miranda L.; Brundage, Kathleen M.; Schafer, Rosana

2010-01-15

Cadmium (Cd) is both an environmental pollutant and a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/beta-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/beta-catenin pathways. Pregnant C57Bl/6more » mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways were assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4{sup +} cells and a subpopulation of double-negative cells (DN; CD4{sup -}CD8{sup -}), DN4 (CD44{sup -}CD25{sup -}). Shh and Wnt/beta-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/beta-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.« less

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

PubMed

Mehinto, Alvine C; Prucha, Melinda S; Colli-Dula, Reyna C; Kroll, Kevin J; Lavelle, Candice M; Barber, David S; Vulpe, Christopher D; Denslow, Nancy D

2014-07-01

Cadmium is a heavy metal that can accumulate to toxic levels in the environment leading to detrimental effects in animals and humans including kidney, liver and lung injuries. Using a transcriptomics approach, genes and cellular pathways affected by a low dose of cadmium were investigated. Adult largemouth bass were intraperitoneally injected with 20μg/kg of cadmium chloride (mean exposure level - 2.6μg of cadmium per fish) and microarray analyses were conducted in the liver and testis 48h after injection. Transcriptomic profiles identified in response to cadmium exposure were tissue-specific with the most differential expression changes found in the liver tissues, which also contained much higher levels of cadmium than the testis. Acute exposure to a low dose of cadmium induced oxidative stress response and oxidative damage pathways in the liver. The mRNA levels of antioxidants such as catalase increased and numerous transcripts related to DNA damage and DNA repair were significantly altered. Hepatic mRNA levels of metallothionein, a molecular marker of metal exposure, did not increase significantly after 48h exposure. Carbohydrate metabolic pathways were also disrupted with hepatic transcripts such as UDP-glucose, pyrophosphorylase 2, and sorbitol dehydrogenase highly induced. Both tissues exhibited a disruption of steroid signaling pathways. In the testis, estrogen receptor beta and transcripts linked to cholesterol metabolism were suppressed. On the contrary, genes involved in cholesterol metabolism were highly increased in the liver including genes encoding for the rate limiting steroidogenic acute regulatory protein and the catalytic enzyme 7-dehydrocholesterol reductase. Integration of the transcriptomic data using functional enrichment analyses revealed a number of enriched gene networks associated with previously reported adverse outcomes of cadmium exposure such as liver toxicity and impaired reproduction. Copyright © 2014 Elsevier B.V. All rights reserved.

In vivo nuclear magnetic resonance studies of hepatic methoxyflurane metabolism. II. A reevaluation of hepatic metabolic pathways.

PubMed

Selinsky, B S; Perlman, M E; London, R E

1988-05-01

Methoxyflurane (2,2-dichloro-1,1-difluoro-ethyl methyl ether) is believed to be metabolized via two convergent metabolic pathways. The relative flux through these two metabolic pathways has been investigated using a combination of in vivo surface coil NMR techniques and in vitro analyses of urinary metabolites. Analysis of the measured concentrations of inorganic fluoride, oxalate, and methoxydifluoroacetate in the urine of methoxyflurane-treated rats for 4 days after anesthesia indicates that the anesthetic is metabolized primarily via dechlorination to yield methoxydifluoroacetate. The methoxydifluoroacetate is largely excreted without further metabolism, although a small percentage of this metabolite is broken down to yield fluoride and oxalate, as determined by urine analysis of rats dosed with synthetic methoxydifluoroacetate. At early times after methoxyflurane exposure, the relative concentrations of methoxyflurane metabolites indicate that a significant fraction of the metabolic flux occurs via a different pathway, presumably demethylation, to yield dichloroacetate as an intermediate. Direct analysis of dichloroacetate in the urine using water-suppressed proton NMR indicates that the level of this metabolite is below the detection threshold of the method. Measurements made on the urine of rats dosed directly with dichloroacetate indicate that this compound is quickly metabolized, and dichloroacetate levels in urine are again found to be below the detection threshold. These results demonstrate the quantitative importance of the dechlorination pathway in the metabolism of methoxyflurane in rats.

From betrayal to the bottle: investigating possible pathways from trauma to problematic substance use.

PubMed

Delker, Brianna C; Freyd, Jennifer J

2014-10-01

Research in both community and clinical settings has found that exposure to cumulative interpersonal trauma predicts substance use problems. Less is known about betrayal as a dimension of trauma exposure that predicts substance use, and about the behavioral and psychological pathways that explain the relation between trauma and substance use. In a sample of 362 young adults, this study evaluated three intervening pathways between betrayal trauma exposure prior to age 18 years and problematic substance use: (a) substance use to cope with negative affect, (b) difficulty discerning and/or heeding risk, and (c) self-destructiveness. In addition, exposure to trauma low in betrayal (e.g., earthquake) was included in the model. Bootstrap tests of indirect effects revealed that betrayal trauma prior to age 18 years was associated with problematic substance use via posttraumatic stress and two intervening pathways: difficulty discerning/heeding risk (β = .07, p < .001), and self-destructiveness (β = .12, p < .001). Exposure to lower betrayal trauma was not associated with posttraumatic stress or problematic substance use. Results contribute to a trauma-informed understanding of substance use that persists despite potentially harmful consequences. Copyright © 2014 International Society for Traumatic Stress Studies.

Role of the ceramide-signaling pathways in ionizing radiation-induced apoptosis.

PubMed

Vit, Jean-Philippe; Rosselli, Filippo

2003-11-27

Ionizing radiations (IR) exposure leads to damage on several cellular targets. How signals from different targets are integrated to determine the cell fate remains a controversial issue. Understanding the pathway(s) responsible(s) for the cell killing effect of the IR exposure is of prime importance in light of using radiations as anticancer agent or as diagnostic tool. In this study, we have established that IR-induced cell damage initiates two independent signaling pathways that lead to a biphasic intracellular ceramide increase. A transitory increase of ceramide is observed within minutes after IR exposure as a consequence of DNA damage-independent acid sphingomyelinase activation. Several hours after irradiation, a second wave of ceramide accumulation is observed depending on the DNA damage-dependent activation of ceramide synthase, which requires a signaling pathway involving ATM. Importantly, we have demonstrated that the late ceramide accumulation is also dependent on the first one and is rate limiting for the apoptotic process induced by IR. In conclusion, our observations suggest that ceramide is a major determinant of the IR-induced apoptotic process at the cross-point of different signal transduction pathways.

A conceptual framework to support exposure science research ...

EPA Pesticide Factsheets

While knowledge of exposure is fundamental to assessing and mitigating risks, exposure information has been costly and difficult to generate. Driven by major scientific advances in analytical methods, biomonitoring, computational tools, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition that allows it to be more agile, predictive, and data- and knowledge-driven. A necessary element of this evolved paradigm is an organizational and predictive framework for exposure science that furthers the application of systems-based approaches. To enable such systems-based approaches, we proposed the Aggregate Exposure Pathway (AEP) concept to organize data and information emerging from an invigorated and expanding field of exposure science. The AEP framework is a layered structure that describes the elements of an exposure pathway, as well as the relationship between those elements. The basic building blocks of an AEP adopt the naming conventions used for Adverse Outcome Pathways (AOPs): Key Events (KEs) to describe the measurable, obligate steps through the AEP; and Key Event Relationships (KERs) describe the linkages between KEs. Importantly, the AEP offers an intuitive approach to organize exposure information from sources to internal site of action, setting the stage for predicting stressor concentrations at an internal target site. These predicted concentrations can help inform the r

Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eveillard, Alexandre; Lasserre, Frederic; Tayrac, Marie de

2009-05-01

Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this work we investigated potential mechanisms underlying the impact of DEHP on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPAR{alpha} targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NRmore » pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and to the Rev-erb{alpha} pathway that senses endogenous heme level. We further confirmed the combined impact of DEHP on the hepatic expression of Alas1, a critical enzyme in heme synthesis and on the expression of Rev-erb{alpha} target genes involved in the cellular clock and in energy metabolism. This work shows that DEHP interferes with hepatic CAR and Rev-erb{alpha} pathways which are both involved in the control of metabolism. The identification of these new hepatic pathways targeted by DEHP could contribute to metabolic and endocrine disruption associated with phthalate exposure. Gene expression profiles performed on microdissected testis territories displayed a differential responsiveness to DEHP. Altogether, this suggests that impacts of DEHP on adult organs, including testis, could be documented and deserve further investigations.« less

Transcriptomic analyses and leukocyte telomere length measurement in subjects exposed to severe recent stressful life events.

PubMed

Lopizzo, N; Tosato, S; Begni, V; Tomassi, S; Cattane, N; Barcella, M; Turco, G; Ruggeri, M; Riva, M A; Pariante, C M; Cattaneo, A

2017-02-21

Stressful life events occurring in adulthood have been found able to affect mood and behavior, thus increasing the vulnerability for several stress-related psychiatric disorders. However, although there is plenty of clinical data supporting an association between stressful life events in adulthood and an enhanced vulnerability for psychopathology, the underlying molecular mechanisms are still poorly investigated. Thus, in this study we performed peripheral/whole-genome transcriptomic analyses in blood samples obtained from 53 adult subjects characterized for recent stressful life events occurred within the previous 6 months. Transcriptomic data were analyzed using Partek Genomics Suite; pathway and network analyses were performed using Ingenuity Pathway Analysis and GeneMANIA Software. We found 207 genes significantly differentially expressed in adult subjects who reported recent stressful life experiences (n=21) compared with those without such experiences (n=32). Moreover, the same subjects exposed to such stressful experiences showed a reduction in leukocyte telomere length. A correlation analyses between telomere length and transcriptomic data indicated an association between the exposures to recent stressful life events and the modulation of several pathways, mainly involved in immune-inflammatory-related processes and oxidative stress, such as natural killer cell signaling, interleukin-1 (IL-1) signaling, MIF regulation of innate immunity and IL-6 signaling. Our data suggest an association between exposures to recent stressful life events in adulthood and alterations in the immune, inflammatory and oxidative stress pathways, which could be also involved in the negative effect of stressful life events on leukocyte telomere length. The modulation of these mechanisms may underlie the clinical association between the exposure to recent Stressful life events in adulthood and an enhanced vulnerability to develop psychiatric diseases in adulthood.

USE OF METAL- AND FLUORESCEIN-TAGGED MATERIALS TO STUDY SETTLED PARTICLES EXPOSURE PATHWAYS

EPA Science Inventory

Through the use of ten size ranges of tagged materials (Antley et. al., 2000a), inductively coupled plasma- mass spectrometry (ICP-MS) and flourometry are being used to study the movement of settled particles in the indoor environment, exposure pathways, and the collection effi...

Expanding on Successful Concepts, Models, and Organization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Teeguarden, Justin G.; Tan, Yu-Mei; Edwards, Stephen W.

In her letter to the editor1 regarding our recent Feature Article “Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework” 2, Dr. von Göetz expressed several concerns about terminology, and the perception that we propose the replacement of successful approaches and models for exposure assessment with a concept. We are glad to have the opportunity to address these issues here. If the goal of the AEP framework was to replace existing exposure models or databases for organizing exposure data with a concept, we would share Dr. von Göetz concerns. Instead,more » the outcome we promote is broader use of an organizational framework for exposure science. The framework would support improved generation, organization, and interpretation of data as well as modeling and prediction, not replacement of models. The field of toxicology has seen the benefits of wide use of one or more organizational frameworks (e.g., mode and mechanism of action, adverse outcome pathway). These frameworks influence how experiments are designed, data are collected, curated, stored and interpreted and ultimately how data are used in risk assessment. Exposure science is poised to similarly benefit from broader use of a parallel organizational framework, which Dr. von Göetz correctly points out, is currently used in the exposure modeling community. In our view, the concepts used so effectively in the exposure modeling community, expanded upon in the AEP framework, could see wider adoption by the field as a whole. The value of such a framework was recognized by the National Academy of Sciences.3 Replacement of models, databases, or any application with the AEP framework was not proposed in our article. The positive role broader more consistent use of such a framework might have in enabling and advancing “general activities such as data acquisition, organization…,” and exposure modeling was discussed in some detail. Like Dr. von Göetz, we recognized the challenges associated with acceptance of the terminology, definitions, and structure proposed in the paper. To address these challenges, an expert workshop was held in May, 2016 to consider and revise the “basic elements” outlined in the paper. The attendees produced revisions to the terminology (e.g., key events) that align with terminology currently in use in the field. We were also careful in our paper to acknowledge a point raised by Dr. von Göetz, that the term AEP implies aggregation, providing these clarifications: “The simplest form of an AEP represents a single source and a single pathway and may more commonly be referred to as an exposure pathway,”; and “An aggregate exposure pathway may represent multiple sources and transfer through single pathways to the TSE, single sources and transfer through multiple pathways to the target site exposure (TSE), or any combination of these.” These clarifications address the concern that the AEP term is not accurate or logical, and further expands upon the word “aggregate” in a broader context. Our use of AEP is consistent with the definition for “aggregate exposure”, which refers to the combined exposures to a single chemical across multiple routes and pathways.3 The AEP framework embraces existing methods for collection, prediction, organization, and interpretation of human and ecological exposure data cited by Dr. von Göetz. We remain hopeful that wider recognition and use of an organizing concept for exposure information across the exposure science, toxicology and epidemiology communities advances the development of the kind of infrastructure and models Dr. von Göetz discusses. This outcome would be a step forward, rather than a step backward.« less

Metabolic Pathways and Networks Associated with Tobacco Use in Military Personnel

PubMed Central

Jones, Dean P.; Walker, Douglas I.; Uppal, Karan; Rohrbeck, Patricia; Mallon, Timothy M.; Go, Young-Mi

2016-01-01

Objective Use high-resolution metabolomics (HRM) to identify metabolic pathways and networks associated with tobacco use in military personnel. Methods Four hundred de-identified samples obtained from the Department of Defense Serum Repository were classified as tobacco users or non-users according to cotinine content. HRM and bioinformatic methods were used to determine pathways and networks associated with classification. Results Eighty individuals were classified as tobacco users compared to 320 non-users based on cotinine levels ≥10 ng/mL. Alterations in lipid and xenobiotic metabolism, and diverse effects on amino acid, sialic acid and purine and pyrimidine metabolism were observed. Importantly, network analysis showed broad effects on metabolic associations not simply linked to well-defined pathways. Conclusions Tobacco use has complex metabolic effects which must be considered in evaluation of deployment-associated environmental exposures in military personnel. PMID:27501098

Metabolic Pathways and Networks Associated With Tobacco Use in Military Personnel.

PubMed

Jones, Dean P; Walker, Douglas I; Uppal, Karan; Rohrbeck, Patricia; Mallon, Col Timothy M; Go, Young-Mi

2016-08-01

The aim of this study is to use high-resolution metabolomics (HRM) to identify metabolic pathways and networks associated with tobacco use in military personnel. Four hundred deidentified samples obtained from the Department of Defense Serum Repository were classified as tobacco users or nonusers according to cotinine content. HRM and bioinformatic methods were used to determine pathways and networks associated with classification. Eighty individuals were classified as tobacco users compared with 320 nonusers on the basis of cotinine levels at least 10 ng/mL. Alterations in lipid and xenobiotic metabolism, and diverse effects on amino acid, sialic acid, and purine and pyrimidine metabolism were observed. Importantly, network analysis showed broad effects on metabolic associations not simply linked to well-defined pathways. Tobacco use has complex metabolic effects that must be considered in evaluation of deployment-associated environmental exposures in military personnel.

Transcriptome-wide analyses indicate mitochondrial responses to particulate air pollution exposure.

PubMed

Winckelmans, Ellen; Nawrot, Tim S; Tsamou, Maria; Den Hond, Elly; Baeyens, Willy; Kleinjans, Jos; Lefebvre, Wouter; Van Larebeke, Nicolas; Peusens, Martien; Plusquin, Michelle; Reynders, Hans; Schoeters, Greet; Vanpoucke, Charlotte; de Kok, Theo M; Vrijens, Karen

2017-08-18

Due to their lack of repair capacity mitochondria are critical targets for environmental toxicants. We studied genes and pathways reflecting mitochondrial responses to short- and medium-term PM 10 exposure. Whole genome gene expression was measured in peripheral blood of 98 adults (49% women). We performed linear regression analyses stratified by sex and adjusted for individual and temporal characteristics to investigate alterations in gene expression induced by short-term (week before blood sampling) and medium-term (month before blood sampling) PM 10 exposure. Overrepresentation analyses (ConsensusPathDB) were performed to identify enriched mitochondrial associated pathways and gene ontology sets. Thirteen Human MitoCarta genes were measured by means of quantitative real-time polymerase chain reaction (qPCR) along with mitochondrial DNA (mtDNA) content in an independent validation cohort (n = 169, 55.6% women). Overrepresentation analyses revealed significant pathways (p-value <0.05) related to mitochondrial genome maintenance and apoptosis for short-term exposure and to the electron transport chain (ETC) for medium-term exposure in women. For men, medium-term PM 10 exposure was associated with the Tri Carbonic Acid cycle. In an independent study population, we validated several ETC genes, including UQCRH and COX7C (q-value <0.05), and some genes crucial for the maintenance of the mitochondrial genome, including LONP1 (q-value: 0.07) and POLG (q-value: 0.04) in women. In this exploratory study, we identified mitochondrial genes and pathways associated with particulate air pollution indicating upregulation of energy producing pathways as a potential mechanism to compensate for PM-induced mitochondrial damage.

Prenatal low-dose methylmercury exposure impairs neurite outgrowth and synaptic protein expression and suppresses TrkA pathway activity and eEF1A1 expression in the rat cerebellum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujimura, Masatake, E-mail: fujimura@nimd.go.jp; Usuki, Fusako; Cheng, Jinping

Methylmercury (MeHg) is a highly neurotoxic environmental chemical that can cause developmental impairments. Human fetuses and neonates are particularly susceptible to MeHg toxicity; however, the mechanisms governing its effects in the developing brain are unclear. In the present study, we investigated the effects of prenatal and lactational MeHg exposure on the developing cerebellum in rats. We demonstrated that exposure to 5 ppm MeHg decreased postnatal expression of pre- and postsynaptic proteins, suggesting an impairment in synaptic development. MeHg exposure also reduced neurite outgrowth, as shown by a decrease in the expression of the neurite marker neurofilament H. These changes weremore » not observed in rats exposed to 1 ppm MeHg. In order to define the underlying mechanism, we investigated the effects of MeHg exposure on the tropomyosin receptor kinase (Trk) A pathway, which plays important roles in neuronal differentiation and synapse formation. We demonstrated suppression of the TrkA pathway on gestation day 20 in rats exposed to 5 ppm MeHg. In addition, down-regulation of eukaryotic elongation factor 1A1 (eEF1A1) was observed on postnatal day 1. eEF1A1 knockdown in differentiating PC12 cells impaired neurite outgrowth and synaptic protein expression, similar to the results of MeHg exposure in the cerebellum. These results suggest that suppression of the TrkA pathway and subsequent decreases in eEF1A1 expression induced by prenatal exposure to MeHg may lead to reduced neurite outgrowth and synaptic protein expression in the developing cerebellum. - Highlights: • Prenatal exposure to MeHg decreased postnatal expression of synaptic proteins. • MeHg exposure also reduced neurite outgrowth postnatally. • Suppression of the TrkA pathway and eEF1A1 expression was induced by MeHg exposure. • eEF1A1 knockdown impaired neurite outgrowth and synaptic protein expression.« less

Metabolomic Analysis of the Secretome of Human Embryonic Stem Cells Following Methyl Parathion and Methyl Paraoxon Exposure, Phase 1: Initial Nontargeted LC-MS

DTIC Science & Technology

2014-01-01

and threonine metabolism 6 40 0.006188 0.10 MP H hsa00260 Glycine, serine and threonine metabolism 3 40 0.010283 0.07 MP H hsa00280 Valine, leucine...hsa00770 Pantothenate and CoA biosynthesis 5 24 0.005066 0.07 MP M hsa04142 Lysosome 2 4 0.002426 0.10 MPO M hsa04930 Type II diabetes mellitus 3 5...of MPO and increased after exposure to all three dose levels of MP. The glycine, serine and threonine metabolism pathway is of interest because

Single-Cell Analysis Reveals that Insulation Maintains Signaling Specificity between Two Yeast MAPK Pathways with Common Components

PubMed Central

Patterson, Jesse C.; Klimenko, Evguenia S.; Thorner, Jeremy

2014-01-01

Eukaryotic cells use multiple mitogen-activated protein kinase (MAPK) cascades to evoke appropriate responses to external stimuli. In Saccharomyces cerevisiae, the MAPK Fus3 is activated by pheromone-binding G protein-coupled receptors to promote mating, whereas the MAPK Hog1 is activated by hyperosmotic stress to elicit the high osmolarity glycerol (HOG) response. Although these MAPK pathways share several upstream components, exposure to either pheromone or osmolyte alone triggers only the appropriate response. We used fluorescent localization- and transcription-specific reporters to assess activation of these pathways in individual cells on the minute and hour timescale, respectively. Dual activation of these two MAPK pathways occurred over a broad range of stimulant concentrations and temporal regimes in wild-type cells subjected to co-stimulation. Thus, signaling specificity is achieved through an “insulation” mechanism, not a “cross-inhibition” mechanism. Furthermore, we showed that there was a critical period during which Hog1 activity had to occur for proper insulation of the HOG pathway. PMID:20959523

β-N-Methylamino-L-alanine (BMAA) perturbs alanine, aspartate and glutamate metabolism pathways in human neuroblastoma cells as determined by metabolic profiling.

PubMed

Engskog, Mikael K R; Ersson, Lisa; Haglöf, Jakob; Arvidsson, Torbjörn; Pettersson, Curt; Brittebo, Eva

2017-05-01

β-Methylamino-L-alanine (BMAA) is a non-proteinogenic amino acid that induces long-term cognitive deficits, as well as an increased neurodegeneration and intracellular fibril formation in the hippocampus of adult rodents following short-time neonatal exposure and in vervet monkey brain following long-term exposure. It has also been proposed to be involved in the etiology of neurodegenerative disease in humans. The aim of this study was to identify metabolic effects not related to excitotoxicity or oxidative stress in human neuroblastoma SH-SY5Y cells. The effects of BMAA (50, 250, 1000 µM) for 24 h on cells differentiated with retinoic acid were studied. Samples were analyzed using LC-MS and NMR spectroscopy to detect altered intracellular polar metabolites. The analysis performed, followed by multivariate pattern recognition techniques, revealed significant perturbations in protein biosynthesis, amino acid metabolism pathways and citrate cycle. Of specific interest were the BMAA-induced alterations in alanine, aspartate and glutamate metabolism and as well as alterations in various neurotransmitters/neuromodulators such as GABA and taurine. The results indicate that BMAA can interfere with metabolic pathways involved in neurotransmission in human neuroblastoma cells.

Profiling of Cytokines Secreted by Conventional Aqueous Outflow Pathway Endothelial Cells Activated In Vitro and Ex Vivo With Laser Irradiation

PubMed Central

Alvarado, Jorge A.; Chau, Phuonglan; Wu, Jianfeng; Juster, Richard; Shifera, Amde Selassie; Geske, Michael

2015-01-01

Purpose To profile which cytokine genes are differentially expressed (DE) as up- or downregulated by cultured human trabecular meshwork (TMEs) and Schlemm's canal endothelial cells (SCEs) after three experimental treatments consisting of selective laser trabeculoplasty (SLT) irradiation, exposure to media conditioned either by SLT-irradiated TMEs (TME-cm) or by SCEs (SCE-cm). Also, to profile which cytokines are upregulated ex vivo in SLT-irradiated human conventional aqueous outflow pathway (CAOP) tissues. Methods After each treatment, Affymetrix microarray assays were used to detect upregulated and downregulated genes for cytokines and their receptors in TMEs and SCEs. ELISA and protein antibody arrays were used to detect upregulated cytokines secreted in SLT-irradiated CAOP tissues ex vivo. Results The SLT irradiation upregulated numerous cytokine genes in TMEs, but only a few in SCEs. Exposure to TME- and SCE-cm induced SCEs to upregulate many more cytokine genes than TMEs. Selective laser trabeculoplasty irradiation and exposure to TME-cm downregulated several cytokine genes in TMEs but none in SCEs. Selective laser trabeculoplasty irradiation induced one upregulated and three downregulated cytokine-receptor genes in TMEs but none in SCEs. Exposure to TME-cm induced upregulation of one and downregulation of another receptor gene in TMEs, whereas two unique cytokine-receptor genes were upregulated in SCEs. Cytokine protein expression analysis showed that at least eight cytokines were upregulated in SLT-irradiated human CAOP tissues in situ/ex vivo. Conclusions This study has helped us identify a cytokine signaling pathway and to consider newly identified mechanisms regulating aqueous outflow that may lay the foundation for the future development of cytokine-based glaucoma therapies. PMID:26529044

Profiling of Cytokines Secreted by Conventional Aqueous Outflow Pathway Endothelial Cells Activated In Vitro and Ex Vivo With Laser Irradiation.

PubMed

Alvarado, Jorge A; Chau, Phuonglan; Wu, Jianfeng; Juster, Richard; Shifera, Amde Selassie; Geske, Michael

2015-11-01

To profile which cytokine genes are differentially expressed (DE) as up- or downregulated by cultured human trabecular meshwork (TMEs) and Schlemm's canal endothelial cells (SCEs) after three experimental treatments consisting of selective laser trabeculoplasty (SLT) irradiation, exposure to media conditioned either by SLT-irradiated TMEs (TME-cm) or by SCEs (SCE-cm). Also, to profile which cytokines are upregulated ex vivo in SLT-irradiated human conventional aqueous outflow pathway (CAOP) tissues. After each treatment, Affymetrix microarray assays were used to detect upregulated and downregulated genes for cytokines and their receptors in TMEs and SCEs. ELISA and protein antibody arrays were used to detect upregulated cytokines secreted in SLT-irradiated CAOP tissues ex vivo. The SLT irradiation upregulated numerous cytokine genes in TMEs, but only a few in SCEs. Exposure to TME- and SCE-cm induced SCEs to upregulate many more cytokine genes than TMEs. Selective laser trabeculoplasty irradiation and exposure to TME-cm downregulated several cytokine genes in TMEs but none in SCEs. Selective laser trabeculoplasty irradiation induced one upregulated and three downregulated cytokine-receptor genes in TMEs but none in SCEs. Exposure to TME-cm induced upregulation of one and downregulation of another receptor gene in TMEs, whereas two unique cytokine-receptor genes were upregulated in SCEs. Cytokine protein expression analysis showed that at least eight cytokines were upregulated in SLT-irradiated human CAOP tissues in situ/ex vivo. This study has helped us identify a cytokine signaling pathway and to consider newly identified mechanisms regulating aqueous outflow that may lay the foundation for the future development of cytokine-based glaucoma therapies.

The effect of misunderstanding the chemical properties of environmental contaminants on exposure beliefs: A case involving dioxins

PubMed Central

Zikmund-Fisher, Brian J.; Turkelson, Angela; Franzblau, Alfred; Diebol, Julia K.; Allerton, Lindsay A.; Parker, Edith A.

2013-01-01

Chemical properties of contaminants lead them to behave in particular ways in the environment and hence have specific pathways to human exposure. If residents of affected communities lack awareness of these properties, however, they could make incorrect assumptions about where and how exposure occurs. We conducted a mailed survey of 904 residents of Midland and Saginaw counties in Michigan, USA to assess to what degree residents of a community with known dioxin contamination appear to understand the hydrophobic nature of dioxins and the implications of that fact on different potential exposure pathways. Participants assessed whether various statements about dioxins were true, including multiple statements assessing beliefs about dioxins in different types of water. Participants also stated whether they believed different exposure pathways were currently significant sources of dioxin exposure in this community. A majority of residents believed that dioxins can be found in river water that has been filtered to completely remove all particulates, well water, and even city tap water, beliefs which are incongruous with the hydrophobic nature of dioxins. Mistrust of government and personal concern about dioxins predicted greater beliefs about dioxins in water. In turn, holding more beliefs about dioxins in water predicted beliefs that drinking and touching water are currently significant exposure pathways for dioxins. Ensuring that community residents’ mental models accurately reflect the chemical properties of different contaminants can be important to helping them to adjust their risk perceptions and potentially their risk mitigation behaviors accordingly. PMID:23391895

Increased DNA double-strand break was associated with downregulation of repair and upregulation of apoptotic factors in rat hippocampus after alcohol exposure.

PubMed

Suman, Shubhankar; Kumar, Santosh; N'Gouemo, Prosper; Datta, Kamal

2016-08-01

Binge drinking is known to cause damage in critical areas of the brain, including the hippocampus, which is important for relational memory and is reported to be sensitive to alcohol toxicity. However, the roles of DNA double-strand break (DSB) and its repair pathways, homologous recombination (HR), and non-homologous end joining (NHEJ) in alcohol-induced hippocampal injury remain to be elucidated. The purpose of this first study was to assess alcohol-induced DNA DSB and the mechanism by which alcohol affects DSB repair pathways in rat hippocampus. Male Sprague-Dawley rats (8-10 weeks old) were put on a 4-day binge ethanol treatment regimen. Control animals were maintained under similar conditions but were given the vehicle without ethanol. All animals were humanely euthanized 24 h after the last dose of ethanol administration and the hippocampi were dissected for immunoblot and immunohistochemistry analysis. Ethanol exposure caused increased 4-hydroxynonenal (4-HNE) staining as well as elevated γH2AX and 53BP1 foci in hippocampal cells. Immunoblot analysis showed decreased Mre11, Rad51, Rad50, and Ku86 as well as increased Bax and p21 in samples from ethanol-treated rats. Additionally, we also observed increased activated caspase3 staining in hippocampal cells 24 h after ethanol withdrawal. Taken together, our data demonstrated that ethanol concurrently induced DNA DSB, downregulated DSB repair pathway proteins, and increased apoptotic factors in hippocampal cells. We believe these findings will provide the impetus for further research on DNA DSB and its repair pathways in relation to alcohol toxicity in brain. Copyright © 2016 Elsevier Inc. All rights reserved.

The left dorsolateral prefrontal cortex and caudate pathway: New evidence for cue-induced craving of smokers.

PubMed

Yuan, Kai; Yu, Dahua; Bi, Yanzhi; Wang, Ruonan; Li, Min; Zhang, Yajuan; Dong, Minghao; Zhai, Jinquan; Li, Yangding; Lu, Xiaoqi; Tian, Jie

2017-09-01

Although the activation of the prefrontal cortex (PFC) and the striatum had been found in smoking cue induced craving task, whether and how the functional interactions and white matter integrity between these brain regions contribute to craving processing during smoking cue exposure remains unknown. Twenty-five young male smokers and 26 age- and gender-matched nonsmokers participated in the smoking cue-reactivity task. Craving related brain activation was extracted and psychophysiological interactions (PPI) analysis was used to specify the PFC-efferent pathways contributed to smoking cue-induced craving. Diffusion tensor imaging (DTI) and probabilistic tractography was used to explore whether the fiber connectivity strength facilitated functional coupling of the circuit with the smoking cue-induced craving. The PPI analysis revealed the negative functional coupling of the left dorsolateral prefrontal cortex (DLPFC) and the caudate during smoking cue induced craving task, which positively correlated with the craving score. Neither significant activation nor functional connectivity in smoking cue exposure task was detected in nonsmokers. DTI analyses revealed that fiber tract integrity negatively correlated with functional coupling in the DLPFC-caudate pathway and activation of the caudate induced by smoking cue in smokers. Moreover, the relationship between the fiber connectivity integrity of the left DLPFC-caudate and smoking cue induced caudate activation can be fully mediated by functional coupling strength of this circuit in smokers. The present study highlighted the left DLPFC-caudate pathway in smoking cue-induced craving in smokers, which may reflect top-down prefrontal modulation of striatal reward processing in smoking cue induced craving processing. Hum Brain Mapp 38:4644-4656, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Impact of Physical Abuse on Internalizing Behavior Across Generations.

PubMed

Esteves, Kyle; Gray, Sarah A O; Theall, Katherine P; Drury, Stacy S

2017-10-01

This study investigated the multigenerational impact of mothers' own exposure to physical maltreatment on internalizing symptoms in her child after accounting for her parenting practices, depression, and the child's own exposure to stressful life events. Children ( n = 101, ages 5-16), predominantly African American, were recruited into this cross sectional study using ethnographic mapping and targeted sampling for high-risk neighborhoods. Mothers reported retrospectively on their own exposure to physical maltreatment in childhood, their parenting practices, as well as current depressive symptoms. Maternal report of her child's exposure to stressful life events and child behavior was also collected. Maternal childhood exposure to physical maltreatment was significantly associated with her child's internalizing symptoms ( p = .004); this effect remained after accounting for child sex, maternal depressive symptoms, harsh parenting practices, and the child's own exposure to stressful life events. Formal tests of mediation through these pathways were non-significant. Findings suggest mothers' experience of childhood maltreatment contributes uniquely to children's internalizing symptoms, potentially through previously uncharacterized pathways. Examination of additional behavioral, psychosocial and biological pathways may help better describe the multi-generational effects of child maltreatment.

Existence of Inverted Profile in Chemically Responsive Molecular Pathways in the Zebrafish Liver

PubMed Central

Zhang, Xun; Li, Hu; Ma, Jing; Zhang, Louxin; Li, Baowen; Gong, Zhiyuan

2011-01-01

How a living organism maintains its healthy equilibrium in response to endless exposure of potentially harmful chemicals is an important question in current biology. By transcriptomic analysis of zebrafish livers treated by various chemicals, we defined hubs as molecular pathways that are frequently perturbed by chemicals and have high degree of functional connectivity to other pathways. Our network analysis revealed that these hubs were organized into two groups showing inverted functionality with each other. Intriguingly, the inverted activity profiles in these two groups of hubs were observed to associate only with toxicopathological states but not with physiological changes. Furthermore, these inverted profiles were also present in rat, mouse, and human under certain toxicopathological conditions. Thus, toxicopathological-associated anti-correlated profiles in hubs not only indicate their potential use in diagnosis but also development of systems-based therapeutics to modulate gene expression by chemical approach in order to rewire the deregulated activities of hubs back to normal physiology. PMID:22140468

Low-level maternal exposure to nicotine associates with significant metabolic perturbations in second-trimester amniotic fluid.

PubMed

Fischer, S Taylor; Lili, Loukia N; Li, Shuzhao; Tran, ViLinh T; Stewart, Kim B; Schwartz, Charles E; Jones, Dean P; Sherman, Stephanie L; Fridovich-Keil, Judith L

2017-10-01

Decades of public health research have documented that smoking in pregnancy poses significant health risks to both mother and child. More recent studies have shown that even passive maternal exposure to secondhand smoke associates with negative birth outcomes. However, the mechanisms linking exposure to outcomes have remained obscure. As a first step toward defining the metabolic consequence of low-level nicotine exposure on fetal development, we conducted an untargeted metabolomic analysis of 81 paired samples of maternal serum and amniotic fluid collected from karyotypically normal pregnancies in the second trimester. By comparing the m/z and retention times of our mass spectral features with confirmed standards, we identified cotinine, a nicotine derivative, and used the calculated cotinine concentrations to classify our maternal serum samples into exposure groups using previously defined cut-offs. We found that cotinine levels consistent with low-level maternal exposure to nicotine associated with distinct metabolic perturbations, particularly in amniotic fluid. In fact, the metabolic effects in amniotic fluid of ostensibly low-level exposed mothers showed greater overlap with perturbations previously observed in the sera of adult smokers than did the perturbations observed in the corresponding maternal sera. Dysregulated fetal pathways included aspartate and asparagine metabolism, pyrimidine metabolism, and metabolism of other amino acids. We also observed a strong negative association between level of maternal serum cotinine and acetylated polyamines in the amniotic fluid. Combined, these results confirm that low-level maternal nicotine exposure, indicated by a maternal serum cotinine level of 2-10ng/mL, is associated with striking metabolic consequences in the fetal compartment, and that the affected pathways overlap those perturbed in the sera of adult smokers. Copyright © 2017 Elsevier Ltd. All rights reserved.

Aggregate Exposure Pathways in Support of Risk Assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tan, Yu-Mei; Leonard, Jeremy A.; Edwards, Stephen

Over time, risk assessment has shifted from establishing relationships between exposure to a single chemical and a resulting adverse health outcome, to evaluation of multiple chemicals and disease outcomes simultaneously. As a result, there is an increasing need to better understand the complex mechanisms that influence risk of chemical and non-chemical stressors, beginning at their source and ending at a biological endpoint relevant to human or ecosystem health risk assessment. Just as the Adverse Outcome Pathway (AOP) framework has emerged as a means of providing insight into mechanism-based toxicity, the exposure science community has seen the recent introduction of themore » Aggregate Exposure Pathway (AEP) framework. AEPs aid in making exposure data applicable to the FAIR (i.e., findable, accessible, interoperable, and reusable) principle, especially by (1) organizing continuous flow of disjointed exposure information;(2) identifying data gaps, to focus resources on acquiring the most relevant data; (3) optimizing use and repurposing of existing exposure data; and (4) facilitating interoperability among predictive models. Herein, we discuss integration of the AOP and AEP frameworks and how such integration can improve confidence in both traditional and cumulative risk assessment approaches.« less

Aggregate Exposure Pathways in Support of Risk Assessment

DOE PAGES

Tan, Yu-Mei; Leonard, Jeremy A.; Edwards, Stephen; ...

2018-03-29

Over time, risk assessment has shifted from establishing relationships between exposure to a single chemical and a resulting adverse health outcome, to evaluation of multiple chemicals and disease outcomes simultaneously. As a result, there is an increasing need to better understand the complex mechanisms that influence risk of chemical and non-chemical stressors, beginning at their source and ending at a biological endpoint relevant to human or ecosystem health risk assessment. Just as the Adverse Outcome Pathway (AOP) framework has emerged as a means of providing insight into mechanism-based toxicity, the exposure science community has seen the recent introduction of themore » Aggregate Exposure Pathway (AEP) framework. AEPs aid in making exposure data applicable to the FAIR (i.e., findable, accessible, interoperable, and reusable) principle, especially by (1) organizing continuous flow of disjointed exposure information;(2) identifying data gaps, to focus resources on acquiring the most relevant data; (3) optimizing use and repurposing of existing exposure data; and (4) facilitating interoperability among predictive models. Herein, we discuss integration of the AOP and AEP frameworks and how such integration can improve confidence in both traditional and cumulative risk assessment approaches.« less

Signaling Pathways Involved in Lunar Dust Induced Cytotoxicity

NASA Technical Reports Server (NTRS)

Zhang, Ye; Lam, Chiu-Wing; Scully, Robert R.; Williams, Kyle; Zalesak, Selina; Wu, Honglu; James, John T.

2014-01-01

The Moon's surface is covered by a layer of fine, reactive dust. Lunar dust contain about 1-2% of very fine dust (< 3 micron), that is respirable. The habitable area of any lunar landing vehicle and outpost would inevitably be contaminated with lunar dust that could pose a health risk. The purpose of the study is to evaluate the toxicity of Apollo moon dust in rodents to assess the health risk of dust exposures to humans. One of the particular interests in the study is to evaluate dust-induced changes of the expression of fibrosis-related genes, and to identify specific signaling pathways involved in lunar dust-induced toxicity. F344 rats were exposed for 4 weeks (6h/d; 5d/wk) in nose-only inhalation chambers to concentrations of 0 (control air), 2.1, 6.1, 21, and 61 mg/m(exp 3) of lunar dust. Five rats per group were euthanized 1 day, 1 week, 1 month, and 3 months after the last inhalation exposure. The total RNAs were isolated from the blood or lung tissue after being lavaged, using the Qigen RNeasy kit. The Rat Fibrosis RT2 Profile PCR Array was used to profile the expression of 84 genes relevant to fibrosis. The genes with significant expression changes are identified and the gene expression data were further analyzed using IPA pathway analysis tool to determine the signaling pathways with significant changes.

Oxidative stress induced by potassium bromate exposure results in altered tight junction protein expression in renal proximal tubule cells.

PubMed

Limonciel, Alice; Wilmes, Anja; Aschauer, Lydia; Radford, Robert; Bloch, Katarzyna M; McMorrow, Tara; Pfaller, Walter; van Delft, Joost H; Slattery, Craig; Ryan, Michael P; Lock, Edward A; Jennings, Paul

2012-11-01

Potassium bromate (KBrO(3)) is an oxidising agent that has been widely used in the food and cosmetic industries. It has shown to be both a nephrotoxin and a renal carcinogen in in vivo and in vitro models. Here, we investigated the effects of KBrO(3) in the human and rat proximal tubular cell lines RPTEC/TERT1 and NRK-52E. A genome-wide transcriptomic screen was carried out from cells exposed to a sub-lethal concentration of KBrO(3) for 6, 24 and 72 h. Pathway analysis identified "glutathione metabolism", "Nrf2-mediated oxidative stress" and "tight junction (TJ) signalling" as the most enriched pathways. TJ signalling was less impacted in the rat model, and further studies revealed low transepithelial electrical resistance (TEER) and an absence of several TJ proteins in NRK-52E cells. In RPTEC/TERT1 cells, KBrO(3) exposure caused a decrease in TEER and resulted in altered expression of several TJ proteins. N-Acetylcysteine co-incubation prevented these effects. These results demonstrate that oxidative stress has, in conjunction with the activation of the cytoprotective Nrf2 pathway, a dramatic effect on the expression of tight junction proteins. The further understanding of the cross-talk between these two pathways could have major implications for epithelial repair, carcinogenesis and metastasis.

The Peroxisome Proliferator-Activated Receptor α is dispensable for cold-induced adipose tissue browning in mice.

PubMed

Defour, Merel; Dijk, Wieneke; Ruppert, Philip; Nascimento, Emmani B M; Schrauwen, Patrick; Kersten, Sander

2018-04-01

Chronic cold exposure causes white adipose tissue (WAT) to adopt features of brown adipose tissue (BAT), a process known as browning. Previous studies have hinted at a possible role for the transcription factor Peroxisome Proliferator-Activated Receptor alpha (PPARα) in cold-induced browning. Here we aimed to investigate the importance of PPARα in driving transcriptional changes during cold-induced browning in mice. Male wildtype and PPARα-/- mice were housed at thermoneutrality (28 °C) or cold (5 °C) for 10 days. Whole genome expression analysis was performed on inguinal WAT. In addition, other analyses were carried out. Whole genome expression data of livers of wildtype and PPARα-/- mice fasted for 24 h served as positive control for PPARα-dependent gene regulation. Cold exposure increased food intake and decreased weight of BAT and WAT to a similar extent in wildtype and PPARα-/- mice. Except for plasma non-esterified fatty acids, none of the cold-induced changes in plasma metabolites were dependent on PPARα genotype. Histological analysis of inguinal WAT showed clear browning upon cold exposure but did not reveal any morphological differences between wildtype and PPARα-/- mice. Transcriptomics analysis of inguinal WAT showed a marked effect of cold on overall gene expression, as revealed by principle component analysis and hierarchical clustering. However, wildtype and PPARα-/- mice clustered together, even after cold exposure, indicating a similar overall gene expression profile in the two genotypes. Pathway analysis revealed that cold upregulated pathways involved in energy usage, oxidative phosphorylation, and fatty acid β-oxidation to a similar extent in wildtype and PPARα-/- mice. Furthermore, cold-mediated induction of genes related to thermogenesis such as Ucp1, Elovl3, Cox7a1, Cox8, and Cidea, as well as many PPAR target genes, was similar in wildtype and PPARα-/- mice. Finally, pharmacological PPARα activation had a minimal effect on expression of cold-induced genes in murine WAT. Cold-induced changes in gene expression in inguinal WAT are unaltered in mice lacking PPARα, indicating that PPARα is dispensable for cold-induced browning. Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

Moderate UV Exposure Enhances Learning and Memory by Promoting a Novel Glutamate Biosynthetic Pathway in the Brain.

PubMed

Zhu, Hongying; Wang, Ning; Yao, Lei; Chen, Qi; Zhang, Ran; Qian, Junchao; Hou, Yiwen; Guo, Weiwei; Fan, Sijia; Liu, Siling; Zhao, Qiaoyun; Du, Feng; Zuo, Xin; Guo, Yujun; Xu, Yan; Li, Jiali; Xue, Tian; Zhong, Kai; Song, Xiaoyuan; Huang, Guangming; Xiong, Wei

2018-06-14

Sunlight exposure is known to affect mood, learning, and cognition. However, the molecular and cellular mechanisms remain elusive. Here, we show that moderate UV exposure elevated blood urocanic acid (UCA), which then crossed the blood-brain barrier. Single-cell mass spectrometry and isotopic labeling revealed a novel intra-neuronal metabolic pathway converting UCA to glutamate (GLU) after UV exposure. This UV-triggered GLU synthesis promoted its packaging into synaptic vesicles and its release at glutamatergic terminals in the motor cortex and hippocampus. Related behaviors, like rotarod learning and object recognition memory, were enhanced after UV exposure. All UV-induced metabolic, electrophysiological, and behavioral effects could be reproduced by the intravenous injection of UCA and diminished by the application of inhibitor or short hairpin RNA (shRNA) against urocanase, an enzyme critical for the conversion of UCA to GLU. These findings reveal a new GLU biosynthetic pathway, which could contribute to some of the sunlight-induced neurobehavioral changes. Copyright © 2018 Elsevier Inc. All rights reserved.

Secondhand Smoke Exposure Reduced the Compensatory Effects of IGF-I Growth Signaling in the Aging Rat Hearts

PubMed Central

Wu, Jia-Ping; Hsieh, Dennis Jine-Yuan; Kuo, Wei-Wen; Han, Chien-Kuo; Pai, Peiying; Yeh, Yu-Lan; Lin, Chien-Chung; Padma, V. Vijaya; Day, Cecilia Hsuan; Huang, Chih-Yang

2015-01-01

Background: Secondhand smoke (SHS) exposure is associated with increased risk of cardiovascular disease. Aging is a physiological process that involves progressive impairment of normal heart functions due to increased vulnerability to damage. This study examines secondhand smoke exposure in aging rats to determine the age-related death-survival balance. Methods: Rats were placed into a SHS exposure chamber and exposed to smog. Old age male Sprague-Dawley rats were exposed to 10 cigarettes for 30 min, day and night, continuing for one week. After 4 weeks the rats underwent morphological and functional studies. Left ventricular sections were stained with hematoxylin-eosin for histopathological examination. TUNEL detected apoptosis cells and protein expression related death and survival pathway were analyzed using western blot. Results: Death receptor-dependent apoptosis upregulation pathways and the mitochondria apoptosis proteins were apparent in young SHS exposure and old age rats. These biological markers were enhanced in aging SHS-exposed rats. The survival pathway was found to exhibit compensation only in young SHS-exposed rats, but not in the aging rats. Further decrease in the activity of this pathway was observed in aging SHS-exposed rats. TUNEL apoptotic positive cells were increased in young SHS-exposed rats, and in aging rats with or without SHS-exposure. Conclusions: Aging reduces IGF-I compensated signaling with accelerated cardiac apoptotic effects from second-hand smoke. PMID:26392808

Childhood sexual abuse, intimate partner violence during pregnancy, and posttraumatic stress symptoms following childbirth: a path analysis.

PubMed

Oliveira, Aline Gaudard E Silva de; Reichenheim, Michael Eduardo; Moraes, Claudia Leite; Howard, Louise Michele; Lobato, Gustavo

2017-04-01

The aim of the study was to explore the pathways by which childhood sexual abuse (CSA), psychological and physical intimate partner violence (IPV) during pregnancy, and other covariates relate to each other and to posttraumatic stress disorder (PTSD) symptoms in the postpartum period. The sample comprised 456 women who gave birth at a maternity service for high-risk pregnancies in Rio de Janeiro, Brazil, interviewed at 6-8 weeks after birth. A path analysis was carried out to explore the postulated pathways between exposures and outcome. Trauma History Questionnaire, Conflict Tactics Scales and Posttraumatic Stress Disorder Checklist were used to assess information about exposures of main interest and outcome. The link between CSA and PTSD symptoms was mediated by history of trauma, psychiatric history, psychological IPV, and fear of childbirth during pregnancy. Physical IPV was directly associated with postnatal PTSD symptoms, whereas psychological IPV connection seemed to be partially mediated by physical abuse and fear of childbirth during pregnancy. The role of CSA, IPV, and other psychosocial characteristics on the occurrence of PTSD symptoms following childbirth as well as the intricate network of these events should be acknowledged in clinic and intervention approaches.

Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood-brain barrier primary triple coculture model.

PubMed

Xu, Liming; Dan, Mo; Shao, Anliang; Cheng, Xiang; Zhang, Cuiping; Yokel, Robert A; Takemura, Taro; Hanagata, Nobutaka; Niwa, Masami; Watanabe, Daisuke

2015-01-01

Silver nanoparticles (Ag-NPs) can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood-brain barrier (BBB) and the underlying mechanism(s) of action on the BBB and the brain are not well understood. To investigate Ag-NP suspension (Ag-NPS)-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM). Global gene expression of astrocytes was measured using a DNA microarray. A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200 Ω·cm(2). After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the tight junction (TJ) protein ZO-1 was decreased. Discontinuous TJs were also observed between microvascular endothelial cells. After Ag-NPS exposure, severe mitochondrial shrinkage, vacuolations, endoplasmic reticulum expansion, and Ag-NPs were observed in astrocytes by TEM. Global gene expression analysis showed that three genes were upregulated and 20 genes were downregulated in astrocytes treated with Ag-NPS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the 23 genes were associated with metabolic processes, biosynthetic processes, response to stimuli, cell death, the MAPK pathway, and so on. No GO term and KEGG pathways were changed in the released-ion or polystyrene-NP groups. Ag-NPS inhibited the antioxidant defense of the astrocytes by increasing thioredoxin interacting protein, which inhibits the Trx system, and decreasing Nr4a1 and Dusp1. Meanwhile, Ag-NPS induced inflammation and apoptosis through modulation of the MAPK pathway or B-cell lymphoma-2 expression or mTOR activity in astrocytes. These results draw our attention to the importance of Ag-NP-induced toxicity on the neurovascular unit and provide a better understanding of its toxicological mechanisms on astrocytes.

Radiation Quality Effects on Transcriptome Profiles in 3-d Cultures After Particle Irradiation

NASA Technical Reports Server (NTRS)

Patel, Z. S.; Kidane, Y. H.; Huff, J. L.

2014-01-01

In this work, we evaluate the differential effects of low- and high-LET radiation on 3-D organotypic cultures in order to investigate radiation quality impacts on gene expression and cellular responses. Reducing uncertainties in current risk models requires new knowledge on the fundamental differences in biological responses (the so-called radiation quality effects) triggered by heavy ion particle radiation versus low-LET radiation associated with Earth-based exposures. We are utilizing novel 3-D organotypic human tissue models that provide a format for study of human cells within a realistic tissue framework, thereby bridging the gap between 2-D monolayer culture and animal models for risk extrapolation to humans. To identify biological pathway signatures unique to heavy ion particle exposure, functional gene set enrichment analysis (GSEA) was used with whole transcriptome profiling. GSEA has been used extensively as a method to garner biological information in a variety of model systems but has not been commonly used to analyze radiation effects. It is a powerful approach for assessing the functional significance of radiation quality-dependent changes from datasets where the changes are subtle but broad, and where single gene based analysis using rankings of fold-change may not reveal important biological information. We identified 45 statistically significant gene sets at 0.05 q-value cutoff, including 14 gene sets common to gamma and titanium irradiation, 19 gene sets specific to gamma irradiation, and 12 titanium-specific gene sets. Common gene sets largely align with DNA damage, cell cycle, early immune response, and inflammatory cytokine pathway activation. The top gene set enriched for the gamma- and titanium-irradiated samples involved KRAS pathway activation and genes activated in TNF-treated cells, respectively. Another difference noted for the high-LET samples was an apparent enrichment in gene sets involved in cycle cycle/mitotic control. It is plausible that the enrichment in these particular pathways results from the complex DNA damage resulting from high-LET exposure where repair processes are not completed during the same time scale as the less complex damage resulting from low-LET radiation.

Zebrafish Get Connected: Investigating Neurotransmission Targets and Alterations in Chemical Toxicity

PubMed Central

Horzmann, Katharine A.; Freeman, Jennifer L.

2016-01-01

Neurotransmission is the basis of neuronal communication and is critical for normal brain development, behavior, learning, and memory. Exposure to drugs and chemicals can alter neurotransmission, often through unknown pathways and mechanisms. The zebrafish (Danio rerio) model system is increasingly being used to study the brain and chemical neurotoxicity. In this review, the major neurotransmitter systems, including glutamate, GABA, dopamine, norepinephrine, serotonin, acetylcholine, histamine, and glutamate are surveyed and pathways of synthesis, transport, metabolism, and action are examined. Differences between human and zebrafish neurochemical pathways are highlighted. We also review techniques for evaluating neurological function, including the measurement of neurotransmitter levels, assessment of gene expression through transcriptomic analysis, and the recording of neurobehavior. Finally examples of chemical toxicity studies evaluating alterations in neurotransmitter systems in the zebrafish model are reviewed. PMID:28730152

Delayed neurochemical effects of prenatal exposure to MeHg in the cerebellum of developing rats.

PubMed

Heimfarth, Luana; Delgado, Jeferson; Mingori, Moara Rodrigues; Moresco, Karla Suzana; Pureur, Regina Pessoa; Gelain, Daniel Pens; Moreira, José Cláudio Fonseca

2018-03-01

Human fetuses and neonates are particularly vulnerable to methylmercury (MeHg)-induced brain damage and are sensitive even to low exposure levels. Previous work of our group evidence that prenatal exposure to MeHg causes cognitive and behavioral alterations and disrupt hippocampus signaling. The current study aimed to investigate the effect of gestational exposure of rats to MeHg at low doses (1 or 2 mg/kg) on parameters of redox imbalance and key signaling pathways in the cerebellum of their offspring. Pregnant females received MeHg (treated group) or 0.9% saline water (control group) by gavage in alternated days from gestational day 5 (GD5) until parturition and analyzes were proceed in the cerebellum of 30-day-old pups. We found increased lipid peroxidation and protein carbonylation levels as well as decreased SH content in pups prenatally exposed to 2 mg/kg MeHg. In addition, misregulated SOD/catalase activities supported imbalanced redox equilibrium. We found decreased GSK3β(Ser9) phosphorylation, suggesting activation of this enzyme and dephosphorylation/inhibition of ERK1/2 and JNK pathways. Increased PKAα catalytic subunit could be upstream of hyperphosphorylated c-Raf(Ser259) and downregulated MAPK pathway. In addition, we found raised levels of the Ca 2+ -dependent protein phosphatase 2 B (PP2B). We also found preserved immunohistochemical staining for both glial fibrillary acidic protein (GFAP) and NeuN in MeHg-exposed pups. Western blot analysis showed unaltered levels of BAX/BCL-XL, BAD/BCL-2 and active caspase 3. Together, these findings support absence of reactive astrocytes, neuronal damage and apoptotic cell death in the cerebellum of MeHg treated pups. The present study provides evidence that prenatal exposure to MeHg leads to later redox imbalance and disrupted signaling mechanisms in the cerebellum of 30-day-old pups potentially predisposing them to long-lasting neurological impairments in CNS. Copyright © 2017 Elsevier B.V. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Feng; Waters, Katrina M.; Miller, John H.

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 peakmore » 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 different radiation doses and elucidate the impact of low dose radiation exposure on human health.« less

Developmental Toxicity of Zinc Oxide Nanoparticles to Zebrafish (Danio rerio): A Transcriptomic Analysis

PubMed Central

Choi, Jin Soo; Kim, Ryeo-Ok; Yoon, Seokjoo

2016-01-01

Zinc oxide nanoparticles (ZnO NPs) are being utilized in an increasing number of fields and commercial applications. While their general toxicity and associated oxidative stress have been extensively studied, the toxicological pathways that they induce in developmental stages are still largely unknown. In this study, the developmental toxicity of ZnO NPs to embryonic/larval zebrafish was investigated. The transcriptional expression profiles induced by ZnO NPs were also investigated to ascertain novel genomic responses related to their specific toxicity pathway. Zebrafish embryos were exposed to 0.01, 0.1, 1, and 10 mg/L ZnO NPs for 96 h post-fertilization. The toxicity of ZnO NPs, based on their Zn concentration, was quite similar to that in embryonic/larval zebrafish exposed to corresponding ZnSO4 concentrations. Pericardial edema and yolk-sac edema were the principal malformations induced by ZnO NPs. Gene-expression profiling using microarrays demonstrated 689 genes that were differentially regulated (fold change >1.5) following exposure to ZnO NPs (498 upregulated, 191 downregulated). Several genes that were differentially regulated following ZnO NP exposure shared similar biological pathways with those observed with ZnSO4 exposure, but six genes (aicda, cyb5d1, edar, intl2, ogfrl2 and tnfsf13b) associated with inflammation and the immune system responded specifically to ZnO NPs (either in the opposite direction or were unchanged in ZnSO4 exposure). Real-time reverse-transcription quantitative polymerase chain reaction confirmed that the responses of these genes to ZnO NPs were significantly different from their response to ZnSO4 exposure. ZnO NPs may affect genes related to inflammation and the immune system, resulting in yolk-sac edema and pericardia edema in embryonic/larval developmental stages. These results will assist in elucidating the mechanisms of toxicity of ZnO NPs during development of zebrafish. PMID:27504894

Carcinogenic Effects of Oil Dispersants: a KEGG Pathway-based RNA-seq Study of Human Airway Epithelial Cells

PubMed Central

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

2016-01-01

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. PMID:27866042

Integrating human health and ecological data into cumulative risk assessment through the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks

EPA Science Inventory

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from relevant stressors across different species. Integration is important to provide a more complete assessment of risk, but evaluating endpoints a...

Integrating Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Estimate Exposure-relevant Responses

EPA Science Inventory

High throughput toxicity testing (HTT) holds the promise of providing data for tens of thousands of chemicals that currently have no data due to the cost and time required for animal testing. Interpretation of these results require information linking the perturbations seen in vi...

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

PubMed Central

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

2015-01-01

Background CFTR 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. Methods The molecular mechanisms leading to down-regulation of CFTR by cigarette smoke were determined using pharmacologic inhibitors and silencing RNAs. Results Using human bronchial epithelial cells, here we show that cigarette smoke induces degradation of CFTR that is attenuated by the lysosomal inhibitors, but not proteasome inhibitors. Cigarette smoke can activate multiple signaling pathways in airway epithelial cells, including the MEK/Erk1/2 MAPK 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 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 NAC inhibited activation of Erk1/2 by cigarette smoke and precluded the cigarette smoke-induced decrease of CFTR. Conclusions These results show that the MEK/Erk1/2 MAPK pathway regulates plasma membrane CFTR in human airway cells. General Significance The MEK/Erk1/2 MAPK pathway should be considered as a target for strategies to maintain/restore CFTR expression in the lung of smokers. PMID:25697727

Transcriptional responses in the rat nasal epithelium following subchronic inhalation of naphthalene vapor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clewell, H.J., E-mail: hclewell@thehamner.org; Efremenko, A.; Campbell, J.L.

Male and female Fischer 344 rats were exposed to naphthalene vapors at 0 (controls), 0.1, 1, 10, and 30 ppm for 6 h/d, 5 d/wk, over a 90-day period. Following exposure, the respiratory epithelium and olfactory epithelium from the nasal cavity were dissected separately, RNA was isolated, and gene expression microarray analysis was conducted. Only a few significant gene expression changes were observed in the olfactory or respiratory epithelium of either gender at the lowest concentration (0.1 ppm). At the 1.0 ppm concentration there was limited evidence of an oxidative stress response in the respiratory epithelium, but not in themore » olfactory epithelium. In contrast, a large number of significantly enriched cellular pathway responses were observed in both tissues at the two highest concentrations (10 and 30 ppm, which correspond to tumorigenic concentrations in the NTP bioassay). The nature of these responses supports a mode of action involving oxidative stress, inflammation and proliferation. These results are consistent with a dose-dependent transition in the mode of action for naphthalene toxicity/carcinogenicity between 1.0 and 10 ppm in the rat. In the female olfactory epithelium (the gender/site with the highest incidences of neuroblastomas in the NTP bioassay), the lowest concentration at which any signaling pathway was significantly affected, as characterized by the median pathway benchmark dose (BMD) or its 95% lower bound (BMDL) was 6.0 or 3.7 ppm, respectively, while the lowest female olfactory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 16.1, 11.1, and 8.4 ppm, respectively. In the male respiratory epithelium (the gender/site with the highest incidences of adenomas in the NTP bioassay), the lowest pathway BMD and BMDL were 0.4 and 0.3 ppm, respectively, and the lowest male respiratory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 0.5, 0.7, and 0.9 ppm, respectively. Using a published physiologically based pharmacokinetic (PBPK) model to estimate target tissue dose relevant to the proposed mode of action (total naphthalene metabolism per gram nasal tissue), the lowest transcriptional BMDLs from this analysis equate to human continuous naphthalene exposure at approximately 0.3 ppm. It is unlikely that significant effects of naphthalene or its metabolites will occur at exposures below this concentration. - Highlights: • We investigated mode of action for carcinogenicity of inhaled naphthalene in rats. • Gene expression changes were measured in rat nasal tissues after 90 day exposures. • Support a non-linear mode of action (oxidative stress, inflammation, and proliferation) • Suggest a dose-dependent transition in the mode of action between 1.0 and 10 ppm • Transcriptional benchmark doses could inform point of departure for risk assessment.« less

Dose response evaluation of gene expression profiles in the skin of K6/ODC mice exposed to sodium arsenite.

PubMed

Ahlborn, Gene J; Nelson, Gail M; Ward, William O; Knapp, Geremy; Allen, James W; Ouyang, Ming; Roop, Barbara C; Chen, Yan; O'Brien, Thomas; Kitchin, Kirk T; Delker, Don A

2008-03-15

Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, we characterized gene expression profiles from analysis of K6/ODC mice administered 0, 0.05, 0.25, 1.0 and 10 ppm sodium arsenite in their drinking water for 4 weeks. Following exposure, total RNA was isolated from mouse skin and processed to biotin-labeled cRNA for microarray analyses. Skin gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 GeneChips, and pathway analysis was conducted with DAVID (NIH), Ingenuity Systems and MetaCore's GeneGo. Differential expression of several key genes was verified through qPCR. Only the highest dose (10 ppm) resulted in significantly altered KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, including MAPK, regulation of actin cytoskeleton, Wnt, Jak-Stat, Tight junction, Toll-like, phosphatidylinositol and insulin signaling pathways. Approximately 20 genes exhibited a dose response, including several genes known to be associated with carcinogenesis or tumor progression including cyclin D1, CLIC4, Ephrin A1, STAT3 and DNA methyltransferase 3a. Although transcription changes in all identified genes have not previously been linked to arsenic carcinogenesis, their association with carcinogenesis in other systems suggests that these genes may play a role in the early stages of arsenic-induced skin carcinogenesis and can be considered potential biomarkers.

A biosphere modeling methodology for dose assessments of the potential Yucca Mountain deep geological high level radioactive waste repository.

PubMed

Watkins, B M; Smith, G M; Little, R H; Kessler, J

1999-04-01

Recent developments in performance standards for proposed high level radioactive waste disposal at Yucca Mountain suggest that health risk or dose rate limits will likely be part of future standards. Approaches to the development of biosphere modeling and dose assessments for Yucca Mountain have been relatively lacking in previous performance assessments due to the absence of such a requirement. This paper describes a practical methodology used to develop a biosphere model appropriate for calculating doses from use of well water by hypothetical individuals due to discharges of contaminated groundwater into a deep well. The biosphere model methodology, developed in parallel with the BIOMOVS II international study, allows a transparent recording of the decisions at each step, from the specification of the biosphere assessment context through to model development and analysis of results. A list of features, events, and processes relevant to Yucca Mountain was recorded and an interaction matrix developed to help identify relationships between them. Special consideration was given to critical/potential exposure group issues and approaches. The conceptual model of the biosphere system was then developed, based on the interaction matrix, to show how radionuclides migrate and accumulate in the biosphere media and result in potential exposure pathways. A mathematical dose assessment model was specified using the flexible AMBER software application, which allows users to construct their own compartment models. The starting point for the biosphere calculations was a unit flux of each radionuclide from the groundwater in the geosphere into the drinking water in the well. For each of the 26 radionuclides considered, the most significant exposure pathways for hypothetical individuals were identified. For 14 of the radionuclides, the primary exposure pathways were identified as consumption of various crops and animal products following assumed agricultural use of the contaminated water derived from the deep well. Inhalation of dust (11 radionuclides) and external irradiation (1 radionuclide) were also identified as significant exposure modes. Contribution to the total flux to dose conversion factor from the drinking water pathway for each radionuclide was also assessed and for most radionuclides was found to be less than 10% of the total flux to dose conversion factor summed across all pathways. Some of the uncertainties related to the results were considered. The biosphere modeling results have been applied within an EPRI Total Systems Performance Assessment of Yucca Mountain. Conclusions and recommendations for future performance assessments are provided.

Radiation doses to critical groups since the early 1950s due to discharges of liquid radioactive waste from Sellafield.

PubMed

Hunt, G J

1997-04-01

First, some of the early work is reviewed on exposure pathways in connection with proposed and early liquid radioactive waste discharges from Sellafield. The main historical features of these discharges, affected by relevant plant operations, are then briefly described. The important radiological exposure pathways resulting from the discharges and people's consumption and occupancy habits are considered. To place the changing scenario onto a consistent basis using present-day methodology, a reconstruction of exposures has been carried out using environmental monitoring data and models. The three major pathways are examined of Porphyra/laverbread consumption in South Wales, fish and shellfish consumption near Sellafield, and external exposure over local and more distant sediments. The results show that over the period 1952 to about 1970 the laverbread pathway was probably critical, taking a cautious approach. Effective dose rates fluctuated at around 1 mSv y(-1) from about 1956 to 1971. From about 1970 to 1985, the fish and shellfish pathway was likely to have been critical, with effective dose rates peaking at about 2 mSv y(-1) in 1975-1976. External exposure was likely to have been of lesser importance than the other two pathways until about 1985, when with the retention of previously-released radiocesium on sediments it has become dominant. This phenomenon applies particularly further afield where radiocesium concentrations have been slower to decline; in the Ribble estuary, houseboat dwellers have been the critical group from about 1985. Effective doses have been at about 0.3 mSv y(-1) and declining; they are due to the effects of radiocesium discharges in earlier years. Dose rates have remained within contemporary ICRP dose limits.

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

PubMed Central

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

2016-01-01

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. All previously identified high-risk jobs had high air concentrations, dermal mass loading, or both, and none had low dermal and air. We have found that both pathways are relevant. PMID:25357184

Subacute developmental exposure of zebrafish to the organophosphate pesticide metabolite, chlorpyrifos-oxon, results in defects in Rohon-Beard sensory neuron development

PubMed Central

Jacobson, Saskia M.; Birkholz, Denise A.; McNamara, Marcy L.; Bharate, Sandip B.; George, Kathleen M.

2010-01-01

Organophosphate pesticides (OPs) are environmental toxicants known to inhibit the catalytic activity of acetylcholinesterase (AChE) resulting in hypercholinergic toxicity symptoms. In developing embryos, OPs have been hypothesized to affect both cholinergic and non-cholinergic pathways. In order to understand the neurological pathways affected by OP exposure during embryogenesis, we developed a subacute model of OP developmental exposure in zebrafish by exposing embryos to a dose of the OP metabolite chlorpyrifos oxon (CPO) that is non-lethal and significantly inhibited AChE enzymatic activity compared to control embryos (43% at 1 day post-fertilization (dpf) and 11% at 2 dpf). Phenotypic analysis of CPO-exposed embryos demonstrated that embryonic growth, as analyzed by gross morphology, was normal in 85% of treated embryos. Muscle fiber formation was similar to control embryos as analyzed by birefringence, and nicotinic acetylcholine receptor (nAChR) cluster formation was quantitatively similar to control embryos as analyzed by α-bungarotoxin staining. These results indicate that partial AChE activity during the early days of zebrafish development is sufficient for general development, muscle fiber, and nAChR development. Rohon-Beard (RB) sensory neurons exhibited aberrant peripheral axon extension and gene expression profiling suggests that several genes responsible for RB neurogenesis are down-regulated. Stability of CPO in egg water at 28.5 °C was determined by HPLC-UV-MS analysis which revealed that the CPO concentration used in our studies hydrolyzes in egg water with a half-life of one day. The result that developmental CPO exposure affected RB neurogenesis without affecting muscle fiber or nAChR cluster formation demonstrates that zebrafish are a strong model system for characterizing subtle neurological pathologies resulting from environmental toxicants. PMID:20701988

EPA EcoBox Tools by Exposure Pathways

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

A Systems Toxicology Approach Reveals Biological Pathways Dysregulated by Prenatal Arsenic Exposure

PubMed Central

Laine, Jessica E.; Fry, Rebecca C.

2016-01-01

BACKGROUND Prenatal exposure to inorganic arsenic (iAs) is associated with dysregulated gene and protein expression in the fetus, both evident at birth. Potential epigenetic mechanisms that underlie these changes include but are not limited to the methylation of cytosines (CpG). OBJECTIVE The aim of the present study was to compile datasets from studies on prenatal arsenic exposure to identify whether key genes, proteins, or both and their associated biological pathways are perturbed. METHODS We compiled datasets from 12 studies that analyzed the relationship between prenatal iAs exposure and fetal changes to the epigenome (5-methyl cytosine), transcriptome (mRNA expression), and/or proteome (protein expression changes). FINDINGS Across the 12 studies, a set of 845 unique genes was identified and found to enrich for their role in biological pathways, including those signaled by peroxisome proliferator-activated receptor, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, and the glucocorticoid receptor. Tumor necrosis factor was identified as a putative cellular regulator underlying most (n = 277) of the identified iAs-associated genes or proteins. CONCLUSIONS Given their common identification across numerous human cohorts and their known toxicologic role in disease, the identified genes and pathways may underlie altered disease susceptibility associated with prenatal exposure to iAs. PMID:27325076

Exposure to Community Violence and Sexual Behaviors Among African American Youth: Testing Multiple Pathways.

PubMed

Voisin, Dexter R; Hotton, Anna; Neilands, Torsten

2018-01-01

African American youth bear a disproportionate burden of sexually transmitted infections. A growing number of studies document that youth exposure to community violence and sexual behaviors are highly correlated. Despite such growing evidence, only a few studies have empirically tested conceptually driven pathways that may account for such relationships. This study seeks to address that gap by exploring multiple pathways linking exposure to community violence and youth sexual behaviors. Using an existing sample of 563 African American youth attending high school, we examined whether possible links between exposure to community violence and sexual activity, sexual risk behaviors were mediated by aggression, low student-teacher connectedness, and negative peer norms. Major findings indicated indirect relationships between exposures to community violence and both sexual activity and risky sex, mediated by aggression and negative peer norms with no significant differences based on gender or socioeconomic status. Overall findings also indicated a significant indirect effect of aggression to risky sex via negative peer norms and from community violence to risky peer norms via aggression. By illuminating ways that community violence, aggression, peer norms, and sexual behaviors are dynamically interrelated, these findings have significant implications for future research and intervention initiatives aimed at addressing the different pathways.

Qualitative environmental health research: an analysis of the literature, 1991-2008.

PubMed

Scammell, Madeleine Kangsen

2011-10-01

Qualitative research uses nonnumeric data to understand people's opinions, motives, understanding, and beliefs about events or phenomena. In this analysis, I report the use of qualitative methods and data in the study of the relationship between environmental exposures and human health. A primary search for peer-reviewed journal articles dated from 1991 through 2008 included the following three terms: qualitative, environ*, and health. Searches resulted in 3,155 records. Data were extracted and findings of articles analyzed to determine where and by whom qualitative environmental health research is conducted and published, the types of methods and analyses used in qualitative studies of environmental health, and the types of information qualitative data contribute to environmental health. The results highlight a diversity of disciplines and techniques among researchers who used qualitative methods to study environmental health. Nearly all of the studies identified increased scientific understanding of lay perceptions of environmental health exposures. This analysis demonstrates the potential of qualitative data to improve understanding of complex exposure pathways, including the influence of social factors on environmental health, and health outcomes.

Transcriptomic response and perturbation of toxicity pathways in zebrafish larvae after exposure to graphene quantum dots (GQDs).

PubMed

Deng, Shun; Jia, Pan-Pan; Zhang, Jing-Hui; Junaid, Muhammad; Niu, Aping; Ma, Yan-Bo; Fu, Ailing; Pei, De-Sheng

2018-05-29

Graphene quantum dots (GQDs) are widely used for biomedical applications. Previously, the low-level toxicity of GQDs in vivo and in vitro has been elucidated, but the underlying molecular mechanisms remained largely unknown. Here, we employed the Illumina high-throughput RNA-sequencing to explore the whole-transcriptome profiling of zebrafish larvae after exposure to GQDs. Comparative transcriptome analysis identified 2116 differentially expressed genes between GQDs exposed groups and control. Functional classification demonstrated that a large proportion of genes involved in acute inflammatory responses and detoxifying process were significantly up-regulated by GQDs. The inferred gene regulatory network suggested that activator protein 1 (AP-1) was the early-response transcription factor in the linkage of a cascade of downstream (pro-) inflammatory signals with the apoptosis signals. Moreover, hierarchical signaling threshold determined the high sensitivity of complement system in zebrafish when exposed to the sublethal dose of GQDs. Further, 35 candidate genes from various signaling pathways were further validated by qPCR after exposure to 25, 50, and 100 μg/mL of GQDs. Taken together, our study provided a valuable insight into the molecular mechanisms of potential bleeding risks and detoxifying processes in response to GQDs exposure, thereby establishing a mechanistic basis for the biosafety evaluation of GQDs. Copyright © 2018 Elsevier B.V. All rights reserved.

Bridging Plant and Human Radiation Response and DNA Repair through an In Silico Approach

PubMed Central

Nikitaki, Zacharenia; Pavlopoulou, Athanasia; Holá, Marcela; Donà, Mattia; Michalopoulos, Ioannis; Balestrazzi, Alma; Angelis, Karel J.; Georgakilas, Alexandros G.

2017-01-01

The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals might facilitate interdisciplinary studies that cross traditional boundaries between animal and plant biology in order to expand the collection of biomarkers currently used for radiation exposure monitoring (REM) in environmental and biomedical settings. Genes implicated in trans-kingdom conserved DDR networks often triggered by ionizing radiation (IR) and UV light are deposited into biological databases. In this study, we have applied an innovative approach utilizing data pertinent to plant and human genes from publicly available databases towards the design of a ‘plant radiation biodosimeter’, that is, a plant and DDR gene-based platform that could serve as a REM reliable biomarker for assessing environmental radiation exposure and associated risk. From our analysis, in addition to REM biomarkers, a significant number of genes, both in human and Arabidopsis thaliana, not yet characterized as DDR, are suggested as possible DNA repair players. Last but not least, we provide an example on the applicability of an Arabidopsis thaliana—based plant system monitoring the role of cancer-related DNA repair genes BRCA1, BARD1 and PARP1 in processing DNA lesions. PMID:28587301

Bridging Plant and Human Radiation Response and DNA Repair through an In Silico Approach.

PubMed

Nikitaki, Zacharenia; Pavlopoulou, Athanasia; Holá, Marcela; Donà, Mattia; Michalopoulos, Ioannis; Balestrazzi, Alma; Angelis, Karel J; Georgakilas, Alexandros G

2017-06-06

The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals might facilitate interdisciplinary studies that cross traditional boundaries between animal and plant biology in order to expand the collection of biomarkers currently used for radiation exposure monitoring (REM) in environmental and biomedical settings. Genes implicated in trans-kingdom conserved DDR networks often triggered by ionizing radiation (IR) and UV light are deposited into biological databases. In this study, we have applied an innovative approach utilizing data pertinent to plant and human genes from publicly available databases towards the design of a 'plant radiation biodosimeter', that is, a plant and DDR gene-based platform that could serve as a REM reliable biomarker for assessing environmental radiation exposure and associated risk. From our analysis, in addition to REM biomarkers, a significant number of genes, both in human and Arabidopsis thaliana, not yet characterized as DDR, are suggested as possible DNA repair players. Last but not least, we provide an example on the applicability of an Arabidopsis thaliana- based plant system monitoring the role of cancer-related DNA repair genes BRCA1 , BARD1 and PARP1 in processing DNA lesions.

Epigenetic modulations in early endothelial cells and DNA hypermethylation in human skin after sulfur mustard exposure.

PubMed

Steinritz, Dirk; Schmidt, Annette; Balszuweit, Frank; Thiermann, Horst; Simons, Thilo; Striepling, Enno; Bölck, Birgit; Bloch, Wilhelm

2016-02-26

Victims that were exposed to the chemical warfare agent sulfur mustard (SM) suffer from chronic dermal and ocular lesions, severe pulmonary problems and cancer development. It has been proposed that epigenetic perturbations might be involved in that process but this has not been investigated so far. In this study, we investigated epigenetic modulations in vitro using early endothelial cells (EEC) that were exposed to different SM concentrations (0.5, 1.0, 23.5 and 50μM). A comprehensive analysis of 78 genes related to epigenetic pathways (i.e., DNA-methylation and post-translational histone modifications) was performed. Moreover, we analyzed global DNA methylation in vitro in EEC after SM exposure as a maker for epigenetic modulations and in vivo using human skin samples that were obtained from a patient 1 year after an accidently exposure to pure SM. SM exposure resulted in a complex regulation pattern of epigenetic modulators which was accompanied by a global increase of DNA methylation in vitro. Examination of the SM exposed human skin samples also revealed a significant increase of global DNA methylation in vivo, underlining the biological relevance of our findings. Thus, we demonstrated for the first time that SM affects epigenetic pathways and causes epigenetic modulations both in vivo and in vitro. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Staphylococcus aureus methicillin resistance detected by HPLC-MS/MS targeted metabolic profiling.

PubMed

Schelli, Katie; Rutowski, Joshua; Roubidoux, Julia; Zhu, Jiangjiang

2017-03-15

Recently, novel bioanalytical methods, such as NMR and mass spectrometry based metabolomics approaches, have started to show promise in providing rapid, sensitive and reproducible detection of Staphylococcus aureus antibiotic resistance. Here we performed a proof-of-concept study focused on the application of HPLC-MS/MS based targeted metabolic profiling for detecting and monitoring the bacterial metabolic profile changes in response to sub-lethal levels of methicillin exposure. One hundred seventy-seven targeted metabolites from over 20 metabolic pathways were specifically screened and one hundred and thirty metabolites from in vitro bacterial tests were confidently detected from both methicillin susceptible and methicillin resistant Staphylococcus aureus (MSSA and MRSA, respectively). The metabolic profiles can be used to distinguish the isogenic pairs of MSSA strains from MRSA strains, without or with sub-lethal levels of methicillin exposure. In addition, better separation between MSSA and MRSA strains can be achieved in the latter case using principal component analysis (PCA). Metabolite data from isogenic pairs of MSSA and MRSA strains were further compared without and with sub-lethal levels of methicillin exposure, with metabolic pathway analyses additionally performed. Both analyses suggested that the metabolic activities of MSSA strains were more susceptible to the perturbation of the sub-lethal levels of methicillin exposure compared to the MRSA strains. Copyright © 2016 Elsevier B.V. All rights reserved.

The Role of Body Image in the Relationship Between Internet Use and Bulimic Symptoms: Three Theoretical Frameworks.

PubMed

Melioli, Tiffany; Rodgers, Rachel F; Rodrigues, Marie; Chabrol, Henri

2015-11-01

Exposure to traditional media has been associated with bulimic symptoms. However, to date, little is known regarding the effects of Internet exposure. The aim of this study was to explore the relationships between Internet use and bulimic symptoms within the competing frameworks of sociocultural, impression management, and self-objectification theory. A sample of 289 French women aged 18-25 years completed an online questionnaire assessing bulimic symptoms, body dissatisfaction, body image avoidance, self-surveillance, body shame, and weekly Internet use. Bootstrapping analyses revealed that body shame and body image avoidance mediated the effect of weekly Internet use on bulimic symptoms. Furthermore, when entered into a multiple mediation analysis, these two variables provided independent mediation pathways of equal magnitude. The findings support the usefulness of both the self-objectification and impression management frameworks for investigating the relationship between Internet use and bulimic symptoms. Longitudinal research would help to clarify these pathways further.

A systematic evaluation of the potential effects of trichloroethylene exposure on cardiac development.

PubMed

Makris, Susan L; Scott, Cheryl Siegel; Fox, John; Knudsen, Thomas B; Hotchkiss, Andrew K; Arzuaga, Xabier; Euling, Susan Y; Powers, Christina M; Jinot, Jennifer; Hogan, Karen A; Abbott, Barbara D; Hunter, E Sidney; Narotsky, Michael G

2016-10-01

The 2011 EPA trichloroethylene (TCE) IRIS assessment, used developmental cardiac defects from a controversial drinking water study in rats (Johnson et al. [51]), along with several other studies/endpoints to derive reference values. An updated literature search of TCE-related developmental cardiac defects was conducted. Study quality, strengths, and limitations were assessed. A putative adverse outcome pathway (AOP) construct was developed to explore key events for the most commonly observed cardiac dysmorphologies, particularly those involved with epithelial-mesenchymal transition (EMT) of endothelial origin (EndMT); several candidate pathways were identified. A hypothesis-driven weight-of-evidence analysis of epidemiological, toxicological, in vitro, in ovo, and mechanistic/AOP data concluded that TCE has the potential to cause cardiac defects in humans when exposure occurs at sufficient doses during a sensitive window of fetal development. The study by Johnson et al. [51] was reaffirmed as suitable for hazard characterization and reference value derivation, though acknowledging study limitations and uncertainties. Published by Elsevier Inc.

Assessment of Fecal Exposure Pathways in Low-Income Urban Neighborhoods in Accra, Ghana: Rationale, Design, Methods, and Key Findings of the SaniPath Study

PubMed Central

Robb, Katharine; Null, Clair; Teunis, Peter; Yakubu, Habib; Armah, George; Moe, Christine L.

2017-01-01

Abstract. Rapid urbanization has contributed to an urban sanitation crisis in low-income countries. Residents in low-income, urban neighborhoods often have poor sanitation infrastructure and services and may experience frequent exposure to fecal contamination through a range of pathways. There are little data to prioritize strategies to decrease exposure to fecal contamination in these complex and highly contaminated environments, and public health priorities are rarely considered when planning urban sanitation investments. The SaniPath Study addresses this need by characterizing pathways of exposure to fecal contamination. Over a 16 month period, an in-depth, interdisciplinary exposure assessment was conducted in both public and private domains of four neighborhoods in Accra, Ghana. Microbiological analyses of environmental samples and behavioral data collection techniques were used to quantify fecal contamination in the environment and characterize the behaviors of adults and children associated with exposure to fecal contamination. Environmental samples (n = 1,855) were collected and analyzed for fecal indicators and enteric pathogens. A household survey with 800 respondents and over 500 hours of structured observation of young children were conducted. Approximately 25% of environmental samples were collected in conjunction with structured observations (n = 441 samples). The results of the study highlight widespread and often high levels of fecal contamination in both public and private domains and the food supply. The dominant fecal exposure pathway for young children in the household was through consumption of uncooked produce. The SaniPath Study provides critical information on exposure to fecal contamination in low-income, urban environments and ultimately can inform investments and policies to reduce these public health risks. PMID:28722599

Transcriptional response to 131I exposure of rat thyroid gland.

PubMed

Rudqvist, Nils; Spetz, Johan; Schüler, Emil; Parris, Toshima Z; Langen, Britta; Helou, Khalil; Forssell-Aronsson, Eva

2017-01-01

Humans are exposed to 131I in medical diagnostics and treatment but also from nuclear accidents, and better knowledge of the molecular response in thyroid is needed. The aim of the study was to examine the transcriptional response in thyroid tissue 24 h after 131I administration in rats. The exposure levels were chosen to simulate both the clinical situation and the case of nuclear fallout. Thirty-six male rats were i.v. injected with 0-4700 kBq 131I, and killed at 24 h after injection (Dthyroid = 0.0058-3.0 Gy). Total RNA was extracted from individual thyroid tissue samples and mRNA levels were determined using oligonucleotide microarray technique. Differentially expressed transcripts were determined using Nexus Expression 3.0. Hierarchical clustering was performed in the R statistical computing environment. Pathway analysis was performed using the Ingenuity Pathway Analysis tool and the Gene Ontology database. T4 and TSH plasma concentrations were measured using ELISA. Totally, 429 differentially regulated transcripts were identified. Downregulation of thyroid hormone biosynthesis associated genes (e.g. thyroglobulin, thyroid peroxidase, the sodium-iodine symporter) was identified in some groups, and an impact on thyroid function was supported by the pathway analysis. Recurring downregulation of Dbp and Slc47a2 was found. Dbp exhibited a pattern with monotonous reduction of downregulation with absorbed dose at 0.0058-0.22 Gy. T4 plasma levels were increased and decreased in rats whose thyroids were exposed to 0.057 and 0.22 Gy, respectively. Different amounts of injected 131I gave distinct transcriptional responses in the rat thyroid. Transcriptional response related to thyroid function and changes in T4 plasma levels were found already at very low absorbed doses to thyroid.

Arsenic exposure triggers a shift in microRNA expression.

PubMed

Sturchio, Elena; Colombo, Teresa; Boccia, Priscilla; Carucci, Nicoletta; Meconi, Claudia; Minoia, Claudio; Macino, Giuseppe

2014-02-15

Exposure to inorganic Arsenic (iAs) through drinking water is a major public health problem affecting most countries. iAs has been classified by the International Agency for Research on Cancer as Group 1: "Carcinogenic to humans". Although numerous studies have shown the related adverse effects of iAs, sensitive appropriate biomarkers for studies of environmental epidemiology are still required. The present work aims at investigate the role of microRNAs (miRNAs), powerful negative regulators of gene expression, playing a key role in many physiological and pathological cellular processes, in iAs exposure. To this end, we analyzed miRNA changes in expression profile triggered by iAs exposure in Jurkat cell line. We used microarray technology to profile the expression of miRNAs following 2 μmol/L sodium arsenite treatment at different time points. Moreover, we performed phenotypic analysis of iAs treated cells. Real Time Polymerase Chain Reaction (RT-PCR) was used to validate miRNA microarray data and to assay expression modulation of selected relevant mRNAs. Finally, bioinformatics techniques were applied to reconstruct iAs-relevant molecular pathways and miRNA regulatory networks from the expression data. We report miRNAs modulated after iAs treatment in Jurkat cells. In particular, we highlight 36 miRNAs exhibiting consistent dysregulation and particularly a panel of 8 miRNAs which we also validated by RT-PCR analysis. Computational analysis of lists of putative target genes for these 8 miRNAs points to an involvement in arsenic-response pathways, for a subset of them, that were analyzed by RT-PCR. Furthermore, iAs exposure reveals induction of cell cycle progression and the failure of apoptosis, supporting the idea of iAs carcinogenic activity. Our study provides a list of miRNAs whose expression levels are affected by iAs treatment, corroborating the importance of proceeding with the hunt for specific subset of miRNAs, which can serve as potential biomarkers of iAs effects with useful diagnostic value. Copyright © 2013 Elsevier B.V. All rights reserved.

Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Eunyoung

Low-level formaldehyde exposure is inevitable in industrialized countries. Although daily-life formaldehyde exposure level is practically impossible to induce cell death, most of mechanistic studies related to formaldehyde toxicity have been performed in cytotoxic concentrations enough to trigger cell death mechanism. Currently, toxicological mechanisms underlying the sub-cytotoxic exposure to formaldehyde are not clearly elucidated in skin cells. In this study, the genome-scale transcriptional analysis in normal human keratinocytes (NHKs) was performed to investigate cutaneous biological pathways associated with daily life formaldehyde exposure. We selected the 175 upregulated differentially expressed genes (DEGs) and 116 downregulated DEGs in NHKs treated with 200 μMmore » formaldehyde. In the Gene Ontology (GO) enrichment analysis of the 175 upregulated DEGs, the endoplasmic reticulum (ER) unfolded protein response (UPR) was identified as the most significant GO biological process in the formaldeyde-treated NHKs. Interestingly, the sub-cytotoxic formaldehyde affected NHKs to upregulate two enzymes important in the cellular transsulfuration pathway, cystathionine γ-lyase (CTH) and cystathionine-β-synthase (CBS). In the temporal expression analysis, the upregulation of the pro-inflammatory DEGs such as MMP1 and PTGS2 was detected earlier than that of CTH, CBS and other ER UPR genes. The metabolites of CTH and CBS, L-cystathionine and L-cysteine, attenuated the formaldehyde-induced upregulation of pro-inflammatory DEGs, MMP1, PTGS2, and CXCL8, suggesting that CTH and CBS play a role in the negative feedback regulation of formaldehyde-induced pro-inflammatory responses in NHKs. In this regard, the sub-cytotoxic formaldehyde-induced CBS and CTH may regulate inflammation fate decision to resolution by suppressing the early pro-inflammatory response. - Highlights: • Sub-cytotoxic formaldehyde upregulates ER UPR-associated genes in NHKs. • Formaldehyde-induced ER UPR genes includes cystathionine γ-lyase (CTH). • Sub-cytotoxic formaldehyde upregulates cystathionine-β-synthase (CBS) in NHKs. • Cystathionine metabolic enzymes may attenuate formaldehyde-induced inflammation in NHKs. • Cystathionine metabolic enzymes may play a role in the resolution of inflammation in NHKs.« less

Analysis of aggregation of platelets in thrombosis

NASA Astrophysics Data System (ADS)

Ahuja, Suresh

Platelets are key players in thrombus formation by first rolling over collagen bound von Willebrand factor followed by formation of a stable interaction with collagen. The first adhered platelets bind additional platelets until the whole injury is sealed off by a platelet aggregate. The coagulation system stabilizes the formed platelet plug by creating a tight fibrin network, and then wound contraction takes place because of morphological changes in platelets. Coagulation takes place by platelet activation and aggregation mainly through fibrinogen polymerization into fibrin fibers. The process includes multiple factors, such as thrombin, plasmin, and local shear-rate which regulate and control the process. Coagulation can be divided into two pathways: the intrinsic pathway and the extrinsic pathway. The intrinsic pathway is initiated by the exposure of a negatively charged. It is able to activate factor XII, using a complex reaction that includes prekallikrein and high-molecular-weight kininogen as cofactors.. Thrombin is the final enzyme that is needed to convert fibrinogen into fibrin. The extrinsic pathway starts with the exposure of tissue factor to the circulating blood, which is the major initiator of coagulation. There are several feedback loops that reinforce the coagulation cascade, resulting in large amounts of thrombin. It is dependent on the presence of pro-coagulant surfaces of cells expressing negatively charged phospholipids--which include phosphatidylserine (PS)--on their outer membrane. PS-bearing surfaces are able to increase the efficiency of the reactions by concentrating and co-localizing coagulation factors.. Aggregation of platelets are analyzed and compared to adhesion of platelet to erythrocyte and to endothelial cells. This abstract is replacing MAR16-2015-020003.

Application of the Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks to advance cumulative risk assessment by integrating human health and ecological endpoints

EPA Science Inventory

Evaluating risk of adverse outcomes from chemical exposure is essential for understanding the impacts of environmental contaminants. While human health outcomes are of primary concern and are often the focus of risk assessments, important non-human species are also exposed to co...

An application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) frameworks to mechanistically integrate data sources across multiple species into cumulative risk assessment (CRA)

EPA Science Inventory

Toxicologists use dose-response data from both in vivo and in vitro experiments to evaluate the effects of chemical contaminants on organisms. Cumulative risk assessments (CRAs) consider the effects of multiple stressors on multiple endpoints, and utilize environmental exposure ...

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

EPA Science Inventory

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...

A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways, OpenTox USA 2015 Poster

EPA Science Inventory

Adverse outcome pathways (AOP) link known population outcomes to a molecular initiating event (MIE) that can be quantified using high-throughput in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires consideration of exposure and absorption,...

Mediation Analysis: A Practitioner's Guide.

PubMed

VanderWeele, Tyler J

2016-01-01

This article provides an overview of recent developments in mediation analysis, that is, analyses used to assess the relative magnitude of different pathways and mechanisms by which an exposure may affect an outcome. Traditional approaches to mediation in the biomedical and social sciences are described. Attention is given to the confounding assumptions required for a causal interpretation of direct and indirect effect estimates. Methods from the causal inference literature to conduct mediation in the presence of exposure-mediator interactions, binary outcomes, binary mediators, and case-control study designs are presented. Sensitivity analysis techniques for unmeasured confounding and measurement error are introduced. Discussion is given to extensions to time-to-event outcomes and multiple mediators. Further flexible modeling strategies arising from the precise counterfactual definitions of direct and indirect effects are also described. The focus throughout is on methodology that is easily implementable in practice across a broad range of potential applications.

LOW COST, LOW BURDEN, EXPOSURE MONITORING STRATEGIES

EPA Science Inventory

A birth cohort study designed to evaluate the association between exposures to environmental agents and health outcomes presents many challenges for exposure monitoring. Exposure of the child must be measured for multiple chemicals through multiply pathways over an extended peri...

EPA EcoBox Tools by Exposure Pathways - Soil

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

EPA EcoBox Tools by Exposure Pathways - Food Chains

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

EPA EcoBox Tools by Exposure Pathways - References

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

EPA EcoBox Tools by Exposure Pathways - Air

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

ADVANCES IN DIETARY EXPOSURE RESEARCH AT THE UNITED STATES

EPA Science Inventory

The United States Environmental Protection Agency-National Exposure Research Laboratory's (USEPA-NERL)dietary exposure research program investigates the role of diet, including drinking water, as a potential pathway of human exposure to environmental contaminants. A primary progr...

Dose-related gene expression changes in forebrain following acute, low-level chlorpyrifos exposure in neonatal rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ray, Anamika; Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078; Liu Jing

2010-10-15

Chlorpyrifos (CPF) is a widely used organophosphorus insecticide (OP) and putative developmental neurotoxicant in humans. The acute toxicity of CPF is elicited by acetylcholinesterase (AChE) inhibition. We characterized dose-related (0.1, 0.5, 1 and 2 mg/kg) gene expression profiles and changes in cell signaling pathways 24 h following acute CPF exposure in 7-day-old rats. Microarray experiments indicated that approximately 9% of the 44,000 genes were differentially expressed following either one of the four CPF dosages studied (546, 505, 522, and 3,066 genes with 0.1, 0.5, 1.0 and 2.0 mg/kg CPF). Genes were grouped according to dose-related expression patterns using K-means clusteringmore » while gene networks and canonical pathways were evaluated using Ingenuity Pathway Analysis (registered) . Twenty clusters were identified and differential expression of selected genes was verified by RT-PCR. The four largest clusters (each containing from 276 to 905 genes) constituted over 50% of all differentially expressed genes and exhibited up-regulation following exposure to the highest dosage (2 mg/kg CPF). The total number of gene networks affected by CPF also rose sharply with the highest dosage of CPF (18, 16, 18 and 50 with 0.1, 0.5, 1 and 2 mg/kg CPF). Forebrain cholinesterase (ChE) activity was significantly reduced (26%) only in the highest dosage group. Based on magnitude of dose-related changes in differentially expressed genes, relative numbers of gene clusters and signaling networks affected, and forebrain ChE inhibition only at 2 mg/kg CPF, we focused subsequent analyses on this treatment group. Six canonical pathways were identified that were significantly affected by 2 mg/kg CPF (MAPK, oxidative stress, NF{Kappa}B, mitochondrial dysfunction, arylhydrocarbon receptor and adrenergic receptor signaling). Evaluation of different cellular functions of the differentially expressed genes suggested changes related to olfactory receptors, cell adhesion/migration, synapse/synaptic transmission and transcription/translation. Nine genes were differentially affected in all four CPF dosing groups. We conclude that the most robust, consistent changes in differential gene expression in neonatal forebrain across a range of acute CPF dosages occurred at an exposure level associated with the classical marker of OP toxicity, AChE inhibition. Disruption of multiple cellular pathways, in particular cell adhesion, may contribute to the developmental neurotoxicity potential of this pesticide.« less

DISTRIBUTIONS, ASSOCIATIONS, AND PARTIAL AGGREGATE EXPOSURE OF PESTICIDES AND POLYNUCLEAR AROMATIC HYDROCARBONS IN THE MINNESOTA CHILDREN'S PESTICIDE EXPOSURE STUDY (MNCPES)

EPA Science Inventory

The Minnesota Children's Pesticide Exposure Study (MNCPES) provides exposure, environmental, and biologic data relating to multi-pathway exposures of children for four primary pesticides (chlorpyrifos, malathion, diazinon, and atrazine), 14 secondary pesticides, and 13 polynucl...

Exome sequencing of oral squamous cell carcinoma in users of Arabian snuff reveals novel candidates for driver genes.

PubMed

Al-Hebshi, Nezar Noor; Li, Shiyong; Nasher, Akram Thabet; El-Setouhy, Maged; Alsanosi, Rashad; Blancato, Jan; Loffredo, Christopher

2016-07-15

The study sought to identify genetic aberrations driving oral squamous cell carcinoma (OSCC) development among users of shammah, an Arabian preparation of smokeless tobacco. Twenty archival OSCC samples, 15 of which with a history of shammah exposure, were whole-exome sequenced at an average depth of 127×. Somatic mutations were identified using a novel, matched controls-independent filtration algorithm. CODEX and Exomedepth coupled with a novel, Database of Genomic Variant-based filter were employed to call somatic gene-copy number variations. Significantly mutated genes were identified with Oncodrive FM and the Youn and Simon's method. Candidate driver genes were nominated based on Gene Set Enrichment Analysis. The observed mutational spectrum was similar to that reported by the TCGA project. In addition to confirming known genes of OSCC (TP53, CDKNA2, CASP8, PIK3CA, HRAS, FAT1, TP63, CCND1 and FADD) the analysis identified several candidate novel driver events including mutations of NOTCH3, CSMD3, CRB1, CLTCL1, OSMR and TRPM2, amplification of the proto-oncogenes FOSL1, RELA, TRAF6, MDM2, FRS2 and BAG1, and deletion of the recently described tumor suppressor SMARCC1. Analysis also revealed significantly altered pathways not previously implicated in OSCC including Oncostatin-M signalling pathway, AP-1 and C-MYB transcription networks and endocytosis. There was a trend for higher number of mutations, amplifications and driver events in samples with history of shammah exposure particularly those that tested EBV positive, suggesting an interaction between tobacco exposure and EBV. The work provides further evidence for the genetic heterogeneity of oral cancer and suggests shammah-associated OSCC is characterized by extensive amplification of oncogenes. © 2016 UICC.

Applying Aggregate Exposure Pathway and Adverse Outcome ...

EPA Pesticide Factsheets

Hazard assessment for nanomaterials often involves applying in vitro dose-response data to estimate potential health risks that arise from exposure to products that contain nanomaterials. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the perturbations of biological mechanisms that lead to apical adverse health outcomes in living organisms. The Adverse Outcome Pathway (AOP) framework addresses this uncertainty by acting as a scaffold onto which in vitro toxicity testing and other data can be arranged to aid in the interpretation of these results in terms of biologically-relevant responses, as an AOP connects an upstream molecular initiating event (MIE) to a downstream adverse outcome. In addition to hazard assessment, risk estimation also requires reconciling in vitro concentrations sufficient to produce bioactivity with in vivo concentrations that can trigger a MIE at the relevant biological target. Such target site exposures (TSEs) can be estimated by integrating pharmacokinetic considerations with environmental and exposure factors. Environmental and exposure data have been historically scattered in various resources, such as monitoring data for air pollutants or exposure models for specific chemicals. The Aggregate Exposure Pathway (AEP) framework is introduced to organize existing knowledge concerning biologically, chemically, and physically plausible, as well as empirically supported, links between the i

EPA EcoBox Tools by Exposure Pathways - Water and Sediment

EPA Pesticide Factsheets

Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

Ion transport across the exocrine glands of the frog skin.

PubMed

Mills, J W

1985-01-01

Exposure of the intact frog skin to beta-adrenergic agonists stimulates chloride secretion by the exocrine glands. The secretory response is dependent on Na in the serosal bath and is inhibited by exposure to ouabain and furosemide. Thus the transport mechanism has properties similar to those described for other exocrine glands. Analysis of 3H-ouabain binding sites and determination of intracellular ions by energy dispersive x-ray microanalysis indicates that the transepithelial pathway for Cl flux may be via a distinct group of cells located at the ductal pole of the acinus of two of the gland types; termed mucous and seromucous.

Label-Free Proteomic Analysis of Protein Changes in the Striatum during Chronic Ethanol Use and Early Withdrawal

PubMed Central

Ayers-Ringler, Jennifer R.; Oliveros, Alfredo; Qiu, Yanyan; Lindberg, Daniel M.; Hinton, David J.; Moore, Raymond M.; Dasari, Surendra; Choi, Doo-Sup

2016-01-01

The molecular mechanisms underlying the neuronal signaling changes in alcohol addiction and withdrawal are complex and multifaceted. The cortico-striatal circuit is highly implicated in these processes, and the striatum plays a significant role not only in the early stages of addiction, but in the developed-addictive state as well, including withdrawal symptoms. Transcriptional analysis is a useful method for determining changes in gene expression, however, the results do not always accurately correlate with protein levels. In this study, we employ label-free proteomic analysis to determine changes in protein expression within the striatum during chronic ethanol use and early withdrawal. The striatum, composed primarily of medium spiny GABAergic neurons, glutamatergic and dopaminergic nerve terminals and astrocytes, is relatively homogeneous for proteomic analysis. We were able to analyze more than 5000 proteins from both the dorsal (caudate and putamen) and ventral (nucleus accumbens) striatum and identified significant changes following chronic intermittent ethanol exposure and acute (8 h) withdrawal compared to ethanol naïve and ethanol exposure groups respectively. Our results showed significant changes in proteins involved in glutamate and opioid peptide signaling, and also uncovered novel pathways including mitochondrial function and lipid/cholesterol metabolism, as revealed by changes in electron transport chain proteins and RXR activation pathways. These results will be useful in the development of novel treatments for alcohol withdrawal and thereby aid in recovery from alcohol use disorder. PMID:27014007

Chronic Cigarette Smoke Mediated Global Changes in Lung Mucoepidermoid Cells: A Phosphoproteomic Analysis.

PubMed

Solanki, Hitendra S; Advani, Jayshree; Khan, Aafaque Ahmad; Radhakrishnan, Aneesha; Sahasrabuddhe, Nandini A; Pinto, Sneha M; Chang, Xiaofei; Prasad, Thottethodi Subrahmanya Keshava; Mathur, Premendu Prakash; Sidransky, David; Gowda, Harsha; Chatterjee, Aditi

2017-08-01

Proteomics analysis of chronic cigarette smoke exposure is a rapidly emerging postgenomics research field. While smoking is a major cause of lung cancer, functional studies using proteomics approaches could enrich our mechanistic understanding of the elusive lung cancer global molecular signaling and cigarette smoke relationship. We report in this study on a stable isotope labeling by amino acids in cell culture-based quantitative phosphoproteomic analysis of a human lung mucoepidermoid carcinoma cell line, H292 cells, chronically exposed to cigarette smoke. Using high resolution Orbitrap Velos mass spectrometer, we identified the hyperphosphorylation of 493 sites, which corresponds to 341 proteins and 195 hypophosphorylated sites, mapping to 142 proteins upon smoke exposure (2.0-fold change). We report differential phosphorylation of multiple kinases, including PAK6, EPHA4, LYN, mitogen-activated protein kinase, and phosphatases, including TMEM55B, PTPN14, TIGAR, among others, in response to chronic cigarette smoke exposure. Bioinformatics analysis revealed that the molecules differentially phosphorylated upon chronic exposure of cigarette smoke are associated with PI3K/AKT/mTOR and CDC42-PAK signaling pathways. These signaling networks are involved in multiple cellular processes, including cell polarity, cytoskeletal remodeling, cellular migration, protein synthesis, autophagy, and apoptosis. The present study contributes to emerging proteomics insights on cigarette smoke mediated global signaling in lung cells, which in turn may aid in development of precision medicine therapeutics and postgenomics biomarkers.

JNK pathway activation is controlled by Tao/TAOK3 to modulate ethanol sensitivity.

PubMed

Kapfhamer, David; King, Ian; Zou, Mimi E; Lim, Jana P; Heberlein, Ulrike; Wolf, Fred W

2012-01-01

Neuronal signal transduction by the JNK MAP kinase pathway is altered by a broad array of stimuli including exposure to the widely abused drug ethanol, but the behavioral relevance and the regulation of JNK signaling is unclear. Here we demonstrate that JNK signaling functions downstream of the Sterile20 kinase family gene tao/Taok3 to regulate the behavioral effects of acute ethanol exposure in both the fruit fly Drosophila and mice. In flies tao is required in neurons to promote sensitivity to the locomotor stimulant effects of acute ethanol exposure and to establish specific brain structures. Reduced expression of key JNK pathway genes substantially rescued the structural and behavioral phenotypes of tao mutants. Decreasing and increasing JNK pathway activity resulted in increased and decreased sensitivity to the locomotor stimulant properties of acute ethanol exposure, respectively. Further, JNK expression in a limited pattern of neurons that included brain regions implicated in ethanol responses was sufficient to restore normal behavior. Mice heterozygous for a disrupted allele of the homologous Taok3 gene (Taok3Gt) were resistant to the acute sedative effects of ethanol. JNK activity was constitutively increased in brains of Taok3Gt/+ mice, and acute induction of phospho-JNK in brain tissue by ethanol was occluded in Taok3Gt/+ mice. Finally, acute administration of a JNK inhibitor conferred resistance to the sedative effects of ethanol in wild-type but not Taok3Gt/+ mice. Taken together, these data support a role of a TAO/TAOK3-JNK neuronal signaling pathway in regulating sensitivity to acute ethanol exposure in flies and in mice.

Ameliorative effects of selenium on arsenic-induced cytotoxicity in PC12 cells via modulating autophagy/apoptosis.

PubMed

Rahman, Md Mostafizur; Uson-Lopez, Rachael A; Sikder, Md Tajuddin; Tan, Gongxun; Hosokawa, Toshiyuki; Saito, Takeshi; Kurasaki, Masaaki

2018-04-01

Arsenic is well known toxicant responsible for human diseases including cancers. On the other hand, selenium is an essential trace element with significant chemopreventive effects, anticancer potentials and antioxidant properties. Although previous studies have reported antagonism/synergism between arsenic and selenium in biological systems, the biomolecular mechanism/s is still inconclusive. Therefore, to elucidate the molecular phenomena in cellular level, we hypothesized that co-exposure of selenium with arsenic may have suppressive effects on arsenic-induced cytotoxicity. We found that selenium in co-exposure with arsenic increases cell viability, and suppresses oxidative stress induced by arsenic in PC12 cells. Consequently, DNA fragmentation due to arsenic exposure was also reduced by arsenic and selenium co-exposure. Furthermore, western blot analyses revealed that simultaneous exposure of both metals significantly inhibited autophagy which further suppressed apoptosis through positively regulation of key proteins; p-mTOR, p-Akt, p-Foxo1A, p62, and expression of ubiquitin, Bax, Bcl2, NFкB, and caspases 3 and 9, although those are negatively regulated by arsenic. In addition, reverse transcriptase PCR analysis confirmed the involvement of caspase cascade in cell death process induced by arsenic and subsequent inhibition by co-exposure of selenium with arsenic. The cellular accumulation study of arsenic in presence/absence of selenium via inductively coupled plasma mass spectrometry confirmed that selenium effectively retarded the uptake of arsenic in PC12 cells. Finally, these findings imply that selenium is capable to modulate arsenic-induced intrinsic apoptosis pathway via enhancement of mTOR/Akt autophagy signaling pathway through employing antioxidant potentials and through inhibiting the cellular accumulation of arsenic in PC12 cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

Developmental Exposure to Estrogen Alters Differentiation and Epigenetic Programming in a Human Fetal Prostate Xenograft Model

PubMed Central

Saffarini, Camelia M.; McDonnell-Clark, Elizabeth V.; Amin, Ali; Huse, Susan M.; Boekelheide, Kim

2015-01-01

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. PMID:25799167

Exposure to Cobalt Causes Transcriptomic and Proteomic Changes in Two Rat Liver Derived Cell Lines

PubMed Central

Permenter, Matthew G.; Dennis, William E.; Sutto, Thomas E.; Jackson, David A.; Lewis, John A.; Stallings, Jonathan D.

2013-01-01

Cobalt is a transition group metal present in trace amounts in the human diet, but in larger doses it can be acutely toxic or cause adverse health effects in chronic exposures. Its use in many industrial processes and alloys worldwide presents opportunities for occupational exposures, including military personnel. While the toxic effects of cobalt have been widely studied, the exact mechanisms of toxicity remain unclear. In order to further elucidate these mechanisms and identify potential biomarkers of exposure or effect, we exposed two rat liver-derived cell lines, H4-II-E-C3 and MH1C1, to two concentrations of cobalt chloride. We examined changes in gene expression using DNA microarrays in both cell lines and examined changes in cytoplasmic protein abundance in MH1C1 cells using mass spectrometry. We chose to closely examine differentially expressed genes and proteins changing in abundance in both cell lines in order to remove cell line specific effects. We identified enriched pathways, networks, and biological functions using commercial bioinformatic tools and manual annotation. Many of the genes, proteins, and pathways modulated by exposure to cobalt appear to be due to an induction of a hypoxic-like response and oxidative stress. Genes that may be differentially expressed due to a hypoxic-like response are involved in Hif-1α signaling, glycolysis, gluconeogenesis, and other energy metabolism related processes. Gene expression changes linked to oxidative stress are also known to be involved in the NRF2-mediated response, protein degradation, and glutathione production. Using microarray and mass spectrometry analysis, we were able to identify modulated genes and proteins, further elucidate the mechanisms of toxicity of cobalt, and identify biomarkers of exposure and effect in vitro, thus providing targets for focused in vivo studies. PMID:24386269

Development of a pathway model to assess the exposure of European pine trees to pine wood nematode via the trade of wood.

PubMed

Douma, J C; van der Werf, W; Hemerik, L; Magnusson, C; Robinet, C

2017-04-01

Pine wood nematode (PWN), Bursaphelenchus xylophilus, is a threat for pine species (Pinus spp.) throughout the world. The nematode is native to North America, and invaded Japan, China, Korea, and Taiwan, and more recently Portugal and Spain. PWN enters new areas through trade in wood products. Once established, eradication is not practically feasible. Therefore, preventing entry of PWN into new areas is crucial. Entry risk analysis can assist in targeting management to reduce the probability of entry. Assessing the entry of PWN is challenging due to the complexity of the wood trade and the wood processing chain. In this paper, we develop a pathway model that describes the wood trade and wood processing chain to determine the structure of the entry process. We consider entry of PWN through imported coniferous wood from China, a possible origin of Portuguese populations, to Europe. We show that exposure increased over years due to an increase in imports of sawn wood. From 2000 to 2012, Europe received an estimated 84 PWN propagules from China, 88% of which arose from imported sawn wood and 12% from round wood. The region in Portugal where the PWN was first reported is among those with the highest PWN transfer per unit of imported wood due to a high host cover and vector activity. An estimated 62% of PWN is expected to enter in countries where PWN is not expected to cause the wilt of pine trees because of low summer temperatures (e.g., Belgium, Sweden, Norway). In these countries, PWN is not easily detected, and such countries can thus serve as potential reservoirs of PWN. The model identifies ports and regions with high exposure, which helps targeting monitoring and surveillance, even in areas where wilt disease is not expected to occur. In addition, we show that exposure is most efficiently reduced by additional treatments in the country of origin, and/or import wood from PWN-free zones. Pathway modelling assists plant health managers in analyzing risks along the pathway and planning measures for enhancing biosecurity. © 2016 by the Ecological Society of America.

Arsenite activates NFκB through induction of C-reactive protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Druwe, Ingrid L.; Sollome, James J.; Sanchez-Soria, Pablo

2012-06-15

C-reactive protein (CRP) is an acute phase protein in humans. Elevated levels of CRP are produced in response to inflammatory cytokines and are associated with atherosclerosis, hypertension, cardiovascular disease and insulin resistance. Exposure to inorganic arsenic, a common environmental toxicant, also produces cardiovascular disorders, namely atherosclerosis and is associated with insulin-resistance. Inorganic arsenic has been shown to contribute to cardiac toxicities through production of reactive oxygen species (ROS) that result in the activation of NFκB. In this study we show that exposure of the hepatic cell line, HepG2, to environmentally relevant levels of arsenite (0.13 to 2 μM) results inmore » elevated CRP expression and secretion. ROS analysis of the samples showed that a minimal amount of ROS are produced by HepG2 cells in response to these concentrations of arsenic. In addition, treatment of FvB mice with 100 ppb sodium arsenite in the drinking water for 6 months starting at weaning age resulted in dramatically higher levels of CRP in both the liver and inner medullary region of the kidney. Further, mouse Inner Medullary Collecting Duct cells (mIMCD-4), a mouse kidney cell line, were stimulated with 10 ng/ml CRP which resulted in activation of NFκB. Pretreatment with 10 nM Y27632, a known Rho-kinase inhibitor, prior to CRP exposure attenuated NFκB activation. These data suggest that arsenic causes the expression and secretion of CRP and that CRP activates NFκB through activation of the Rho-kinase pathway, thereby providing a novel pathway by which arsenic can contribute to metabolic syndrome and cardiovascular disease. -- Highlights: ► Exposure to arsenic can induce the expression and secretion of CRP. ► Mice treated with NaAsO{sub 2} showed higher levels of CRP in both the liver and kidney. ► mIMCD-3 were stimulated with CRP which resulted in activation of NFκB. ► CRP activates NFκB through activation of the Rho-kinase pathway. ► Data provide novel pathway for arsenic role in metabolic and cardiovascular disease.« less

Systems toxicology identifies mechanistic impacts of 2-amino-4,6-dinitrotoluene (2A-DNT) exposure in Northern Bobwhite.

PubMed

Gust, Kurt A; Nanduri, Bindu; Rawat, Arun; Wilbanks, Mitchell S; Ang, Choo Yaw; Johnson, David R; Pendarvis, Ken; Chen, Xianfeng; Quinn, Michael J; Johnson, Mark S; Burgess, Shane C; Perkins, Edward J

2015-08-07

A systems toxicology investigation comparing and integrating transcriptomic and proteomic results was conducted to develop holistic effects characterizations for the wildlife bird model, Northern bobwhite (Colinus virginianus) dosed with the explosives degradation product 2-amino-4,6-dinitrotoluene (2A-DNT). A subchronic 60 d toxicology bioassay was leveraged where both sexes were dosed via daily gavage with 0, 3, 14, or 30 mg/kg-d 2A-DNT. Effects on global transcript expression were investigated in liver and kidney tissue using custom microarrays for C. virginianus in both sexes at all doses, while effects on proteome expression were investigated in liver for both sexes and kidney in males, at 30 mg/kg-d. As expected, transcript expression was not directly indicative of protein expression in response to 2A-DNT. However, a high degree of correspondence was observed among gene and protein expression when investigating higher-order functional responses including statistically enriched gene networks and canonical pathways, especially when connected to toxicological outcomes of 2A-DNT exposure. Analysis of networks statistically enriched for both transcripts and proteins demonstrated common responses including inhibition of programmed cell death and arrest of cell cycle in liver tissues at 2A-DNT doses that caused liver necrosis and death in females. Additionally, both transcript and protein expression in liver tissue was indicative of induced phase I and II xenobiotic metabolism potentially as a mechanism to detoxify and excrete 2A-DNT. Nuclear signaling assays, transcript expression and protein expression each implicated peroxisome proliferator-activated receptor (PPAR) nuclear signaling as a primary molecular target in the 2A-DNT exposure with significant downstream enrichment of PPAR-regulated pathways including lipid metabolic pathways and gluconeogenesis suggesting impaired bioenergetic potential. Although the differential expression of transcripts and proteins was largely unique, the consensus of functional pathways and gene networks enriched among transcriptomic and proteomic datasets provided the identification of many critical metabolic functions underlying 2A-DNT toxicity as well as impaired PPAR signaling, a key molecular initiating event known to be affected in di- and trinitrotoluene exposures.

Utilizing ToxCast Data and Lifestage Physiologically-Based Pharmacokinetic (PBPK) models to Drive Adverse Outcome Pathways (AOPs)-Based Margin of Exposures (ABME) to Chemicals.

EPA Science Inventory

Utilizing ToxCast Data and Lifestage Physiologically-Based Pharmacokinetic (PBPK) models to Drive Adverse Outcome Pathways (AOPs)-Based Margin of Exposures (ABME) to Chemicals. Hisham A. El-Masri1, Nicole C. Klienstreur2, Linda Adams1, Tamara Tal1, Stephanie Padilla1, Kristin I...

Nrf2 protects against oxidative stress induced by SiO2 nanoparticles.

PubMed

Liu, Wei; Hu, Tao; Zhou, Li; Wu, Desheng; Huang, Xinfeng; Ren, Xiaohu; Lv, Yuan; Hong, Wenxu; Huang, Guanqin; Lin, Zequn; Liu, Jianjun

2017-10-01

The aim of our study was to explore the role of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) on the exposure of SiO 2 nanoparticles (NPs) and its influence. To understand the mechanism of NP-induced oxidative stress, the involvement of oxidative-stress-responding transcription factors and the Nrf2/antioxidant reactive element (ARE) signaling pathway in the toxicity of SiO 2 NPs' exposure was investigated via in vivo and in vitro models. A549 cells showed a significant cytotoxic effect while A549-shNrf2 cells showed decreased cell viability after nm-SiO 2 exposure. SiO 2 NPs' exposure activated the Nrf2/ARE signaling pathway. Nrf2 -/- exposed mice showed increased reactive oxygen species, 8-hydroxyl deoxyguanosine level and decreased total antioxidant capacity. Nrf2/ARE signaling pathway activation disrupted, leading inhibition of heme oxygenase-1 and upregulation of PKR-like endoplasmic-reticulum-regulated kinase. Our findings suggested that Nrf2 could protect against oxidative stress induced by SiO 2 NPs, and the Nrf2/ARE pathway might be involved in mild-to-moderate SiO 2 NP-induced oxidative stress that was evident from dampened activity of Nrf2.

Arsenic responsive microRNAs in vivo and their potential involvement in arsenic-induced oxidative stress

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, Xuefeng, E-mail: xuefengr@buffalo.edu; Department of Pharmacology and Toxicology, School of Biomedical Sciences, The State University of New York, Buffalo, NY 14214; Gaile, Daniel P.

Arsenic exposure is postulated to modify microRNA (miRNA) expression, leading to changes of gene expression and toxicities, but studies relating the responses of miRNAs to arsenic exposure are lacking, especially with respect to in vivo studies. We utilized high-throughput sequencing technology and generated miRNA expression profiles of liver tissues from Sprague Dawley (SD) rats exposed to various concentrations of sodium arsenite (0, 0.1, 1, 10 and 100 mg/L) for 60 days. Unsupervised hierarchical clustering analysis of the miRNA expression profiles clustered the SD rats into different groups based on the arsenic exposure status, indicating a highly significant association between arsenicmore » exposure and cluster membership (p-value of 0.0012). Multiple miRNA expressions were altered by arsenic in an exposure concentration-dependent manner. Among the identified arsenic-responsive miRNAs, several are predicted to target Nfe2l2-regulated antioxidant genes, including glutamate–cysteine ligase (GCL) catalytic subunit (GCLC) and modifier subunit (GCLM) which are involved in glutathione (GSH) synthesis. Exposure to low concentrations of arsenic increased mRNA expression for Gclc and Gclm, while high concentrations significantly reduced their expression, which were correlated to changes in hepatic GCL activity and GSH level. Moreover, our data suggested that other mechanisms, e.g., miRNAs, rather than Nfe2l2-signaling pathway, could be involved in the regulation of mRNA expression of Gclc and Gclm post-arsenic exposure in vivo. Together, our findings show that arsenic exposure disrupts the genome-wide expression of miRNAs in vivo, which could lead to the biological consequence, such as an altered balance of antioxidant defense and oxidative stress. - Highlights: • Chronic arsenic exposure induces changes of hepatic miRNA expression profiles. • Hepatic GCL activity and GSH level in rats are altered following arsenic exposure. • Arsenic induced GCL expression change is independent to Nfe2l2-signaling pathway. • Expression of several miRNAs predicted to target GCL changed after arsenic exposure.« less

Genome-wide gene expression changes associated with exposure of rat liver, heart, and kidney cells to endosulfan.

PubMed

Liu, Ruifeng; Printz, Richard L; Jenkins, Erin C; O'Brien, Tracy P; Te, Jerez A; Shiota, Masakazu; Wallqvist, Anders

2018-04-01

Endosulfan was once the most commonly used pesticide in agriculture and horticulture. It is an environmentally persistent organochlorine compound with the potential to bioaccumulate as it progresses through the food chain. Its acute and chronic toxicity to mammals, including humans, is well known, but the molecular mechanisms of its toxicity are not fully understood. To gain insight to these mechanisms, we examined genome-wide gene expression changes of rat liver, heart, and kidney cells induced by endosulfan exposure. We found that among the cell types examined, kidney and liver cells were the most sensitive and most resilient, respectively, to endosulfan insult. We acquired RNA sequencing information from cells exposed to endosulfan to identify differentially expressed genes, which we further examined to determine the cellular pathways that were affected. In kidney cells, exposure to endosulfan was uniquely associated with altered expression levels of genes constituting the hypoxia-inducible factor-1 (HIF-1) signaling pathway. In heart and liver cells, exposure to endosulfan altered the expression levels of genes for many members of the extracellular matrix (ECM)-receptor interaction pathway. Because both HIF-1 signaling and ECM-receptor interaction pathways directly or indirectly control cell growth, differentiation, proliferation, and apoptosis, our findings suggest that dysregulation of these pathways is responsible for endosulfan-induced cell death. Copyright © 2018 Elsevier Ltd. All rights reserved.

Transcriptional Pathways Altered in Response to Vibration in a Model of Hand-Arm Vibration Syndrome.

PubMed

Waugh, Stacey; Kashon, Michael L; Li, Shengqiao; Miller, Gerome R; Johnson, Claud; Krajnak, Kristine

2016-04-01

The aim of this study was to use an established model of vibration-induced injury to assess frequency-dependent changes in transcript expression in skin, artery, and nerve tissues. Transcript expression in tissues from control and vibration-exposed rats (4 h/day for 10 days at 62.5, 125, or 250 Hz; 49 m/s, rms) was measured. Transcripts affected by vibration were used in bioinformatics analyses to identify molecular- and disease-related pathways associated with exposure to vibration. Analyses revealed that cancer-related pathways showed frequency-dependent changes in activation or inhibition. Most notably, the breast-related cancer-1 pathway was affected. Other pathways associated with breast cancer type 1 susceptibility protein related signaling, or associated with cancer and cell cycle/cell survivability were also affected. Occupational exposure to vibration may result in DNA damage and alterations in cell signaling pathways that have significant effects on cellular division.

Understanding Exposures in Children’s Environments

EPA Pesticide Factsheets

EPA scientists have conducted a series of studies to provide a better understanding of the chemical sources, pathways and routes of exposure, and other factors that contribute most to children’s exposures to chemicals.

FEASIBILITY OF USING THE MACROACTIVITY APPROACH TO ASSESS CHILDREN'S DERMAL EXPOSURE TO PESTICIDES

EPA Science Inventory

Results derived from an initial assessment of critical exposure pathways for children indicate that dermal contact may result in high residential exposures to pesticides. However, data on children's exposures and activities are insufficient to support quantitative assessments ...

AVAILABLE MICRO-ACTIVITY DATA AND THEIR APPLICABILITY TO AGGREGATE EXPOSURE MODELING

EPA Science Inventory

Several human exposure models have been developed in recent years to address children's aggregate and cumulative exposures to pesticides under the Food Quality Protection Act of 1996. These models estimate children's exposures via all significant routes and pathways including ...

The Major DNA Repair Pathway after Both Proton and Carbon-Ion Radiation is NHEJ, but the HR Pathway is More Relevant in Carbon Ions

PubMed Central

Gerelchuluun, Ariungerel; Manabe, Eri; Ishikawa, Takaaki; Sun, Lue; Itoh, Kazuya; Sakae, Takeji; Suzuki, Kenshi; Hirayama, Ryoichi; Asaithamby, Aroumougame; Chen, David J.; Tsuboi, Koji

2017-01-01

The purpose of this study was to identify the roles of non-homologous end-joining (NHEJ) or homologous recombination (HR) pathways in repairing DNA double-strand breaks (DSBs) induced by exposure to high-energy protons and carbon ions (C ions) versus gamma rays in Chinese hamster cells. Two Chinese hamster cell lines, ovary AA8 and lung fibroblast V79, as well as various mutant sublines lacking DNA-PKcs (V3), X-ray repair cross-complementing protein-4 [XRCC4 (XR1), XRCC3 (irs1SF) and XRCC2 (irs1)] were exposed to gamma rays (137Cs), protons (200 MeV; 2.2 keV/μm) and C ions (290 MeV; 50 keV/μm). V3 and XR1 cells lack the NHEJ pathway, whereas irs1 and irs1SF cells lack the HR pathway. After each exposure, survival was measured using a clonogenic survival assay, in situ DSB induction was evaluated by immunocytochemical analysis of histone H2AX phosphorylation at serine 139 (γ-H2AX foci) and chromosome aberrations were examined using solid staining. The findings from this study showed that clonogenic survival clearly depended on the NHEJ and HR pathway statuses, and that the DNA-PKcs−/− cells (V3) were the most sensitive to all radiation types. While protons and γ rays yielded almost the same biological effects, C-ion exposure greatly enhanced the sensitivity of wild-type and HR-deficient cells. However, no significant enhancement of sensitivity in cell killing was seen after C-ion irradiation of NHEJ deficient cells. Decreases in the number of γ-H2AX foci after irradiation occurred more slowly in the NHEJ deficient cells. In particular, V3 cells had the highest number of residual γ-H2AX foci at 24 h after C-ion irradiation. Chromosomal aberrations were significantly higher in both the NHEJ- and HR-deficient cell lines than in wild-type cell lines in response to all radiation types. Protons and gamma rays induced the same aberration levels in each cell line, whereas C ions introduced higher but not significantly different aberration levels. Our results suggest that the NHEJ pathway plays an important role in repairing DSBs induced by both clinical proton and C-ion beams. Furthermore, in C ions the HR pathway appears to be involved in the repair of DSBs to a greater extent compared to gamma rays and protons. PMID:25738894

Antibiotic Effects on Methicillin-Resistant Staphylococcus aureus Cytoplasmic Peptidoglycan Intermediate Levels and Evidence for Potential Metabolite Level Regulatory Loops.

PubMed

Vemula, Harika; Ayon, Navid J; Burton, Alloch; Gutheil, William G

2017-06-01

Cytoplasmic peptidoglycan (PG) precursor levels were determined in methicillin-resistant Staphylococcus aureus (MRSA) after exposure to several cell wall-targeting antibiotics. Three experiments were performed: (i) exposure to 4× MIC levels (acute); (ii) exposure to sub-MIC levels (subacute); (iii) a time course experiment of the effect of vancomycin. In acute exposure experiments, fosfomycin increased UDP-GlcNAc, as expected, and resulted in substantially lower levels of total UDP-linked metabolite accumulation relative to other pathway inhibitors, indicating reduced entry into this pathway. Upstream inhibitors (fosfomycin, d-cycloserine, or d-boroalanine) reduced UDP-MurNAc-pentapeptide levels by more than fourfold. Alanine branch inhibitors (d-cycloserine and d-boroalanine) reduced d-Ala-d-Ala levels only modestly (up to 4-fold) but increased UDP-MurNAc-tripeptide levels up to 3,000-fold. Downstream pathway inhibitors (vancomycin, bacitracin, moenomycin, and oxacillin) increased UDP-MurNAc-pentapeptide levels up to 350-fold and UDP-MurNAc-l-Ala levels up to 80-fold, suggesting reduced MurD activity by downstream inhibitor action. Sub-MIC exposures demonstrated effects even at 1/8× MIC which strongly paralleled acute exposure changes. Time course data demonstrated that UDP-linked intermediate levels respond rapidly to vancomycin exposure, with several intermediates increasing three- to sixfold within minutes. UDP-linked intermediate level changes were also multiphasic, with some increasing, some decreasing, and some increasing and then decreasing. The total (summed) UDP-linked intermediate pool increased by 1,475 μM/min during the first 10 min after vancomycin exposure, providing a revised estimate of flux in this pathway during logarithmic growth. These observations outline the complexity of PG precursor response to antibiotic exposure in MRSA and indicate likely sites of regulation (entry and MurD). Copyright © 2017 American Society for Microbiology.

Public health assessment for Garden State Cleaners, Cerclis No. NJD053280160 and South Jersey Clothing Company, Minotola, Atlantic County, New Jersey, Region 2. Cerclis No. NJD980766828. addendum. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1995-04-21

The Garden State Cleaners (GSC) and South Jersey Clothing Company (SJCC) sites are located in Buena Borough, Atlantic County, New Jersey. Completed human exposure pathway existed in the past at the site and were associated with groundwater, and ambient air (SJCC). Potential exposure pathways are associated with groundwater and on site soils (SJCC). Based upon the likelihood of past exposure, ATSDR and NJDOH consider this site to have posed a public health hazard.

Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework.

PubMed

Ruiter, Sander; Sippel, Josefine; Bouwmeester, Manon C; Lommelaars, Tobias; Beekhof, Piet; Hodemaekers, Hennie M; Bakker, Frank; van den Brandhof, Evert-Jan; Pennings, Jeroen L A; van der Ven, Leo T M

2016-11-02

Non-communicable diseases (NCDs) are a major cause of premature mortality. Recent studies show that predispositions for NCDs may arise from early-life exposure to low concentrations of environmental contaminants. This developmental origins of health and disease (DOHaD) paradigm suggests that programming of an embryo can be disrupted, changing the homeostatic set point of biological functions. Epigenetic alterations are a possible underlying mechanism. Here, we investigated the DOHaD paradigm by exposing zebrafish to subtoxic concentrations of the ubiquitous contaminant cadmium during embryogenesis, followed by growth under normal conditions. Prolonged behavioral responses to physical stress and altered antioxidative physiology were observed approximately ten weeks after termination of embryonal exposure, at concentrations that were 50-3200-fold below the direct embryotoxic concentration, and interpreted as altered developmental programming. Literature was explored for possible mechanistic pathways that link embryonic subtoxic cadmium to the observed apical phenotypes, more specifically, the probability of molecular mechanisms induced by cadmium exposure leading to altered DNA methylation and subsequently to the observed apical phenotypes. This was done using the adverse outcome pathway model framework, and assessing key event relationship plausibility by tailored Bradford-Hill analysis. Thus, cadmium interaction with thiols appeared to be the major contributor to late-life effects. Cadmium-thiol interactions may lead to depletion of the methyl donor S -adenosyl-methionine, resulting in methylome alterations, and may, additionally, result in oxidative stress, which may lead to DNA oxidation, and subsequently altered DNA methyltransferase activity. In this way, DNA methylation may be affected at a critical developmental stage, causing the observed apical phenotypes.

An Alkylphenol Mix Promotes Seminoma Derived Cell Proliferation through an ERalpha36-Mediated Mechanism

PubMed Central

Ajj, Hussein; Chesnel, Amand; Pinel, Sophie; Plenat, François; Flament, Stephane; Dumond, Helene

2013-01-01

Long chain alkylphenols are man-made compounds still present in industrial and agricultural processes. Their main use is domestic and they are widespread in household products, cleansers and cosmetics, leading to a global environmental and human contamination. These molecules are known to exert estrogen-like activities through binding to classical estrogen receptors. In vitro, they can also interact with the G-protein coupled estrogen receptor. Testicular germ cell tumor etiology and progression are proposed to be stimulated by lifelong estrogeno-mimetic exposure. We studied the transduction signaling pathways through which an alkyphenol mixture triggers testicular cancer cell proliferation in vitro and in vivo. Proliferation assays were monitored after exposure to a realistic mixture of 4-tert-octylphenol and 4-nonylphenol of either TCam-2 seminoma derived cells, NT2/D1 embryonal carcinoma cells or testis tumor in xenografted nude mice. Specific pharmacological inhibitors and gene-silencing strategies were used in TCam-2 cells in order to demonstrate that the alkylphenol mix triggers CREB-phosphorylation through a rapid, ERα36-PI3kinase non genomic pathway. Microarray analysis of the mixture target genes revealed that this pathway can modulate the expression of the DNA-methyltransferase-3 (Dnmt3) gene family which is involved in DNA methylation control. Our results highlight a key role for ERα36 in alkylphenol non genomic signaling in testicular germ cell tumors. Hence, ERα36-dependent control of the epigenetic status opens the way for the understanding of the link between endocrine disruptor exposure and the burden of hormone sensitive cancers. PMID:23626723

Validation of a novel air toxic risk model with air monitoring.

PubMed

Pratt, Gregory C; Dymond, Mary; Ellickson, Kristie; Thé, Jesse

2012-01-01

Three modeling systems were used to estimate human health risks from air pollution: two versions of MNRiskS (for Minnesota Risk Screening), and the USEPA National Air Toxics Assessment (NATA). MNRiskS is a unique cumulative risk modeling system used to assess risks from multiple air toxics, sources, and pathways on a local to a state-wide scale. In addition, ambient outdoor air monitoring data were available for estimation of risks and comparison with the modeled estimates of air concentrations. Highest air concentrations and estimated risks were generally found in the Minneapolis-St. Paul metropolitan area and lowest risks in undeveloped rural areas. Emissions from mobile and area (nonpoint) sources created greater estimated risks than emissions from point sources. Highest cancer risks were via ingestion pathway exposures to dioxins and related compounds. Diesel particles, acrolein, and formaldehyde created the highest estimated inhalation health impacts. Model-estimated air concentrations were generally highest for NATA and lowest for the AERMOD version of MNRiskS. This validation study showed reasonable agreement between available measurements and model predictions, although results varied among pollutants, and predictions were often lower than measurements. The results increased confidence in identifying pollutants, pathways, geographic areas, sources, and receptors of potential concern, and thus provide a basis for informing pollution reduction strategies and focusing efforts on specific pollutants (diesel particles, acrolein, and formaldehyde), geographic areas (urban centers), and source categories (nonpoint sources). The results heighten concerns about risks from food chain exposures to dioxins and PAHs. Risk estimates were sensitive to variations in methodologies for treating emissions, dispersion, deposition, exposure, and toxicity. © 2011 Society for Risk Analysis.

Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway

PubMed Central

Lim, Sanghee; Kwak, Minhye; Gray, Christy D.; Xu, Michael; Choi, Jun H.; Junn, Sue; Kim, Jieun; Xu, Jing; Schaefer, Michele; Johns, Roger A.; Song, Hongjun; Ming, Guo-Li; Mintz, C. David

2017-01-01

Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition. PMID:28683067

Multipathway Quantitative Assessment of Exposure to Fecal Contamination for Young Children in Low-Income Urban Environments in Accra, Ghana: The SaniPath Analytical Approach

PubMed Central

Wang, Yuke; Moe, Christine L.; Null, Clair; Raj, Suraja J.; Baker, Kelly K.; Robb, Katharine A.; Yakubu, Habib; Ampofo, Joseph A.; Wellington, Nii; Freeman, Matthew C.; Armah, George; Reese, Heather E.; Peprah, Dorothy; Teunis, Peter F. M.

2017-01-01

Abstract. Lack of adequate sanitation results in fecal contamination of the environment and poses a risk of disease transmission via multiple exposure pathways. To better understand how eight different sources contribute to overall exposure to fecal contamination, we quantified exposure through multiple pathways for children under 5 years old in four high-density, low-income, urban neighborhoods in Accra, Ghana. We collected more than 500 hours of structured observation of behaviors of 156 children, 800 household surveys, and 1,855 environmental samples. Data were analyzed using Bayesian models, estimating the environmental and behavioral factors associated with exposure to fecal contamination. These estimates were applied in exposure models simulating sequences of behaviors and transfers of fecal indicators. This approach allows us to identify the contribution of any sources of fecal contamination in the environment to child exposure and use dynamic fecal microbe transfer networks to track fecal indicators from the environment to oral ingestion. The contributions of different sources to exposure were categorized into four types (high/low by dose and frequency), as a basis for ranking pathways by the potential to reduce exposure. Although we observed variation in estimated exposure (108–1016 CFU/day for Escherichia coli) between different age groups and neighborhoods, the greatest contribution was consistently from food (contributing > 99.9% to total exposure). Hands played a pivotal role in fecal microbe transfer, linking environmental sources to oral ingestion. The fecal microbe transfer network constructed here provides a systematic approach to study the complex interaction between contaminated environment and human behavior on exposure to fecal contamination. PMID:29031283

Pathway-based approaches for assessment of real-time exposure to an estrogenic wastewater treatment plant effluent on fathead minnow reproduction

USGS Publications Warehouse

Cavallin, Jenna E.; Jensen, Kathleen M.; Kahl, Michael D.; Villeneuve, Daniel L.; Lee, Kathy E.; Schroeder, Anthony L.; Mayasich, Joe; Eid, Evan P.; Nelson, Krysta R.; Milsk, Rebecca Y.; Blackwell, Brett R.; Berninger, Jason P.; LaLone, Carlie A.; Blanskma, Chad; Jicha, Terri M.; Elonen, Colleen M.; Johnson, Rodney C.; Ankley, Gerald T.

2016-01-01

Wastewater treatment plant (WWTP) effluents are known contributors of chemical mixtures into the environment. Of particular concern are endocrine-disrupting compounds, such as estrogens, which can affect the hypothalamic-pituitary-gonadal axis function in exposed organisms. The present study examined reproductive effects in fathead minnows exposed for 21 d to a historically estrogenic WWTP effluent. Fathead minnow breeding pairs were held in control water or 1 of 3 effluent concentrations (5%, 20%, and 100%) in a novel onsite, flow-through system providing real-time exposure. The authors examined molecular and biochemical endpoints representing key events along adverse outcome pathways linking estrogen receptor activation and other molecular initiating events to reproductive impairment. In addition, the authors used chemical analysis of the effluent to construct a chemical-gene interaction network to aid in targeted gene expression analyses and identifying potentially impacted biological pathways. Cumulative fecundity was significantly reduced in fish exposed to 100% effluent but increased in those exposed to 20% effluent, the approximate dilution factor in the receiving waters. Plasma vitellogenin concentrations in males increased in a dose-dependent manner with effluent concentration; however, male fertility was not impacted. Although in vitro analyses, analytical chemistry, and biomarker responses confirmed the effluent was estrogenic, estrogen receptor agonists were unlikely the primary driver of impaired reproduction. The results provide insights into the significance of pathway-based effects with regard to predicting adverse reproductive outcomes.

Toxic metabolites, MAPK and Nrf2/Keap1 signaling pathways involved in oxidative toxicity in mice liver after chronic exposure to Mequindox.

PubMed

Liu, Qianying; Lei, Zhixin; Huang, Anxiong; Wu, Qinghua; Xie, Shuyu; Awais, Ihsan; Dai, Menghong; Wang, Xu; Yuan, Zonghui

2017-02-03

Mequindox (MEQ) is a synthetic antimicrobial agent of quinoxaline-1,4-dioxide group (QdNOs). The liver is regarded as the toxicity target of QdNOs, and the role of N → O group-associated various toxicities mediated by QdNOs is well recognized. However, the mechanism underlying the in vivo effects of MEQ on the liver, and whether the metabolic pathway of MEQ is altered in response to the pathophysiological conditions still remain unclear. We now provide evidence that MEQ triggers oxidative damage in the liver. Moreover, using LC/MS-ITTOF analysis, two metabolites of MEQ were detected in the liver, which directly confirms the potential connection between N → O group reduction metabolism of MEQ and liver toxicity. The gender difference in MEQ-induced oxidative stress might be due to adrenal toxicity and the generation of M4 (2-isoethanol 1-desoxymequindox). Furthermore, up-regulation of the MAPK and Nrf2-Keap1 family and phase II detoxifying enzymes (HO-1, GCLC and NQO1) were also observed. The present study demonstrated for the first time the protein peroxidation and a proposal metabolic pathway after chronic exposure of MEQ, and illustrated that the MAPK, Nrf2-Keap1 and NF-кB signaling pathways, as well as the altered metabolism of MEQ, were involved in oxidative toxicity mediated by MEQ in vivo.

Toxic metabolites, MAPK and Nrf2/Keap1 signaling pathways involved in oxidative toxicity in mice liver after chronic exposure to Mequindox

PubMed Central

Liu, Qianying; Lei, Zhixin; Huang, Anxiong; Wu, Qinghua; Xie, Shuyu; Awais, Ihsan; Dai, Menghong; Wang, Xu; Yuan, Zonghui

2017-01-01

Mequindox (MEQ) is a synthetic antimicrobial agent of quinoxaline-1,4-dioxide group (QdNOs). The liver is regarded as the toxicity target of QdNOs, and the role of N → O group-associated various toxicities mediated by QdNOs is well recognized. However, the mechanism underlying the in vivo effects of MEQ on the liver, and whether the metabolic pathway of MEQ is altered in response to the pathophysiological conditions still remain unclear. We now provide evidence that MEQ triggers oxidative damage in the liver. Moreover, using LC/MS-ITTOF analysis, two metabolites of MEQ were detected in the liver, which directly confirms the potential connection between N → O group reduction metabolism of MEQ and liver toxicity. The gender difference in MEQ-induced oxidative stress might be due to adrenal toxicity and the generation of M4 (2-isoethanol 1-desoxymequindox). Furthermore, up-regulation of the MAPK and Nrf2-Keap1 family and phase II detoxifying enzymes (HO-1, GCLC and NQO1) were also observed. The present study demonstrated for the first time the protein peroxidation and a proposal metabolic pathway after chronic exposure of MEQ, and illustrated that the MAPK, Nrf2-Keap1 and NF-кB signaling pathways, as well as the altered metabolism of MEQ, were involved in oxidative toxicity mediated by MEQ in vivo. PMID:28157180

Arctigenin induces apoptosis in colon cancer cells through ROS/p38MAPK pathway.

PubMed

Li, Qing-chun; Liang, Yun; Tian, Yuan; Hu, Guang-rui

2016-01-01

In the current study the antiproliferative effect of arctigenin, plant lignin, was evaluated on human colon cancer cell line HT-29. Furthermore, attempts were made to explore the signaling mechanism which may be responsible for its effect. Cell growth inhibition was assessed by MTT and LDH assays. Flow cytometric analysis was performed to determine cell arrest in the cell cycle phase and apoptosis. Furthermore, to confirm the apoptotic activity of arctigenin, caspase-9 and -3 activities analysis was performed. The levels of reactive oxygen species (ROS) and p38 mitogen activated protein kinase (MAPK) were investigated to determine their role in inducing apoptosis in arctigenin-treated HT-29 colon cancer cell line. MTT and LDH results demonstrated significant cell growth inhibitory effect of arctigenin on HT-29 cells in a dose-dependent manner. Furthermore, increase in cell number arrested at G2/M phase was observed in flow cytometric analysis upon arctigenin treatment. In addition, arctigenin increased the apoptotic ratio in a dose-dependent manner. The involvement of intrinsic apoptotic pathway was indicated by the activation of caspase-9 and -3. Moreover, increased ROS production, activation of p38 MAPK and changes in mitochondrial membrane potential (ΔΨm) also revealed the role of intrinsic apoptotic signaling pathway in cell growth inhibition after arctigenin exposure. Arctigenin induces apoptosis in HT-29 colon cancer cells by regulating ROS and p38 MAPK pathways.

New insights into the mechanism of phthalate-induced developmental effects.

PubMed

Mu, Xiyan; Huang, Ying; Li, Jia; Yang, Ke; Yang, Wenbo; Shen, Gongming; Li, Xuxing; Lei, Yunlei; Pang, Sen; Wang, Chengju; Li, Xuefeng; Li, Yingren

2018-06-11

To investigate the biological pathways involved in phthalate-induced developmental effects, zebrafish embryos were exposed to different concentrations of di-(2-ethylhexyl) (DEHP) and di-butyl phthalate (DBP) for 96 h. Embryonic exposure to DEHP and DBP induced body length decrease, yolk sac abnormities, and immune responses (up-regulation of immune proteins and genes). The lipidomic results showed that at a concentration of 50 μg/L, DEHP and DBP significantly reduced the levels of fatty acids, triglycerides, diacylglycerol, and cholesterol. These effects are partly explained by biological pathway enrichment based on data from the transcriptional and proteomic profiles. Co-exposure to DBP and ER antagonist did not significantly relieve the toxic symptoms compared with exposure to DBP alone. This indicates that phthalate-induced developmental abnormities in zebrafish might not be mediated by the ER pathway. In conclusion, we identified the possible biological pathways that mediate phthalate-induced developmental effects and found that these effects may not be driven by estrogenic activation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Altered Expression of Genes in Signaling Pathways Regulating Proliferation of Hematopoietic Stem and Progenitor Cells in Mice with Subchronic Benzene Exposure

PubMed Central

Sun, Rongli; Zhang, Juan; Xiong, Mengzhen; Wei, Haiyan; Tan, Kehong; Yin, Lihong; Pu, Yuepu

2015-01-01

Leukemias and hematopoietic disorders induced by benzene may arise from the toxicity of benzene to hematopoietic stem or progenitor cells (HS/PCs). Since there is a latency period between initial benzene exposure and the development of leukemia, subsequent impact of benzene on HS/PCs are crucial for a deeper understanding of the carcinogenicity and hematotoxicity in post-exposure stage. This study aims to explore the effects of benzene on HS/PCs and gene-expression in Wnt, Notch and Hh signaling pathways in post-exposure stage. The C3H/He mice were injected subcutaneously with benzene (0, 150, 300 mg/kg/day) for three months and were monitored for another 10 months post-exposure. The body weights were monitored, the relative organ weights, blood parameters and bone marrow smears were examined. Frequency of lineage- sca-1+ c-kit+ (LSK) cells, capability of colony forming and expression of genes in Wnt, Notch and Hedghog (Hh) signaling pathways were also analyzed. The colony formation of the progenitor cells for BFU-E, CFU-GEMM and CFU-GM was significantly decreased with increasing benzene exposure relative to controls, while no significant difference was observed in colonies for CFU-G and CFU-M. The mRNA level of cyclin D1 was increased and Notch1 and p53 were decreased in LSK cells in mice exposed to benzene but with no statistical significance. These results suggest that subsequent toxic effects of benzene on LSK cells and gene expression in Wnt, Notch and Hh signaling pathways persist in post-exposure stage and may play roles in benzene-induced hematotoxicity. PMID:26262635

Altered Expression of Genes in Signaling Pathways Regulating Proliferation of Hematopoietic Stem and Progenitor Cells in Mice with Subchronic Benzene Exposure.

PubMed

Sun, Rongli; Zhang, Juan; Xiong, Mengzhen; Wei, Haiyan; Tan, Kehong; Yin, Lihong; Pu, Yuepu

2015-08-07

Leukemias and hematopoietic disorders induced by benzene may arise from the toxicity of benzene to hematopoietic stem or progenitor cells (HS/PCs). Since there is a latency period between initial benzene exposure and the development of leukemia, subsequent impact of benzene on HS/PCs are crucial for a deeper understanding of the carcinogenicity and hematotoxicity in post-exposure stage. This study aims to explore the effects of benzene on HS/PCs and gene-expression in Wnt, Notch and Hh signaling pathways in post-exposure stage. The C3H/He mice were injected subcutaneously with benzene (0, 150, 300 mg/kg/day) for three months and were monitored for another 10 months post-exposure. The body weights were monitored, the relative organ weights, blood parameters and bone marrow smears were examined. Frequency of lineage(-) sca-1(+) c-kit(+) (LSK) cells, capability of colony forming and expression of genes in Wnt, Notch and Hedghog (Hh) signaling pathways were also analyzed. The colony formation of the progenitor cells for BFU-E, CFU-GEMM and CFU-GM was significantly decreased with increasing benzene exposure relative to controls, while no significant difference was observed in colonies for CFU-G and CFU-M. The mRNA level of cyclin D1 was increased and Notch 1 and p53 were decreased in LSK cells in mice exposed to benzene but with no statistical significance. These results suggest that subsequent toxic effects of benzene on LSK cells and gene expression in Wnt, Notch and Hh signaling pathways persist in post-exposure stage and may play roles in benzene-induced hematotoxicity.

Analysis of the Exhumation Pathways Experienced in the Cascades Range

NASA Astrophysics Data System (ADS)

Giles, S. M.; Pesek, M.; Perez, N. D.

2017-12-01

The Cascades volcanic arc is the result of subduction of the Juan de Fuca plate beneath North America. The Cascades trend north to south and create a modern orographic precipitation gradient that focuses precipitation along the western flank of the range. However, the deformation style changes from shortening in the north to extension in the south. This experimental design is an ideal location to test how surface and tectonic processes contribute to rock uplift in orogens. In the Oregon Cascades, zircon U-Pb geochronology, and multiple thermochronologic techniques (apatite U-Pb, zircon U-Th/He) will be applied to an intrusive rock exposed along a west-flowing river to investigate the exhumation pathway. These intrusive rocks are capped by late Miocene basalt flows, constraining the timing of surface exposure. The results of this study will define a time-temperature pathway and be compared with existing exhumation constraints from the Washington Cascades to determine whether the exhumation pathways may correspond to the changing structural regimes or consistent climate patterns along strike.

SOURCES AND PATHWAYS OF LEAD EXPOSURE

EPA Science Inventory

Exposure is defined here as the amount of a substance that comes into contact with an absorbing surface during a specified period of time. The normal units of exposure are expressed as micrograms per day. The two components of exposure are the concentration of the substance in ...

Comparative transcriptomics reveals genes involved in metabolic and immune pathways in the digestive gland of scallop Chlamys farreri following cadmium exposure

NASA Astrophysics Data System (ADS)

Zhang, Hui; Zhai, Yuxiu; Yao, Lin; Jiang, Yanhua; Li, Fengling

2017-05-01

Chlamys farreri is an economically important mollusk that can accumulate excessive amounts of cadmium (Cd). Studying the molecular mechanism of Cd accumulation in bivalves is difficult because of the lack of genome background. Transcriptomic analysis based on high-throughput RNA sequencing has been shown to be an efficient and powerful method for the discovery of relevant genes in non-model and genome reference-free organisms. Here, we constructed two cDNA libraries (control and Cd exposure groups) from the digestive gland of C. farreri and compared the transcriptomic data between them. A total of 227 673 transcripts were assembled into 105 071 unigenes, most of which shared high similarity with sequences in the NCBI non-redundant protein database. For functional classification, 24 493 unigenes were assigned to Gene Ontology terms. Additionally, EuKaryotic Ortholog Groups and Kyoto Encyclopedia of Genes and Genomes analyses assigned 12 028 unigenes to 26 categories and 7 849 unigenes to five pathways, respectively. Comparative transcriptomics analysis identified 3 800 unigenes that were differentially expressed in the Cd-treated group compared with the control group. Among them, genes associated with heavy metal accumulation were screened, including metallothionein, divalent metal transporter, and metal tolerance protein. The functional genes and predicted pathways identified in our study will contribute to a better understanding of the metabolic and immune system in the digestive gland of C. farreri. In addition, the transcriptomic data will provide a comprehensive resource that may contribute to the understanding of molecular mechanisms that respond to marine pollutants in bivalves.

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

PubMed

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. All previously identified high-risk jobs had high air concentrations, dermal mass loading, or both, and none had low dermal and air. We have found that both pathways are relevant. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: a file describing the forms of beryllium materials encountered during production and characteristics of the aerosols by process areas.].

Uptake Kinetics and Trophic Transfer of Tungsten from Cabbage to a Herbivorous Animal Model

DOE PAGES

Lindsay, James H.; Kennedy, Alan J.; Seiter-Moser, Jennifer M.; ...

2017-10-20

This paper builds on previous studies on military-relevant tungsten (W) to more thoroughly explore environmental pathways and bioaccumulation kinetics during direct soil exposure versus trophic transfer and elucidate its relative accumulation and speciation in different snail organs. The modeled steady-state concentration and bioaccumulation factor (BAF) of W from soil into cabbage were 302 mg/kg and 0.55, respectively. Steady-state concentrations (34 mg/kg) and BAF values (0.05) obtained for the snail directly exposed to contaminated soil were lower than trophic transfer by consumption of W-contaminated cabbage (tissue concentration of 86 mg/kg; BAF of 0.36). Thus, consumption of contaminated food is the mostmore » important pathway for W mobility in this food chain. The highest concentrations of W compartmentalization were in the snail’s hepatopancreas based on wet chemistry and synchrotron-based investigations. Chemical speciation via inductively couple plasma mass spectrometry showed a higher degree of polytungstate partitioning in the hepatopancreas relative to the rest of the body. Based on synchrotron analysis, W was incorporated into the shell matrix during exposure, particularly during the regeneration of damaged shell. Finally, this offers the potential for application of the shell as a longer-term biomonitoring and forensics tool for historic exposure.« less

Uptake Kinetics and Trophic Transfer of Tungsten from Cabbage to a Herbivorous Animal Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lindsay, James H.; Kennedy, Alan J.; Seiter-Moser, Jennifer M.

This paper builds on previous studies on military-relevant tungsten (W) to more thoroughly explore environmental pathways and bioaccumulation kinetics during direct soil exposure versus trophic transfer and elucidate its relative accumulation and speciation in different snail organs. The modeled steady-state concentration and bioaccumulation factor (BAF) of W from soil into cabbage were 302 mg/kg and 0.55, respectively. Steady-state concentrations (34 mg/kg) and BAF values (0.05) obtained for the snail directly exposed to contaminated soil were lower than trophic transfer by consumption of W-contaminated cabbage (tissue concentration of 86 mg/kg; BAF of 0.36). Thus, consumption of contaminated food is the mostmore » important pathway for W mobility in this food chain. The highest concentrations of W compartmentalization were in the snail’s hepatopancreas based on wet chemistry and synchrotron-based investigations. Chemical speciation via inductively couple plasma mass spectrometry showed a higher degree of polytungstate partitioning in the hepatopancreas relative to the rest of the body. Based on synchrotron analysis, W was incorporated into the shell matrix during exposure, particularly during the regeneration of damaged shell. Finally, this offers the potential for application of the shell as a longer-term biomonitoring and forensics tool for historic exposure.« less

Comparative toxicity of low dose tributyltin chloride on serum, liver, lung and kidney following subchronic exposure.

PubMed

Mitra, Sumonto; Gera, Ruchi; Singh, Vikas; Khandelwal, Shashi

2014-02-01

Tributyltin (TBT) pollution is rampant worldwide and is a growing threat due to its bio-accumulative property. Isolated studies of TBT toxicity on different organs are available but consolidated information is greatly lacking. We planned this study to delineate the effect of subchronic (1 month) exposure to low dose TBT-chloride (TBTC) (1 and 5 mg/kg) in male Wistar rats. Total tin concentration was found to be significantly increased in liver, kidney and blood, and marginally in lungs. Organo-somatic indices were seen to be altered with little effect on serum biochemical markers (liver and kidney function, and general parameters). Reactive oxygen species but not lipid peroxidation content was observed to be significantly elevated both in the tissues and serum. TBTC was found to act as a hyperlipidemic agent and it also affected heme biosynthetic pathway. Hematological analysis showed that TBTC exposure resulted in minor alterations in RBC parameters. Histological studies demonstrated marked tissue damage in all the 3 organs. Calcium inhibitors (BAPTA-AM, EGTA) and antioxidants (NAC, C-PC) significantly restored TBTC induced loss in cell viability, under ex-vivo conditions. Antioxidants were evidently more efficient in comparison to the calcium inhibitors, implying major role of oxidative stress pathways in TBTC toxicity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Modulation of Cholinergic Pathways and Inflammatory Mediators in Blast-Induced Traumatic Brain Injury

DTIC Science & Technology

2013-01-01

matic brain injury (TBI). Centrally acting acetylcholinesterase (AChE) inhibitors are also being considered as potential therapeutic candidates...repeated blast exposures [12]. AChE inhibitors are possible therapeutic candidates against Alzheimer’s disease and TBI [13–15]. In this study, we...esterase inhibitor , as described earlier [12,17–19]. Brain AChE activity was expressed as milliunits/mg protein. 2.3. Microarray analysis Various

Novel transcriptome assembly and comparative toxicity pathway analysis in mahi-mahi (Coryphaena hippurus) embryos and larvae exposed to Deepwater Horizon oil

NASA Astrophysics Data System (ADS)

Xu, Elvis Genbo; Mager, Edward M.; Grosell, Martin; Hazard, E. Starr; Hardiman, Gary; Schlenk, Daniel

2017-03-01

The impacts of Deepwater Horizon (DWH) oil on morphology and function during embryonic development have been documented for a number of fish species, including the economically and ecologically important pelagic species, mahi-mahi (Coryphaena hippurus). However, further investigations on molecular events and pathways responsible for developmental toxicity have been largely restricted due to the limited molecular data available for this species. We sought to establish the de novo transcriptomic database from the embryos and larvae of mahi-mahi exposed to water accommodated fractions (HEWAFs) of two DWH oil types (weathered and source oil), in an effort to advance our understanding of the molecular aspects involved during specific toxicity responses. By high throughput sequencing (HTS), we obtained the first de novo transcriptome of mahi-mahi, with 60,842 assembled transcripts and 30,518 BLAST hits. Among them, 2,345 genes were significantly regulated in 96hpf larvae after exposure to weathered oil. With comparative analysis to a reference-transcriptome-guided approach on gene ontology and tox-pathways, we confirmed the novel approach effective for exploring tox-pathways in non-model species, and also identified a list of co-expressed genes as potential biomarkers which will provide information for the construction of an Adverse Outcome Pathway which could be useful in Ecological Risk Assessments.

Comparative Proteomic Analysis of Carbonylated Proteins from the Striatum and Cortex of Pesticide-Treated Mice

PubMed Central

Coughlan, Christina; Walker, Douglas I.; Lohr, Kelly M.; Richardson, Jason R.; Saba, Laura M.; Caudle, W. Michael; Fritz, Kristofer S.; Roede, James R.

2015-01-01

Epidemiological studies indicate exposures to the herbicide paraquat (PQ) and fungicide maneb (MB) are associated with increased risk of Parkinson's disease (PD). Oxidative stress appears to be a premier mechanism that underlies damage to the nigrostriatal dopamine system in PD and pesticide exposure. Enhanced oxidative stress leads to lipid peroxidation and production of reactive aldehydes; therefore, we conducted proteomic analyses to identify carbonylated proteins in the striatum and cortex of pesticide-treated mice in order to elucidate possible mechanisms of toxicity. Male C57BL/6J mice were treated biweekly for 6 weeks with saline, PQ (10 mg/kg), MB (30 mg/kg), or the combination of PQ and MB (PQMB). Treatments resulted in significant behavioral alterations in all treated mice and depleted striatal dopamine in PQMB mice. Distinct differences in 4-hydroxynonenal-modified proteins were observed in the striatum and cortex. Proteomic analyses identified carbonylated proteins and peptides from the cortex and striatum, and pathway analyses revealed significant enrichment in a variety of KEGG pathways. Further analysis showed enrichment in proteins of the actin cytoskeleton in treated samples, but not in saline controls. These data indicate that treatment-related effects on cytoskeletal proteins could alter proper synaptic function, thereby resulting in impaired neuronal function and even neurodegeneration. PMID:26345149

Comparative Proteomic Analysis of Human Liver Tissue and Isolated Hepatocytes with a Focus on Proteins Determining Drug Exposure.

PubMed

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.

mTOR Activation by PI3K/Akt and ERK Signaling in Short ELF-EMF Exposed Human Keratinocytes

PubMed Central

Patruno, Antonia; Pesce, Mirko; Grilli, Alfredo; Speranza, Lorenza; Franceschelli, Sara; De Lutiis, Maria Anna; Vianale, Giovina; Costantini, Erica; Amerio, Paolo; Muraro, Raffaella; Felaco, Mario; Reale, Marcella

2015-01-01

Several reports suggest that ELF-EMF exposures interact with biological processes including promotion of cell proliferation. However, the molecular mechanisms by which ELF-EMF controls cell growth are not completely understood. The present study aimed to investigate the effect of ELF-EMF on keratinocytes proliferation and molecular mechanisms involved. Effect of ELF-EMF (50 Hz, 1 mT) on HaCaT cell cycle and cells growth and viability was monitored by FACS analysis and BrdU assay. Gene expression profile by microarray and qRT-PCR validation was performed in HaCaT cells exposed or not to ELF-EMF. mTOR, Akt and MAPKs expressions were evaluated by Western blot analysis. In HaCaT cells, short ELF-EMF exposure modulates distinct patterns of gene expression involved in cell proliferation and in the cell cycle. mTOR activation resulted the main molecular target of ELF-EMF on HaCaT cells. Our data showed the increase of the canonical pathway of mTOR regulation (PI3K/Akt) and activation of ERK signaling pathways. Our results indicate that ELF-EMF selectively modulated the expression of multiple genes related to pivotal biological processes and functions that play a key role in physio-pathological mechanisms such as wound healing. PMID:26431550

Comparative peptidomics analysis of neural adaptations in rats repeatedly exposed to amphetamine.

PubMed

Romanova, Elena V; Lee, Ji Eun; Kelleher, Neil L; Sweedler, Jonathan V; Gulley, Joshua M

2012-10-01

Repeated exposure to amphetamine (AMPH) induces long-lasting behavioral changes, referred to as sensitization, that are accompanied by various neuroadaptations in the brain. To investigate the chemical changes that occur during behavioral sensitization, we applied a comparative proteomics approach to screen for neuropeptide changes in a rodent model of AMPH-induced sensitization. By measuring peptide profiles with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and comparing signal intensities using principal component analysis and variance statistics, subsets of peptides are found with significant differences in the dorsal striatum, nucleus accumbens, and medial prefrontal cortex of AMPH-sensitized male Sprague-Dawley rats. These biomarker peptides, identified in follow-up analyses using liquid chromatography and tandem mass spectrometry, suggest that behavioral sensitization to AMPH is associated with complex chemical adaptations that regulate energy/metabolism, neurotransmission, apoptosis, neuroprotection, and neuritogenesis, as well as cytoskeleton integrity and neuronal morphology. Our data contribute to a growing number of reports showing that in addition to the mesolimbic dopamine system, which is the best known signaling pathway involved with reinforcing the effect of psychostimulants, concomitant chemical changes in other pathways and in neuronal organization may play a part in the overall effect of chronic AMPH exposure on behavior. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA)

EPA Science Inventory

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from multiple stressors. While CSMs may encompass multiple species, evaluating end points across taxa can be challenging due to data availability an...

Statistical grand rounds: understanding the mechanism: mediation analysis in randomized and nonrandomized studies.

PubMed

Mascha, Edward J; Dalton, Jarrod E; Kurz, Andrea; Saager, Leif

2013-10-01

In comparative clinical studies, a common goal is to assess whether an exposure, or intervention, affects the outcome of interest. However, just as important is to understand the mechanism(s) for how the intervention affects outcome. For example, if preoperative anemia was shown to increase the risk of postoperative complications by 15%, it would be important to quantify how much of that effect was due to patients receiving intraoperative transfusions. Mediation analysis attempts to quantify how much, if any, of the effect of an intervention on outcome goes though prespecified mediator, or "mechanism" variable(s), that is, variables sitting on the causal pathway between exposure and outcome. Effects of an exposure on outcome can thus be divided into direct and indirect, or mediated, effects. Mediation is claimed when 2 conditions are true: the exposure affects the mediator and the mediator (adjusting for the exposure) affects the outcome. Understanding how an intervention affects outcome can validate or invalidate one's original hypothesis and also facilitate further research to modify the responsible factors, and thus improve patient outcome. We discuss the proper design and analysis of studies investigating mediation, including the importance of distinguishing mediator variables from confounding variables, the challenge of identifying potential mediators when the exposure is chronic versus acute, and the requirements for claiming mediation. Simple designs are considered, as well as those containing multiple mediators, multiple outcomes, and mixed data types. Methods are illustrated with data collected by the National Surgical Quality Improvement Project (NSQIP) and utilized in a companion paper which assessed the effects of preoperative anemic status on postoperative outcomes.

Cancer Risk Assessment of Polycyclic Aromatic Hydrocarbons in the Soils and Sediments of India: A Meta-Analysis.

PubMed

Tarafdar, Abhrajyoti; Sinha, Alok

2017-10-01

A carcinogenic risk assessment of polycyclic aromatic hydrocarbons in soils and sediments was conducted using the probabilistic approach from a national perspective. Published monitoring data of polycyclic aromatic hydrocarbons present in soils and sediments at different study points across India were collected and converted to their corresponding BaP equivalent concentrations. These BaP equivalent concentrations were used to evaluate comprehensive cancer risk for two different age groups. Monte Carlo simulation and sensitivity analysis were applied to quantify uncertainties of risk estimation. The analysis denotes 90% cancer risk value of 1.770E-5 for children and 3.156E-5 for adults at heavily polluted site soils. Overall carcinogenic risks of polycyclic aromatic hydrocarbons in soils of India were mostly in acceptance limits. However, the food ingestion exposure route for sediments leads them to a highly risked zone. The 90% risk values from sediments are 7.863E-05 for children and 3.999E-04 for adults. Sensitivity analysis reveals exposure duration and relative skin adherence factor for soil as the most influential parameter of the assessment, followed by BaP equivalent concentration of polycyclic aromatic hydrocarbons. For sediments, biota to sediment accumulation factor of fish in terms of BaP is most sensitive on the total outcome, followed by BaP equivalent and exposure duration. Individual exposure route analysis showed dermal contact for soils and food ingestion for sediments as the main exposure pathway. Some specific locations such as surrounding areas of Bhavnagar, Raniganj, Sunderban, Raipur, and Delhi demand potential strategies of carcinogenic risk management and reduction. The current study is probably the first attempt to provide information on the carcinogenic risk of polycyclic aromatic hydrocarbons in soil and sediments across India.

Cancer Risk Assessment of Polycyclic Aromatic Hydrocarbons in the Soils and Sediments of India: A Meta-Analysis

NASA Astrophysics Data System (ADS)

Tarafdar, Abhrajyoti; Sinha, Alok

2017-10-01

A carcinogenic risk assessment of polycyclic aromatic hydrocarbons in soils and sediments was conducted using the probabilistic approach from a national perspective. Published monitoring data of polycyclic aromatic hydrocarbons present in soils and sediments at different study points across India were collected and converted to their corresponding BaP equivalent concentrations. These BaP equivalent concentrations were used to evaluate comprehensive cancer risk for two different age groups. Monte Carlo simulation and sensitivity analysis were applied to quantify uncertainties of risk estimation. The analysis denotes 90% cancer risk value of 1.770E-5 for children and 3.156E-5 for adults at heavily polluted site soils. Overall carcinogenic risks of polycyclic aromatic hydrocarbons in soils of India were mostly in acceptance limits. However, the food ingestion exposure route for sediments leads them to a highly risked zone. The 90% risk values from sediments are 7.863E-05 for children and 3.999E-04 for adults. Sensitivity analysis reveals exposure duration and relative skin adherence factor for soil as the most influential parameter of the assessment, followed by BaP equivalent concentration of polycyclic aromatic hydrocarbons. For sediments, biota to sediment accumulation factor of fish in terms of BaP is most sensitive on the total outcome, followed by BaP equivalent and exposure duration. Individual exposure route analysis showed dermal contact for soils and food ingestion for sediments as the main exposure pathway. Some specific locations such as surrounding areas of Bhavnagar, Raniganj, Sunderban, Raipur, and Delhi demand potential strategies of carcinogenic risk management and reduction. The current study is probably the first attempt to provide information on the carcinogenic risk of polycyclic aromatic hydrocarbons in soil and sediments across India.

Dibutyl phthalate exposure aggravates type 2 diabetes by disrupting the insulin-mediated PI3K/AKT signaling pathway.

PubMed

Deng, Ting; Zhang, Yu; Wu, Yang; Ma, Ping; Duan, Jiufei; Qin, Wei; Yang, Xu; Chen, Mingqing

2018-06-15

Epidemiological studies suggest a positive relationship between phthalate exposure and diabetes. However, little is known about the impact of dibutyl phthalate (DBP) exposure on the development of diabetes. To determine the role of DBP exposure on the development of type 2 diabetes, mice were orally exposed to DBP dosages of 0.5, 5, 50 mg/kg/day for 7 weeks, combined with a high fat diet and injections of a low dose of streptozotocin (STZ). The results showed that exposure to 50 mg/kg/day DBP alone induced a marked decrease in insulin secretion and glucose intolerance, but had no influence on insulin resistance. However, combined with a high fat diet and STZ treatment, DBP exposure markedly aggravated glucose intolerance, insulin tolerance and insulin resistance and induced lesions in the pancreas and kidney. Investigation of the role of DBP on the insulin signaling pathway, we found that DBP exposure could disrupt the PI3K expression and AKT phosphorylation, and decrease the level of GLUT-2 in the pancreas. Administering demethylasterriquinone B1, significantly increased the level of PI3K, AKT phosphorylation and GLUT-2 expression, effectively inhibiting the aggravation of diabetes. Our results suggested that DBP aggravated type 2 diabetes by disrupting the insulin signaling pathway and impairing insulin secretion. Copyright © 2018 Elsevier B.V. All rights reserved.

Human health risk assessment of triclosan in land-applied biosolids.

PubMed

Verslycke, Tim; Mayfield, David B; Tabony, Jade A; Capdevielle, Marie; Slezak, Brian

2016-09-01

Triclosan (5-chloro-2-[2,4-dichlorophenoxy]-phenol) is an antimicrobial agent found in a variety of pharmaceutical and personal care products. Numerous studies have examined the occurrence and environmental fate of triclosan in wastewater, biosolids, biosolids-amended soils, and plants and organisms exposed to biosolid-amended soils. Triclosan has a propensity to adhere to organic carbon in biosolids and biosolid-amended soils. Land application of biosolids containing triclosan has the potential to contribute to multiple direct and indirect human health exposure pathways. To estimate exposures and human health risks from biosolid-borne triclosan, a risk assessment was conducted in general accordance with the methodology incorporated into the US Environmental Protection Agency's Part 503 biosolids rule. Human health exposures to biosolid-borne triclosan were estimated on the basis of published empirical data or modeled using upper-end environmental partitioning estimates. Similarly, a range of published triclosan human health toxicity values was evaluated. Margins of safety were estimated for 10 direct and indirect exposure pathways, both individually and combined. The present risk assessment found large margins of safety (>1000 to >100 000) for potential exposures to all pathways, even under the most conservative exposure and toxicity assumptions considered. The human health exposures and risks from biosolid-borne triclosan are concluded to be de minimis. Environ Toxicol Chem 2016;35:2358-2367. © 2016 SETAC. © 2016 SETAC.

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

PubMed

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

2017-04-17

Lead exposure remains a global public health issue, and the recent Flint water crisis has renewed public concern about lead toxicity. The toxicity of lead has been well established in a variety of systems and organs. The gut microbiome has been shown to be highly involved in many critical physiological processes, including food digestion, immune system development, and metabolic homeostasis. However, despite the key role of the gut microbiome in human health, the functional impact of lead exposure on the gut microbiome has not been studied. The aim of this study is to define gut microbiome toxicity induced by lead exposure in C57BL/6 mice using multiomics approaches, including 16S rRNA sequencing, whole genome metagenomics sequencing, and gas chromatography-mass spectrometry (GC-MS) metabolomics. 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, bile acids, nitrogen metabolism, energy metabolism, oxidative stress, and the defense/detoxification mechanism, were significantly disturbed by lead exposure. These perturbed molecules and pathways may have important implications for lead toxicity in the host. Taken together, these results demonstrated that lead exposure not only altered the gut microbiome community structures/diversity but also greatly affected metabolic functions, leading to gut microbiome toxicity.

Refining the aggregate exposure pathway

EPA Science Inventory

Advancements in measurement technologies and modeling capabilities continue to result in an abundance of exposure information, adding to that currently in existence. However, fragmentation within the exposure science community acts as an obstacle for realizing the vision set fort...

Ursolic acid mediates photosensitization by initiating mitochondrial-dependent apoptosis

NASA Astrophysics Data System (ADS)

Lee, Yuan-Hao; Wang, Exing; Kumar, Neeru; Glickman, Randolph D.

2013-02-01

The signaling pathways PI3K/Akt and MAPK play key roles in transcription, translation and carcinogenesis, and may be activated by light exposure. These pathways may be modulated or inhibited by naturally-occurring compounds, such as the triterpenoid, ursolic acid (UA). Previously, the transcription factors p53 and NF-kB, which transactivate mitochondrial apoptosis-related genes, were shown to be differentially modulated by UA. Our current work indicates that UA causes these effects via the mTOR and insulin-mediated pathways. UA-modulated apoptosis, following exposure to UV radiation, is observed to correspond to differential levels of oxidative stress in retinal pigment epithelial (RPE) and skin melanoma (SM) cells. Flow cytometry analysis, DHE (dihydroethidium) staining and membrane permeability assay showed that UA pretreatment potentiated cell cycle arrest and radiation-induced apoptosis selectively on SM cells while DNA photo-oxidative damage (i.e. strand breakage) was reduced, presumably by some antioxidant activity of UA in RPE cells. The UA-mediated NF-κB activation in SM cells was reduced by rapamycin pretreatment, which indicates that these agents exert inter-antagonistic effects in the PI3K/Akt/mTOR pathway. In contrast, the antagonistic effect of UA on the PI3K/Akt pathway was reversed by insulin leading to greater NF-κB and p53 activation in RPE cells. MitoTracker, a mitochondrial functional assay, indicated that mitochondria in RPE cells experienced reduced oxidative stress while those in SM cells exhibited increased oxidative stress upon UA pretreatment. When rapamycin administration was followed by UA, mitochondrial oxidative stress was increased in RPE cells but decreased in SM cells. These results indicate that UA modulates p53 and NF-κB, initiating a mitogenic response to radiation that triggers mitochondria-dependent apoptosis.

Exposure of children with developmental delay to social determinants of poor health: cross-sectional case record review study.

PubMed

Emerson, E; Brigham, P

2015-03-01

Research on child development in general has highlighted the importance that the family environment plays in mediating the pathway between exposure to low socio-economic position (SEP) and child well-being. While child developmental models in intellectual disability have highlighted the interplay between social context, family environment and child development, little empirical work has attempted to formally evaluate the evidence in support of specific mediating pathways between low SEP and child outcomes. Secondary analysis of cross-sectional confidentialized needs analysis data collected in three Primary Care Trusts in England covering a total population of 1.25 million people. Case record reviews were undertaken for 46 023 households, 2236 (4.9%) of which contained a child in the target age range with developmental delay. Children with developmental delay, when compared with their non-disabled peers, were at significantly increased risk of poorer health outcomes and of being exposed to a wide range of social determinants of poor health. Controlling for between-group differences in exposure to social determinants of poor health reduced the risk of developmental delay being associated with poorer health outcomes by 45% for behaviour problems and 89% for risk of significant harm. For children with developmental delay, parenting difficulties appears to play a particularly significant role in partially mediating the effects of low SEP. The findings of the present study point to the potential effectiveness of family-focused early intervention to prevent the emergence and escalation of behavioural difficulties and health problems in children with developmental delay. © 2014 John Wiley & Sons Ltd.

Pathways to Well-Being in Later Life: Socioeconomic and Health Determinants Across the Life Course of Australian Baby Boomers.

PubMed

Kendig, Hal; Loh, Vanessa; O'Loughlin, Kate; Byles, Julie; Nazroo, James Y

2016-01-01

In many countries like Australia and the United States, baby boomers are referred to as the 'lucky cohort', yet there has been little research on the origins and extent of inequalities within this cohort. This study uses path analysis to investigate direct and indirect effects of childhood and adult socioeconomic status and health on two subjective well-being measures: quality of life and life satisfaction. Retrospective life course data were obtained for 1,261 people aged 60 to 64 in the 2011-12 Life Histories and Health survey, a sub-study of the Australian 45 and Up Study. Supporting an accumulation model, the number of negative childhood and adult exposures were inversely related to both types of well-being. Consistent with a critical period model, childhood exposures had small but significant effects on subjective well-being and were relatively more important for quality of life than for life satisfaction. However, these childhood effects were largely indirect and significantly mediated by more proximal adult exposures, providing support for a pathway model. A key implication of this research is that the critical period for later life well-being is significant in adulthood rather than childhood, suggesting that there may be key opportunities for improving individuals' later life well-being far beyond the early, formative years. This research highlights the importance of understanding how earlier life exposures impact experiences in later life, and investing in health and socioeconomic opportunities to reduce inequalities across all stages of life.

Comprehensive gene and microRNA expression profiling on cardiovascular system in zebrafish co-exposured of SiNPs and MeHg.

PubMed

Hu, Hejing; Shi, Yanfeng; Zhang, Yannan; Wu, Jing; Asweto, Collins Otieno; Feng, Lin; Yang, Xiaozhe; Duan, Junchao; Sun, Zhiwei

2017-12-31

Air pollution has been shown to increase cardiovascular diseases. However, little attention has been paid to the combined effects of PM and air pollutants on the cardiovascular system. To explore this, a high-throughput sequencing technology was used to determine combined effects of silica nanoparticles (SiNPs) and MeHg in zebrafish. Our study demonstrated that SiNPs and MeHg co-exposure could cause significant changes in mRNA and miRNA expression patterns in zebrafish. The differentially expressed (DE) genes in profiles 17 and 26 of STC analysis suggest that SiNPs and MeHg co-exposure had more proinflammatory and cardiovascular toxicity in zebrafish than single exposure. Major gene functions associated with cardiovascular system in the co-exposed zebrafish were discerned from the dynamic-gene-network, including stxbp1a, celf4, ahr1b and bai2. In addition, the prominently expressed pathway of cardiac muscle contraction was targeted by 3 DE miRNAs identified by the miRNA-pathway-network (dre-miR-7147, dre-miR-26a and dre-miR-375), which included 23 DE genes. This study presents a global view of the combined SiNPs and MeHg toxicity on the dynamic expression of both mRNAs and miRNAs in zebrafish, and could serve as fundamental research clues for future studies, especially on cardiovascular system toxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Carbon nanopowder acts as a Trojan-horse for benzo(α)pyrene in Danio rerio embryos.

PubMed

Binelli, A; Del Giacco, L; Santo, N; Bini, L; Magni, S; Parolini, M; Madaschi, L; Ghilardi, A; Maggioni, D; Ascagni, M; Armini, A; Prosperi, L; Landi, C; La Porta, C; Della Torre, C

2017-04-01

Carbon-based nanoparticles (CBNs) are largely distributed worldwide due to fossil fuel combustion and their presence in many consumer products. In addition to their proven toxicological effects in several biological models, attention in recent years has focussed on the role played by CBNs as Trojan-horse carriers for adsorbed environmental pollutants. This role has not been conclusively determined to date because CBNs can decrease the bioavailability of contaminants or represent an additional source of intake. Herein, we evaluated the intake, transport and distribution of one of the carbon-based powders, the so-called carbon nanopowder (CNPW), and benzo(α)pyrene, when administered alone and in co-exposure to Danio rerio embryos. Data obtained by means of advanced microscopic techniques illustrated that the "particle-specific" effect induced a modification in the accumulation of benzo(α)pyrene, which is forced to follow the distribution of the physical pollutant instead of its natural bioaccumulation. The combined results from functional proteomics and gene transcription analysis highlighted the different biochemical pathways involved in the action of the two different contaminants administered alone and when bound together. In particular, we observed a clear change in several proteins involved in the homeostatic response to hypoxia only after exposure to the CNPW or co-exposure to the mixture, whereas exposure to benzo(α)pyrene alone mainly modified structural proteins. The entire dataset suggested a Trojan-horse mechanism involved in the biological impacts on Danio rerio embryos especially due to different bioaccumulation pathways and cellular targets.

Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes.

PubMed

Daskalakis, Nikolaos P; Cohen, Hagit; Cai, Guiqing; Buxbaum, Joseph D; Yehuda, Rachel

2014-09-16

Delineating the molecular basis of individual differences in the stress response is critical to understanding the pathophysiology and treatment of posttraumatic stress disorder (PTSD). In this study, 7 d after predator-scent-stress (PSS) exposure, male and female rats were classified into vulnerable (i.e., "PTSD-like") and resilient (i.e., minimally affected) phenotypes on the basis of their performance on a variety of behavioral measures. Genome-wide expression profiling in blood and two limbic brain regions (amygdala and hippocampus), followed by quantitative PCR validation, was performed in these two groups of animals, as well as in an unexposed control group. Differentially expressed genes were identified in blood and brain associated with PSS-exposure and with distinct behavioral profiles postexposure. There was a small but significant between-tissue overlap (4-21%) for the genes associated with exposure-related individual differences, indicating convergent gene expression in both sexes. To uncover convergent signaling pathways across tissue and sex, upstream activated/deactivated transcription factors were first predicted for each tissue and then the respective pathways were identified. Glucocorticoid receptor (GR) signaling was the only convergent pathway associated with individual differences when using the most stringent statistical threshold. Corticosterone treatment 1 h after PSS-exposure prevented anxiety and hyperarousal 7 d later in both sexes, confirming the GR involvement in the PSS behavioral response. In conclusion, genes and pathways associated with extreme differences in the traumatic stress behavioral response can be distinguished from those associated with trauma exposure. Blood-based biomarkers can predict aspects of brain signaling. GR signaling is a convergent signaling pathway, associated with trauma-related individual differences in both sexes.

A tiered approach for integrating exposure and dosimetry with ...

EPA Pesticide Factsheets

High-throughput (HT) risk screening approaches apply in vitro dose-response data to estimate potential health risks that arise from exposure to chemicals. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the perturbations of biological mechanisms that lead to apical adverse health outcomes in living organisms. The chemical-agnostic Adverse Outcome Pathway (AOP) framework addresses this uncertainty by acting as a scaffold onto which pathway-based data can be arranged to aid in the understanding of in vitro toxicity testing results. In addition, risk estimation also requires reconciling chemical concentrations sufficient to produce bioactivity in vitro with concentrations that trigger a molecular initiating event (MIE) at the relevant biological target in vivo. Such target site exposures (TSEs) can be estimated using computational models to integrate exposure information with a chemical’s absorption, distribution, metabolism, and elimination (ADME) processes. In this presentation, the utility of a tiered approach for integrating exposure, ADME, and hazard into risk-based decision making will be demonstrated using several case studies, along with the investigation of how uncertainties in exposure and ADME might impact risk estimates. These case studies involve 1) identifying and prioritizing chemicals capable of altering biological pathways based on their potential to reach an in vivo target; 2) evaluating the infl

Human Exposure Pathways of Heavy Metals in a Lead-Zinc Mining Area, Jiangsu Province, China

PubMed Central

Qu, Chang-Sheng; Ma, Zong-Wei; Yang, Jin; Liu, Yang; Bi, Jun; Huang, Lei

2012-01-01

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. PMID:23152752

The Cek1‑mediated MAP kinase pathway regulates exposure of α‑1,2 and β‑1,2‑mannosides in the cell wall of Candida albicans modulating immune recognition.

PubMed

Román, E; Correia, I; Salazin, A; Fradin, C; Jouault, T; Poulain, D; Liu, F-T; Pla, J

2016-07-03

The Cek1 MAP kinase (MAPK) mediates vegetative growth and cell wall biogenesis in the fungal pathogen Candida albicans. Alterations in the fungal cell wall caused by a defective Cek1‑mediated signaling pathway leads to increased β‑1,3‑glucan exposure influencing dectin‑1 fungal recognition by immune cells. We show here that cek1 cells also display an increased exposure of α‑1,2 and β‑1,2‑mannosides (α‑M and β‑M), a phenotype shared by strains defective in the activating MAPKK Hst7, suggesting a general defect in cell wall assembly. cek1 cells display walls with loosely bound material as revealed by transmission electron microscopy and are sensitive to tunicamycin, an inhibitor of N‑glycosylation. Transcriptomal analysis of tunicamycin treated cells revealed a differential pattern between cek1 and wild type cells which involved mainly cell wall and stress related genes. Mapping α‑M and β‑M epitopes in the mannoproteins of different cell wall fractions (CWMP) revealed an important shift in the molecular weight of the mannan derived from mutants defective in this MAPK pathway. We have also assessed the role of galectin‑3, a member of a β‑galactoside‑binding protein family shown to bind to and kill C. albicans through β‑M recognition, in the infection caused by cek1 mutants. Increased binding of cek1 to murine macrophages was shown to be partially blocked by lactose. Galectin-3(-/-) mice showed increased resistance to fungal infection, although galectin-3 did not account for the reduced virulence of cek1 mutants in a mouse model of systemic infection. All these data support a role for the Cek1‑mediated pathway in fungal cell wall maintenance, virulence and antifungal discovery.

A novel approach to analyzing lung cancer mortality disparities: Using the exposome and a graph-theoretical toolchain

PubMed Central

Juarez, Paul D; Hood, Darryl B; Rogers, Gary L; Baktash, Suzanne H; Saxton, Arnold M; Matthews-Juarez, Patricia; Im, Wansoo; Cifuentes, Myriam Patricia; Phillips, Charles A; Lichtveld, Maureen Y; Langston, Michael A

2017-01-01

Objectives The aim is to identify exposures associated with lung cancer mortality and mortality disparities by race and gender using an exposome database coupled to a graph theoretical toolchain. Methods Graph theoretical algorithms were employed to extract paracliques from correlation graphs using associations between 2162 environmental exposures and lung cancer mortality rates in 2067 counties, with clique doubling applied to compute an absolute threshold of significance. Factor analysis and multiple linear regressions then were used to analyze differences in exposures associated with lung cancer mortality and mortality disparities by race and gender. Results While cigarette consumption was highly correlated with rates of lung cancer mortality for both white men and women, previously unidentified novel exposures were more closely associated with lung cancer mortality and mortality disparities for blacks, particularly black women. Conclusions Exposures beyond smoking moderate lung cancer mortality and mortality disparities by race and gender. Policy Implications An exposome approach and database coupled with scalable combinatorial analytics provides a powerful new approach for analyzing relationships between multiple environmental exposures, pathways and health outcomes. An assessment of multiple exposures is needed to appropriately translate research findings into environmental public health practice and policy. PMID:29152601

Environmental exposure to benzene: an update.

PubMed Central

Wallace, L

1996-01-01

During the 1990s, several large-scale studies of benzene concentrations in air, food, and blood have added to our knowledge of its environmental occurrence. In general, the new studies have confirmed the earlier findings of the U.S. Environmental Protection Agency Total Exposure Assessment Methodology (TEAM) studies and other large-scale studies in Germany and the Netherlands concerning the levels of exposure and major sources. For example, the new studies found that personal exposures exceeded indoor concentrations of benzene, which in turn exceeded outdoor concentrations. The new studies of food concentrations have confirmed earlier indications that food is not an important pathway for benzene exposure. The results of the National Health and Nutrition Examination Survey on blood levels in a nationwide sample of 883 persons are in good agreement with the concentrations in exhaled breath measured in about 800 persons a decade earlier in the TEAM studies. Major sources of exposure continue to be active and passive smoking, auto exhaust, and driving or riding in automobiles. New methods in breath and blood sampling and analysis offer opportunities to investigate short-term peak exposures and resulting body burden under almost any conceivable field conditions. PMID:9118882

Low-dose occupational exposure to benzene and signal transduction pathways involved in the regulation of cellular response to oxidative stress.

PubMed

Fenga, Concettina; Gangemi, Silvia; Giambò, Federica; Tsitsimpikou, Christina; Golokhvast, Kirill; Tsatsakis, Aristidis; Costa, Chiara

2016-02-15

Benzene metabolism seems to modulate NF-κB, p38-MAPK (mitogen-activated protein kinase) and signal transducer and activator of transcription 3 (STAT3) signalling pathways via the production of reactive oxygen species. This study aims to evaluate the effects of low-dose, long-term exposure on NF-κB, STAT3, p38-MAPK and stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK) signal transduction pathways in peripheral blood mononuclear cells in gasoline station attendants. The influence of consumption of vegetables and fruits on these pathways has also been evaluated. A total of 91 men, employed in gasoline stations located in eastern Sicily, were enrolled for this study and compared with a control group of 63 male office workers with no history of exposure to benzene. The exposure was assessed by measuring urinary trans,trans-muconic acid (t,t-MA) concentration. Quantitative analyses were performed for proteins NF-κB p65, phospho-NF-κB p65, phospho-IκB-α, phospho-SAPK/JNK, phospho-p38 MAPK and phospho-STAT3 using an immunoenzymatic assay. The results of this study indicate significantly higher t,t-MA levels in gasoline station attendants. With regard to NF-κB, phospho-IκB-α and phospho-STAT3 proteins, statistically significant differences were observed in workers exposed to benzene. However, no differences were observed in SAPK/JNK and p38-MAPK activation. These changes were positively correlated with t,t-MA levels, but only phospho-NF-κB p65 was associated with the intake of food rich in antioxidant active principles. Chronic exposure to low-dose benzene can modulate signal transduction pathways activated by oxidative stress and involved in cell proliferation and apoptosis. This could represent a possible mechanism of carcinogenic action of chronic benzene exposure. Copyright © 2016 Elsevier Inc. All rights reserved.

Tracing the tracks of genotoxicity by trivalent and hexavalent chromium in Drosophila melanogaster.

PubMed

Mishra, Manish; Sharma, Anurag; Negi, M P S; Dwivedi, U N; Chowdhuri, D Kar

2011-05-18

Mutagen sensitive strains (mus) in Drosophila are known for their hypersensitivity to mutagens and environmental carcinogens. Accordingly, these mutants were grouped in pre- and post-replication repair pathways. However, studying mutants belonging to one particular repair pathway may not be adequate for examining chemical-induced genotoxicity when other repair pathways may neutralize its effect. To test whether both pre-and post-replication pathways are involved and effect of Cr(III)- and Cr(VI)-induced genotoxicity in absence or presence of others, we used double mutant approach in D. melanogaster. We observed DNA damage as evident by changes in Comet assay DNA migration in cells of larvae of Oregon R(+) and single mutants of pre- (mei-9, mus201 and mus210) and post- (mei-41, mus209 and mus309) replication repair pathways and also in double mutants of different combinations (pre-pre, pre-post and post-post replication repair) exposed to increasing concentrations of Cr(VI) (0.0, 5.0, 10.0 and 20.0 μg/ml) for 48 h. The damage was greater in pre-replication repair mutants after exposure to 5.0 μg/ml Cr(VI), while effects on Oregon R(+) and post replication repair mutants were insignificant. Post-replication repair mutants revealed significant DNA damage after exposure to 20.0 μg/ml Cr(VI). Further, double mutants generated in the above repair categories were examined for DNA damage following Cr(VI) exposure and a comparison of damage was studied between single and double mutants. Combinations of double mutants generated in the pre-pre replication repair pathways showed an indifferent interaction between the two mutants after Cr(VI) exposure while a synergistic interaction was evident in exposed post-post replication repair double mutants. Cr(III) (20.0 μg/ml) exposure to these strains did not induce any significant DNA damage in their cells. The study suggests that both pre- and post-replication pathways are affected in Drosophila by Cr(VI) leading to genotoxicity, which may have consequences for metal-induced carcinogenesis. 2011 Elsevier B.V. All rights reserved.

Meta-Analysis of Global Transcriptomics Suggests that Conserved Genetic Pathways are Responsible for Quercetin and Tannic Acid Mediated Longevity in C. elegans

PubMed Central

Pietsch, Kerstin; Saul, Nadine; Swain, Suresh C.; Menzel, Ralph; Steinberg, Christian E. W.; Stürzenbaum, Stephen R.

2012-01-01

Recent research has highlighted that the polyphenols Quercetin and Tannic acid are capable of extending the lifespan of Caenorhabditis elegans. To gain a deep understanding of the underlying molecular genetics, we analyzed the global transcriptional patterns of nematodes exposed to three concentrations of Quercetin or Tannic acid, respectively. By means of an intricate meta-analysis it was possible to compare the transcriptomes of polyphenol exposure to recently published datasets derived from (i) longevity mutants or (ii) infection. This detailed comparative in silico analysis facilitated the identification of compound specific and overlapping transcriptional profiles and allowed the prediction of putative mechanistic models of Quercetin and Tannic acid mediated longevity. Lifespan extension due to Quercetin was predominantly driven by the metabolome, TGF-beta signaling, Insulin-like signaling, and the p38 MAPK pathway and Tannic acid’s impact involved, in part, the amino acid metabolism and was modulated by the TGF-beta and the p38 MAPK pathways. DAF-12, which integrates TGF-beta and Insulin-like downstream signaling, and genetic players of the p38 MAPK pathway therefore seem to be crucial regulators for both polyphenols. Taken together, this study underlines how meta-analyses can provide an insight of molecular events that go beyond the traditional categorization into gene ontology-terms and Kyoto encyclopedia of genes and genomes-pathways. It also supports the call to expand the generation of comparative and integrative databases, an effort that is currently still in its infancy. PMID:22493606

Risk-based indicators of Canadians' exposures to environmental carcinogens.

PubMed

Setton, Eleanor; Hystad, Perry; Poplawski, Karla; Cheasley, Roslyn; Cervantes-Larios, Alejandro; Keller, C Peter; Demers, Paul A

2013-02-12

Tools for estimating population exposures to environmental carcinogens are required to support evidence-based policies to reduce chronic exposures and associated cancers. Our objective was to develop indicators of population exposure to selected environmental carcinogens that can be easily updated over time, and allow comparisons and prioritization between different carcinogens and exposure pathways. We employed a risk assessment-based approach to produce screening-level estimates of lifetime excess cancer risk for selected substances listed as known carcinogens by the International Agency for Research on Cancer. Estimates of lifetime average daily intake were calculated using population characteristics combined with concentrations (circa 2006) in outdoor air, indoor air, dust, drinking water, and food and beverages from existing monitoring databases or comprehensive literature reviews. Intake estimates were then multiplied by cancer potency factors from Health Canada, the United States Environmental Protection Agency, and the California Office of Environmental Health Hazard Assessment to estimate lifetime excess cancer risks associated with each substance and exposure pathway. Lifetime excess cancer risks in excess of 1 per million people are identified as potential priorities for further attention. Based on data representing average conditions circa 2006, a total of 18 carcinogen-exposure pathways had potential lifetime excess cancer risks greater than 1 per million, based on varying data quality. Carcinogens with moderate to high data quality and lifetime excess cancer risk greater than 1 per million included benzene, 1,3-butadiene and radon in outdoor air; benzene and radon in indoor air; and arsenic and hexavalent chromium in drinking water. Important data gaps were identified for asbestos, hexavalent chromium and diesel exhaust in outdoor and indoor air, while little data were available to assess risk for substances in dust, food and beverages. The ability to track changes in potential population exposures to environmental carcinogens over time, as well as to compare between different substances and exposure pathways, is necessary to support comprehensive, evidence-based prevention policy. We used estimates of lifetime excess cancer risk as indicators that, although based on a number of simplifying assumptions, help to identify important data gaps and prioritize more detailed data collection and exposure assessment needs.

Refining the aggregate exposure pathway.

PubMed

Tan, Yu-Mei; Leonard, Jeremy A; Edwards, Stephen; Teeguarden, Justin; Egeghy, Peter

2018-03-01

Advancements in measurement technologies and modeling capabilities continue to result in an abundance of exposure information, adding to that currently in existence. However, fragmentation within the exposure science community acts as an obstacle for realizing the vision set forth in the National Research Council's report on Exposure Science in the 21 st century to consider exposures from source to dose, on multiple levels of integration, and to multiple stressors. The concept of an Aggregate Exposure Pathway (AEP) was proposed as a framework for organizing and integrating diverse exposure information that exists across numerous repositories and among multiple scientific fields. A workshop held in May 2016 followed introduction of the AEP concept, allowing members of the exposure science community to provide extensive evaluation and feedback regarding the framework's structure, key components, and applications. The current work briefly introduces topics discussed at the workshop and attempts to address key challenges involved in refining this framework. The resulting evolution in the AEP framework's features allows for facilitating acquisition, integration, organization, and transparent application and communication of exposure knowledge in a manner that is independent of its ultimate use, thereby enabling reuse of such information in many applications.

Prioritization of pesticides based on daily dietary exposure potential as determined from the SHEDS model

EPA Science Inventory

A major pathway for exposure to many pesticides is through diet. The objectives were to rank pesticides by comparing their calculated daily dietary exposure as determined by EPA's Stochastic Human Exposure and Dose Simulation (SHEDS) to single pesticides for different age groups ...

TESTING DUPLICATE DIET SAMPLE COLLECTION METHODS FOR MEASURING PERSONAL DIETARY EXPOSURES TO CHEMICAL CONTAMINANTS

EPA Science Inventory

Dietary ingestion may be a significant pathway of human exposure to many potentially toxic chemicals. The U.S.Environmental Protection Agency-National Human Exposure Laboratory has made the development of methods for measuring persoanl dietary exposures a high priority for its di...

Transcriptome comparison in the pituitary-adrenal axis between Beagle and Chinese Field dogs after chronic stress exposure.

PubMed

Luo, Wei; Fang, Meixia; Xu, Haiping; Xing, Huijie; Nie, Qinghua

2015-10-01

Chronic stress can induce a series of maladjustments, and the response to stress is partly regulated by the hypothalamus-pituitary-adrenal axis. The aim of this study was to investigate the genetic mechanisms of this axis regulating stress responsiveness. The pituitary and adrenal cortex of Beagle and Chinese Field Dog (CFD) from a stress exposure group [including Beagle pituitary 1 (BP1), CFD pituitary 1 (CFDP1), Beagle adrenal cortex 1 (BAC1), CFD adrenal cortex 1 (CFDAC1)] and a control group [including Beagle pituitary 2 (BP2), CFD pituitary 2 (CFDP2), Beagle adrenal cortex 2 (BAC2), CFD adrenal cortex 2 (CFDAC2)], selected to perform RNA-seq transcriptome comparisons, showed that 40, 346, 376, 69, 70, 38, 57 and 71 differentially expressed genes were detected in BP1 vs. BP2, CFDP1 vs. CFDP2, BP1 vs. CFDP1, BP2 vs. CFDP2, BAC1 vs. BAC2, CFDAC1 vs. CFDAC2, BAC1 vs. CFDAC1 and BAC2 vs. CFDAC2 respectively. NPB was a gene common to BAC1 vs. BAC2 and CFDAC1 vs. CFDAC2, indicating it was a potential gene affecting response to chronic stress, regardless of the extent of chronic stress induced. PLP1 was a gene common to BP1 vs. CFDP1 and BP2 vs. CFDP2, suggesting its important roles in affecting the stress-tolerance difference between the two breeds, regardless of whether there was stress exposure or not. Pathway analysis found 12, 4, 11 and 1 enriched pathway in the comparisons of BP1 vs. CFDP1, BP2 vs. CFDP2, CFDP1 vs. CFDP2 and BAC1 vs. BAC2 respectively. Glutamatergic synapse, neuroactive ligand-receptor interaction, retrograde endocannabinoid signaling, GABAergic synapse, calcium signaling pathway and dopaminergic synapse were the most significantly enriched pathways in both CFDP1 vs. CFDP2 and BP1 vs. CFDP1. GO, KEGG pathway and gene network analysis demonstrated that GRIA3, GRIN2A, GRIN2B and NPY were important in regulating the stress response in CFD. Nevertheless, ADORA1, CAMK2A, GRM1, GRM7 and NR4A1 might be critical genes contributing to the stress-tolerance difference between CFD and Beagle when subjected to stress exposure. In addition, RGS4 and SYN1 might play important roles both in regulating the stress response in CFD and in affecting the stress-tolerance difference in different breeds. These observations clearly showed that some genes in the adrenal cortex and pituitary could regulate the stress response in Beagle and CFDs, whereas some others could affect the stress-tolerance difference between these two breeds. Our results can contribute to a more comprehensive understanding of the genetic mechanisms of response to chronic stress. © 2015 Stichting International Foundation for Animal Genetics.

The RdDM Pathway Is Required for Basal Heat Tolerance in Arabidopsis

PubMed Central

Jonak, Claudia

2013-01-01

Heat stress affects epigenetic gene silencing in Arabidopsis. To test for a mechanistic involvement of epigenetic regulation in heat-stress responses, we analyzed the heat tolerance of mutants defective in DNA methylation, histone modifications, chromatin-remodeling, or siRNA-based silencing pathways. Plants deficient in NRPD2, the common second-largest subunit of RNA polymerases IV and V, and in the Rpd3-type histone deacetylase HDA6 were hypersensitive to heat exposure. Microarray analysis demonstrated that NRPD2 and HDA6 have independent roles in transcriptional reprogramming in response to temperature stress. The misexpression of protein-coding genes in nrpd2 mutants recovering from heat correlated with defective epigenetic regulation of adjacent transposon remnants which involved the loss of control of heat-stress-induced read-through transcription. We provide evidence that the transcriptional response to temperature stress, at least partially, relies on the integrity of the RNA-dependent DNA methylation pathway. PMID:23376771

Silver nanoparticles induce tight junction disruption and astrocyte neurotoxicity in a rat blood–brain barrier primary triple coculture model

PubMed Central

Xu, Liming; Dan, Mo; Shao, Anliang; Cheng, Xiang; Zhang, Cuiping; Yokel, Robert A; Takemura, Taro; Hanagata, Nobutaka; Niwa, Masami; Watanabe, Daisuke

2015-01-01

Background Silver nanoparticles (Ag-NPs) can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood–brain barrier (BBB) and the underlying mechanism(s) of action on the BBB and the brain are not well understood. Method To investigate Ag-NP suspension (Ag-NPS)-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM). Global gene expression of astrocytes was measured using a DNA microarray. Results A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200 Ω·cm2. After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the tight junction (TJ) protein ZO-1 was decreased. Discontinuous TJs were also observed between microvascular endothelial cells. After Ag-NPS exposure, severe mitochondrial shrinkage, vacuolations, endoplasmic reticulum expansion, and Ag-NPs were observed in astrocytes by TEM. Global gene expression analysis showed that three genes were upregulated and 20 genes were downregulated in astrocytes treated with Ag-NPS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the 23 genes were associated with metabolic processes, biosynthetic processes, response to stimuli, cell death, the MAPK pathway, and so on. No GO term and KEGG pathways were changed in the released-ion or polystyrene-NP groups. Ag-NPS inhibited the antioxidant defense of the astrocytes by increasing thioredoxin interacting protein, which inhibits the Trx system, and decreasing Nr4a1 and Dusp1. Meanwhile, Ag-NPS induced inflammation and apoptosis through modulation of the MAPK pathway or B-cell lymphoma-2 expression or mTOR activity in astrocytes. Conclusion These results draw our attention to the importance of Ag-NP-induced toxicity on the neurovascular unit and provide a better understanding of its toxicological mechanisms on astrocytes. PMID:26491287

HUMAN EXPOSURE MEASUREMENTS - CHILDREN'S FOCUS

EPA Science Inventory

In support of the Food Quality Protection Act of 1996, research under this task is designed to identify those pesticides, pathways, and activities that represent the highest potential exposures to children and to determine the factors that influence these exposures. The research...

Aggregate Exposure Pathway Workshop

EPA Science Inventory

Recognizing the growing demands for conducting rapid, cost-effective, and reliable exposure assessment on the thousands of chemicals in commerce, a committee convened by the National Research Council (NRC) developed its vision for exposure science in the 21st century. A necessary...

Essential Oils of Hyptis pectinata Chemotypes: Isolation, Binary Mixtures and Acute Toxicity on Leaf-Cutting Ants.

PubMed

Feitosa-Alcantara, Rosana B; Bacci, Leandro; Blank, Arie F; Alves, Péricles B; Silva, Indira Morgana de A; Soares, Caroline A; Sampaio, Taís S; Nogueira, Paulo Cesar de L; Arrigoni-Blank, Maria de Fátima

2017-04-12

Leaf-cutting ants are pests of great economic importance due to the damage they cause to agricultural and forest crops. The use of organosynthetic insecticides is the main form of control of these insects. In order to develop safer technology, the objective of this work was to evaluate the formicidal activity of the essential oils of two Hyptis pectinata genotypes (chemotypes) and their major compounds on the leaf-cutting ants Acromyrmex balzani Emery and Atta sexdens rubropilosa Forel. Bioassays of exposure pathways (contact and fumigation) and binary mixtures of the major compounds were performed. The major compounds identified in the essential oils of H. pectinata were β-caryophyllene, caryophyllene oxide and calamusenone. The essential oils of H. pectinata were toxic to the ants in both exposure pathways. Essential oils were more toxic than their major compounds alone. The chemotype calamusenone was more toxic to A. balzani in both exposure pathways. A. sexdens rubropilosa was more susceptible to the essential oil of the chemotype β-caryophyllene in both exposure pathways. In general, the binary mixtures of the major compounds resulted in additive effect of toxicity. The essential oils of H. pectinata is a raw material of great potential for the development of new insecticides.

The consistent differential expression of genetic pathways following exposure of an industrial Pseudomonas aeruginosa strain to preservatives and a laundry detergent formulation.

PubMed

Green, Angharad E; Amézquita, Alejandro; Le Marc, Yvan; Bull, Matthew J; Connor, Thomas R; Mahenthiralingam, Eshwar

2018-05-01

Pseudomonas aeruginosa is a common contaminant associated with product recalls in the home and personal care industry. Preservation systems are used to prevent spoilage and protect consumers, but greater knowledge is needed of preservative resistance mechanisms used by P. aeruginosa contaminants. We aimed to identify genetic pathways associated with preservative exposure by using an industrial P. aeruginosa strain and implementing RNA-Seq to understand gene expression changes in response to industry relevant conditions. The consistent differential expression of five genetic pathways during exposure to multiple industrial growth conditions associated with benzisothiazolone (BIT) and phenoxyethanol (POE) preservatives, and a laundry detergent (LD) formulation, was observed. A MexPQ-OpmE Resistance Nodulation Division efflux pump system was commonly upregulated in response to POE, a combination of BIT and POE, and LD together with BIT. In response to all industry conditions, a putative sialic acid transporter and isoprenoid biosynthesis gnyRDBHAL operon demonstrated consistent upregulation. Two operons phnBA and pqsEDCBA involved in Pseudomonas quinolone signaling production and quorum-sensing were also consistently downregulated during exposure to all the industry conditions. The ability to identify consistently differentially expressed genetic pathways in P. aeruginosa can inform the development of future targeted preservation systems that maintain product safety and minimise resistance development.

Biomarkers of World Trade Center Particulate Matter Exposure: Physiology of distal airway and blood biomarkers that predict FEV1 decline

PubMed Central

Weiden, Michael D.; Kwon, Sophia; Caraher, Erin; Berger, Kenneth I.; Reibman, Joan; Rom, William N.; Prezant, David J.; Nolan, Anna

2016-01-01

Biomarkers can be important predictors of disease severity and progression. The intense exposure to particulates and other toxins from the destruction of the World Trade Center (WTC) overwhelmed the lung’s normal protective barriers. The Fire Department of New York (FDNY) cohort not only had baseline pre-exposure lung function measures but also had serum samples banked soon after their WTC exposure. This well phenotyped group of highly exposed first responders is an ideal cohort for biomarker discovery and eventual validation. Disease progression was heterogeneous in this group in that some individuals subsequently developed abnormal lung function while others recovered. Airflow obstruction predominated in WTC exposed patients who were symptomatic. Multiple independent disease pathways may cause this abnormal FEV1 after irritant exposure. WTC exposure activates one or more of these pathways causing abnormal FEV1 in an individual. Our hypothesis was that serum biomarkers expressed within 6 months after World Trade Center (WTC) exposure reflect active disease pathways and predict subsequent development or protection from abnormal FEV1

Skin Transcriptomes of common bottlenose dolphins (Tursiops truncatus) from the northern Gulf of Mexico and southeastern U.S. Atlantic coasts.

PubMed

Neely, Marion G; Morey, Jeanine S; Anderson, Paul; Balmer, Brian C; Ylitalo, Gina M; Zolman, Eric S; Speakman, Todd R; Sinclair, Carrie; Bachman, Melannie J; Huncik, Kevin; Kucklick, John; Rosel, Patricia E; Mullin, Keith D; Rowles, Teri K; Schwacke, Lori H; Van Dolah, Frances M

2018-04-01

Common bottlenose dolphins serve as sentinels for the health of their coastal environments as they are susceptible to health impacts from anthropogenic inputs through both direct exposure and food web magnification. Remote biopsy samples have been widely used to reveal contaminant burdens in free-ranging bottlenose dolphins, but do not address the health consequences of this exposure. To gain insight into whether remote biopsies can also identify health impacts associated with contaminant burdens, we employed RNA sequencing (RNA-seq) to interrogate the transcriptomes of remote skin biopsies from 116 bottlenose dolphins from the northern Gulf of Mexico and southeastern U.S. Atlantic coasts. Gene expression was analyzed using principal component analysis, differential expression testing, and gene co-expression networks, and the results correlated to season, location, and contaminant burden. Season had a significant impact, with over 60% of genes differentially expressed between spring/summer and winter months. Geographic location exhibited lesser effects on the transcriptome, with 23.5% of genes differentially expressed between the northern Gulf of Mexico and the southeastern U.S. Atlantic locations. Despite a large overlap between the seasonal and geographical gene sets, the pathways altered in the observed gene expression profiles were somewhat distinct. Co-regulated gene modules and differential expression analysis both identified epidermal development and cellular architecture pathways to be expressed at lower levels in animals from the northern Gulf of Mexico. Although contaminant burdens measured were not significantly different between regions, some correlation with contaminant loads in individuals was observed among co-expressed gene modules, but these did not include classical detoxification pathways. Instead, this study identified other, possibly downstream pathways, including those involved in cellular architecture, immune response, and oxidative stress, that may prove to be contaminant responsive markers in bottlenose dolphin skin. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Hexavalent Chromium Cr(VI) Up-Regulates COX-2 Expression through an NFκB/c-Jun/AP-1–Dependent Pathway

PubMed Central

Zuo, Zhenghong; Cai, Tongjian; Li, Jingxia; Zhang, Dongyun; Yu, Yonghui

2012-01-01

Background: Hexavalent chromium [Cr(VI)] is recognized as a human carcinogen via inhalation. However, the molecular mechanisms by which Cr(VI) causes cancers are not well understood. Objectives: We evaluated cyclooxygenase-2 (COX-2) expression and the signaling pathway leading to this induction due to Cr(VI) exposure in cultured cells. Methods: We used the luciferase reporter assay and Western blotting to determine COX-2 induction by Cr(VI). We used dominant negative mutant, genetic knockout, gene knockdown, and chromatin immunoprecipitation approaches to elucidate the signaling pathway leading to COX-2 induction. Results: We found that Cr(VI) exposure induced COX-2 expression in both normal human bronchial epithelial cells and mouse embryonic fibroblasts in a concentration- and time-dependent manner. Deletion of IKKβ [inhibitor of transcription factor NFκB (IκB) kinase β; an upstream kinase responsible for nuclear factor κB (NFκB) activation] or overexpression of TAM67 (a dominant-negative mutant of c-Jun) dramatically inhibited the COX-2 induction due to Cr(VI), suggesting that both NFκB and c-Jun/AP-1 pathways were required for Cr(VI)-induced COX-2 expression. Our results show that p65 and c-Jun are two major components involved in NFκB and AP-1 activation, respectively. Moreover, our studies suggest crosstalk between NFκB and c-Jun/AP-1 pathways in cellular response to Cr(VI) exposure for COX-2 induction. Conclusion: We demonstrate for the first time that Cr(VI) is able to induce COX-2 expression via an NFκB/c-Jun/AP-1–dependent pathway. Our results provide novel insight into the molecular mechanisms linking Cr(VI) exposure to lung inflammation and carcinogenesis. PMID:22472290

Transcriptome Profile Analysis of Breast Muscle Tissues from High or Low Levels of Atmospheric Ammonia Exposed Broilers (Gallus gallus)

PubMed Central

Sa, Renna; Zhong, Ruqing; Xing, Huan; Zhang, Hongfu

2016-01-01

Atmospheric ammonia is a common problem in poultry industry. High concentrations of aerial ammonia cause great harm to broilers' health and production. For the consideration of human health, the limit exposure concentration of ammonia in houses is set at 25 ppm. Previous reports have shown that 25 ppm is still detrimental to livestock, especially the gastrointestinal tract and respiratory tract, but the negative relationship between ammonia exposure and the tissue of breast muscle of broilers is still unknown. In the present study, 25 ppm ammonia in poultry houses was found to lower slaughter performance and breast yield. Then, high-throughput RNA sequencing was utilized to identify differentially expressed genes in breast muscle of broiler chickens exposed to high (25 ppm) or low (3 ppm) levels of atmospheric ammonia. The transcriptome analysis showed that 163 genes (fold change ≥ 2 or ≤ 0.5; P-value < 0.05) were differentially expressed between Ammonia25 (treatment group) and Ammonia3 (control group), including 96 down-regulated and 67 up-regulated genes. qRT-PCR analysis validated the transcriptomic results of RNA sequencing. Gene Ontology (GO) functional annotation analysis revealed potential genes, processes and pathways with putative involvement in growth and development inhibition of breast muscle in broilers caused by aerial ammonia exposure. This study facilitates understanding of the genetic architecture of the chicken breast muscle transcriptome, and has identified candidate genes for breast muscle response to atmospheric ammonia exposure. PMID:27611572

Assessing Residential Exposure Risk from Spills of Flowback Water from Marcellus Shale Hydraulic Fracturing Activity

PubMed Central

Abualfaraj, Noura; Olson, Mira S.

2018-01-01

Identifying sources of concern and risk from shale gas development, particularly from the hydraulic fracturing process, is an important step in better understanding sources of uncertainty within the industry. In this study, a risk assessment of residential exposure pathways to contaminated drinking water is carried out. In this model, it is assumed that a drinking water source is contaminated by a spill of flowback water; probability distributions of spill size and constituent concentrations are fit to historical datasets and Monte Carlo simulation was used to calculate a distribution of risk values for two scenarios: (1) use of a contaminated reservoir for residential drinking water supply and (2) swimming in a contaminated pond. The swimming scenario did not produce risks of concern from a single exposure of 1 h duration, but 11 such 1-h exposures did produce risks of 10−6 due to radionuclide exposure. The drinking water scenario over a 30-year exposure duration produced cancer risk values exceeding 10−6 for arsenic, benzene, benzo(a)pyrene, heptachlor, heptachlor epoxide, pentachlorophenol, and vinyl chloride. However, this extended exposure duration is probably not realistic for exposure by a spill event. Radionuclides produced risks in the residential drinking water scenario of 10−6 in just 8 h, a much more realistic timeline for continual exposure due to a spill event. In general, for contaminants for which inhalation exposure was applicable, this pathway produced the highest risks with exposure from ingestion posing the next greatest risk to human health followed by dermal absorption (or body emersion for radionuclides). Considering non-carcinogenic effects, only barium and thallium exceed target limits, where the ingestion pathway seems to be of greater concern than dermal exposure. Exposure to radionuclides in flowback water, particularly through the inhalation route, poses a greater threat to human health than other contaminants examined in this assessment and should be the focus of risk assessment and risk mitigation efforts. PMID:29641504

Assessing Residential Exposure Risk from Spills of Flowback Water from Marcellus Shale Hydraulic Fracturing Activity.

PubMed

Abualfaraj, Noura; Gurian, Patrick L; Olson, Mira S

2018-04-11

Identifying sources of concern and risk from shale gas development, particularly from the hydraulic fracturing process, is an important step in better understanding sources of uncertainty within the industry. In this study, a risk assessment of residential exposure pathways to contaminated drinking water is carried out. In this model, it is assumed that a drinking water source is contaminated by a spill of flowback water; probability distributions of spill size and constituent concentrations are fit to historical datasets and Monte Carlo simulation was used to calculate a distribution of risk values for two scenarios: (1) use of a contaminated reservoir for residential drinking water supply and (2) swimming in a contaminated pond. The swimming scenario did not produce risks of concern from a single exposure of 1 h duration, but 11 such 1-h exposures did produce risks of 10 -6 due to radionuclide exposure. The drinking water scenario over a 30-year exposure duration produced cancer risk values exceeding 10 -6 for arsenic, benzene, benzo(a)pyrene, heptachlor, heptachlor epoxide, pentachlorophenol, and vinyl chloride. However, this extended exposure duration is probably not realistic for exposure by a spill event. Radionuclides produced risks in the residential drinking water scenario of 10 -6 in just 8 h, a much more realistic timeline for continual exposure due to a spill event. In general, for contaminants for which inhalation exposure was applicable, this pathway produced the highest risks with exposure from ingestion posing the next greatest risk to human health followed by dermal absorption (or body emersion for radionuclides). Considering non-carcinogenic effects, only barium and thallium exceed target limits, where the ingestion pathway seems to be of greater concern than dermal exposure. Exposure to radionuclides in flowback water, particularly through the inhalation route, poses a greater threat to human health than other contaminants examined in this assessment and should be the focus of risk assessment and risk mitigation efforts.

Application of Signaling Pathway-Based Adverse Outcome Pathways and High Throughput Toxicokinetic-PBPK for Developmental Cardiac Malformations

EPA Science Inventory

Associating putative molecular initiating events (MIE) with downstream cell signaling pathways and modeling fetal exposure kinetics is an important challenge for integration in developmental systems toxicology. Here, we describe an integrative systems toxicology model for develop...

Short term exposure to elevated levels of leptin reduces proximal tubule cell metabolic activity.

PubMed

Briffa, Jessica F; Grinfeld, Esther; McAinch, Andrew J; Poronnik, Philip; Hryciw, Deanne H

2014-01-25

Leptin plays a pathophysiological role in the kidney, however, its acute effects on the proximal tubule cells (PTCs) are unknown. In opossum kidney (OK) cells in vitro, Western blot analysis identified that exposure to leptin increases the phosphorylation of the mitogen-activated protein kinase (MAPK) p44/42 and the mammalian target of rapamycin (mTOR). Importantly leptin (0.05, 0.10, 0.25 and 0.50 μg/ml) significantly reduced the metabolic activity of PTCs, and significantly decreased protein content per cell. Investigation of the role of p44/42 and mTOR on metabolic activity and protein content per cell, demonstrated that in the presence of MAPK inhibitor U0126 and mTOR inhibitor Ku-63794, that the mTOR pathway is responsible for the reduction in PTC metabolic activity in response to leptin. However, p44/42 and mTOR play no role the reduced protein content per cell in OKs exposed to leptin. Therefore, leptin modulates metabolic activity in PTCs via an mTOR regulated pathway. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Testing chemical carcinogenicity by using a transcriptomics HepaRG-based model?

PubMed Central

Doktorova, T. Y.; Yildirimman, Reha; Ceelen, Liesbeth; Vilardell, Mireia; Vanhaecke, Tamara; Vinken, Mathieu; Ates, Gamze; Heymans, Anja; Gmuender, Hans; Bort, Roque; Corvi, Raffaella; Phrakonkham, Pascal; Li, Ruoya; Mouchet, Nicolas; Chesne, Christophe; van Delft, Joost; Kleinjans, Jos; Castell, Jose; Herwig, Ralf; Rogiers, Vera

2014-01-01

The EU FP6 project carcinoGENOMICS explored the combination of toxicogenomics and in vitro cell culture models for identifying organotypical genotoxic- and non-genotoxic carcinogen-specific gene signatures. Here the performance of its gene classifier, derived from exposure of metabolically competent human HepaRG cells to prototypical non-carcinogens (10 compounds) and hepatocarcinogens (20 compounds), is reported. Analysis of the data at the gene and the pathway level by using independent biostatistical approaches showed a distinct separation of genotoxic from non-genotoxic hepatocarcinogens and non-carcinogens (up to 88 % correct prediction). The most characteristic pathway responding to genotoxic exposure was DNA damage. Interlaboratory reproducibility was assessed by blindly testing of three compounds, from the set of 30 compounds, by three independent laboratories. Subsequent classification of these compounds resulted in correct prediction of the genotoxicants. As expected, results on the non-genotoxic carcinogens and the non-carcinogens were less predictive. In conclusion, the combination of transcriptomics with the HepaRG in vitro cell model provides a potential weight of evidence approach for the evaluation of the genotoxic potential of chemical substances. PMID:26417288

Transcriptional Pathways Altered in Response to Vibration in a Model of Hand-Arm Vibration Syndrome

PubMed Central

Waugh, Stacey; Kashon, Michael L.; Li, Shengqiao; Miller, Gerome R.; Johnson, Claud; Krajnak, Kristine

2016-01-01

Objective The aim of this study was to use an established model of vibration-induced injury to assess frequency-dependent changes in transcript expression in skin, artery, and nerve tissues. Methods Transcript expression in tissues from control and vibration-exposed rats (4 h/day for 10 days at 62.5, 125, or 250 Hz; 49 m/s2, rms) was measured. Transcripts affected by vibration were used in bioinformatics analyses to identify molecular- and disease-related pathways associated with exposure to vibration. Results Analyses revealed that cancer-related pathways showed frequency-dependent changes in activation or inhibition. Most notably, the breast-related cancer-1 pathway was affected. Other pathways associated with breast cancer type 1 susceptibility protein related signaling, or associated with cancer and cell cycle/cell survivability were also affected. Conclusion Occupational exposure to vibration may result in DNA damage and alterations in cell signaling pathways that have significant effects on cellular division. PMID:27058473

NEAR ROADWAYS EXPOSURE TO URBAN AIR POLLUTANTS STUDY (NEXUS)

EPA Science Inventory

The proposed research addresses both the effects and the mechanisms by which traffic-associated exposures induce exaggerated airway responses in children with asthma, and how these exposures cause biologic responses on inflammatory pathways, oxidative stress, and the frequ...

INTEGRATED HUMAN EXPOSURE SOURCE-TO-DOSE MODELING

EPA Science Inventory

The NERL human exposure research program is designed to provide a sound, scientifically-based approach to understanding how people are actually exposed to pollutants and the factors and pathways influencing exposure and dose. This research project serves to integrate and incorpo...

Identification of Biomarkers of Exposure to FTOHs and PAPs in Humans Using a Targeted and Nontargeted Analysis Approach.

PubMed

Dagnino, Sonia; Strynar, Mark J; McMahen, Rebecca L; Lau, Christopher S; Ball, Carol; Garantziotis, Stavros; Webster, Thomas F; McClean, Michael D; Lindstrom, Andrew B

2016-09-20

Although historic perfluorinated compounds are currently under scrutiny and growing regulatory control in the world, little is known about human exposure to other polyfluorinated compounds presently in use. Fluorotelomer alcohols (FTOHs) and polyfluoroalkyl phosphate esters (PAPs) are known to degrade to terminal perfluorinated acids and toxic reactive intermediates through metabolic pathways. Therefore, it is important to characterize their human exposure by the identification of unique biomarkers. With the use of liquid chromatography-mass spectrometry-time-of-flight analysis (LC-MS-TOF), we developed a workflow for the identification of metabolites for the 8:2 FTOH and 8:2 diPAP. Analysis of serum and urine of dosed rats indicated the 8:2 FTOH-sulfate and the 8:2 diPAP as potential biomarkers. These compounds, as well as 25 other fluorinated compounds and metabolites, were analyzed in human serum and urine samples from the general population (n = 100) and office workers (n = 30). The 8:2 FTOH-sulfate was measured for the first time in human samples in 5 to 10% of the serum samples, ranging from 50 to 80 pg/mL. The 8:2 diPAP was measured in 58% of the samples, ranging from 100 to 800 pg/mL. This study indicates the FTOH-sulfate conjugate as a biomarker of exposure to FTOHs and PAPs in humans.

Eye-Specific Gene Expression following Embryonic Ethanol Exposure in Zebrafish: Roles for Heat Shock Factor 1

PubMed Central

Kashyap, Bhavani; Pegorsch, Laurel; Frey, Ruth A.; Sun, Chi; Shelden, Eric A.; Stenkamp, Deborah L.

2014-01-01

The mechanisms through which ethanol exposure results in developmental defects remain unclear. We used the zebrafish model to elucidate eye-specific mechanisms that underlie ethanol-mediated microphthalmia (reduced eye size), through time-series microarray analysis of gene expression within eyes of embryos exposed to 1.5% ethanol. 62 genes were differentially expressed (DE) in ethanol-treated as compared to control eyes sampled during retinal neurogenesis (24-48 hours post-fertilization). The EDGE (extraction of differential gene expression) algorithm identified >3000 genes DE over developmental time in ethanol-exposed eyes as compared to controls. The DE lists included several genes indicating a mis-regulated cellular stress response due to ethanol exposure. Combined treatment with sub-threshold levels of ethanol and a morpholino targeting heat shock factor 1 mRNA resulted in microphthalmia, suggesting convergent molecular pathways. Thermal preconditioning partially prevented ethanol-mediated microphthalmia while maintaining Hsf-1 expression. These data suggest roles for reduced Hsf-1 in mediating microphthalmic effects of embryonic ethanol exposure. PMID:24355176

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

PubMed Central

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

2014-01-01

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

Vascular surgery knowledge and exposure obtained during medical school and the potential impact on career decisions.

PubMed

Singh, Niten; Causey, Wayne; Brounts, Lionel; Clouse, W Darrin; Curry, Thomas; Andersen, Charles

2010-01-01

The pathway to primary certification in vascular surgery is evolving, requiring trainees to make earlier career decisions. The goal of this study was to evaluate exposure to and knowledge of vascular surgery obtained during medical school that could affect career decisions. A survey was conducted of recent medical school graduates entering military residency programs. Questions were designed to ascertain the medical school attended and degree obtained, exposure to and perception of vascular surgery, and basic vascular surgery knowledge. Of 316 individuals who were identified and sent surveys, 218 (69%) responded. There were 131 allopathic graduates (60%), 87 (40%) osteopathic graduates, and 53 (25%) were entering a surgical residency. Clinical clerkships (32%) were the primary reason for specialty selection, followed by lifestyle (29%). Most respondents (66%) did not have a vascular clinical clerkship. Regarding perception, 56% of respondents would consult interventional radiology for a peripheral arteriogram vs vascular surgery (39%). The mean score of the knowledge-based questions was 69%. Incoming postgraduate year (PGY) 1 surgical residents had a statistically higher mean score on the knowledge portion (P < .001). In addition, a positive correlation was noted with the number of weeks spent on a surgical (P < .03) and a vascular surgical (P < .001) rotation and the mean score. Subgroup analysis revealed a higher percentage of individuals with a vascular clerkship achieved a "high" score vs those without a vascular surgery clerkship (P < .001). Our cohort of medical school graduates had limited exposure to and knowledge of vascular surgery. Providing more clinical exposure in medical school appears necessary to ensure success of the modified pathways for primary certification in vascular surgery. Published by Mosby, Inc.

Evaluation of the Genetic Response of U937 and Jurkat Cells to 10-Nanosecond Electrical Pulses (nsEP)

PubMed Central

Glickman, Randolph D.; Tolstykh, Gleb P.; Estlack, Larry E.; Moen, Erick K.; Echchgadda, Ibtissam; Beier, Hope T.; Barnes, Ronald A.; Ibey, Bennett L.

2016-01-01

Nanosecond electrical pulse (nsEP) exposure activates signaling pathways, produces oxidative stress, stimulates hormone secretion, causes cell swelling and induces apoptotic and necrotic death. The underlying biophysical connection(s) between these diverse cellular reactions and nsEP has yet to be elucidated. Using global genetic analysis, we evaluated how two commonly studied cell types, U937 and Jurkat, respond to nsEP exposure. We hypothesized that by studying the genetic response of the cells following exposure, we would gain direct insight into the stresses experienced by the cell and in turn better understand the biophysical interaction taking place during the exposure. Using Ingenuity Systems software, we found genes associated with cell growth, movement and development to be significantly up-regulated in both cell types 4 h post exposure to nsEP. In agreement with our hypothesis, we also found that both cell lines exhibit significant biological changes consistent with mechanical stress induction. These results advance nsEP research by providing strong evidence that the interaction of nsEPs with cells involves mechanical stress. PMID:27135944

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

PubMed Central

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:26824464

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

PubMed

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

2016-07-01

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. 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. 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. 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. 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. 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.

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

PubMed

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

2017-10-01

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

Hepatic gene expression in rainbow trout (Oncorhynchus mykiss) exposed to different hydrocarbon mixtures.

PubMed

Hook, Sharon E; Lampi, Mark A; Febbo, Eric J; Ward, Jeff A; Parkerton, Thomas F

2010-09-01

Traditional biomarkers for hydrocarbon exposure are not induced by all petroleum substances. The objective of this study was to determine if exposure to a crude oil and different refined oils would generate a common hydrocarbon-specific response in gene expression profiles that could be used as generic biomarkers of hydrocarbon exposure. Juvenile rainbow trout (Oncorhynchus mykiss) were exposed to the water accommodated fraction (WAF) of either kerosene, gas oil, heavy fuel oil, or crude oil for 96 h. Tissue was collected for RNA extraction and microarray analysis. Exposure to each WAF resulted in a different list of differentially regulated genes, with few genes in common across treatments. Exposure to crude oil WAF changed the expression of genes including cytochrome P4501A (CYP1A) and glutathione-S-transferase (GST) with known roles in detoxification pathways. These gene expression profiles were compared to others from previous experiments that used a diverse suite of toxicants. Clustering algorithms successfully identified gene expression profiles resulting from hydrocarbon exposure. These preliminary analyses highlight the difficulties of using single genes as diagnostic of petroleum hydrocarbon exposures. Further work is needed to determine if multivariate transcriptomic-based biomarkers may be a more effective tool than single gene studies for exposure monitoring of different oils. Copyright 2010 SETAC.

Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework

PubMed Central

Ruiter, Sander; Sippel, Josefine; Bouwmeester, Manon C.; Lommelaars, Tobias; Beekhof, Piet; Hodemaekers, Hennie M.; Bakker, Frank; van den Brandhof, Evert-Jan; Pennings, Jeroen L. A.; van der Ven, Leo T. M.

2016-01-01

Non-communicable diseases (NCDs) are a major cause of premature mortality. Recent studies show that predispositions for NCDs may arise from early-life exposure to low concentrations of environmental contaminants. This developmental origins of health and disease (DOHaD) paradigm suggests that programming of an embryo can be disrupted, changing the homeostatic set point of biological functions. Epigenetic alterations are a possible underlying mechanism. Here, we investigated the DOHaD paradigm by exposing zebrafish to subtoxic concentrations of the ubiquitous contaminant cadmium during embryogenesis, followed by growth under normal conditions. Prolonged behavioral responses to physical stress and altered antioxidative physiology were observed approximately ten weeks after termination of embryonal exposure, at concentrations that were 50–3200-fold below the direct embryotoxic concentration, and interpreted as altered developmental programming. Literature was explored for possible mechanistic pathways that link embryonic subtoxic cadmium to the observed apical phenotypes, more specifically, the probability of molecular mechanisms induced by cadmium exposure leading to altered DNA methylation and subsequently to the observed apical phenotypes. This was done using the adverse outcome pathway model framework, and assessing key event relationship plausibility by tailored Bradford-Hill analysis. Thus, cadmium interaction with thiols appeared to be the major contributor to late-life effects. Cadmium-thiol interactions may lead to depletion of the methyl donor S-adenosyl-methionine, resulting in methylome alterations, and may, additionally, result in oxidative stress, which may lead to DNA oxidation, and subsequently altered DNA methyltransferase activity. In this way, DNA methylation may be affected at a critical developmental stage, causing the observed apical phenotypes. PMID:27827847

The p-ERK–p-c-Jun–cyclinD1 pathway is involved in proliferation of smooth muscle cells after exposure to cigarette smoke extract

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Tianjia; Song, Ting; Ni, Leng

Highlights: • Smooth muscle cells proliferated after exposure to cigarette smoke extract. • The p-ERK, p-c-Jun, and cyclinD1 expressions increased in the process. • The p-ERK inhibitor, U0126, can reverse these effects. • The p-ERK → p-c-Jun → cyclinD1 pathway is involved in the process. - Abstract: An epidemiological survey has shown that smoking is closely related to atherosclerosis, in which excessive proliferation of vascular smooth muscle cells (SMCs) plays a key role. To investigate the mechanism underlying this unusual smoking-induced proliferation, cigarette smoke extract (CSE), prepared as smoke-bubbled phosphate-buffered saline (PBS), was used to induce effects mimicking those exertedmore » by smoking on SMCs. As assessed by Cell Counting Kit-8 detection (an improved MTT assay), SMC viability increased significantly after exposure to CSE. Western blot analysis demonstrated that p-ERK, p-c-Jun, and cyclinD1 expression increased. When p-ERK was inhibited using U0126 (inhibitor of p-ERK), cell viability decreased and the expression of p-c-Jun and cyclinD1 was reduced accordingly, suggesting that p-ERK functions upstream of p-c-Jun and cyclinD1. When a c-Jun over-expression plasmid was transfected into SMCs, the level of cyclinD1 in these cells increased. Moreover, when c-Jun was knocked down by siRNA, cyclinD1 levels decreased. In conclusion, our findings indicate that the p-ERK–p-c-Jun–cyclinD1 pathway is involved in the excessive proliferation of SMCs exposed to CSE.« less

Chemoresistance to Cancer Treatment: Benzo-α-Pyrene as Friend or Foe?

PubMed

Dzobo, Kevin; Hassen, Naseeha; Senthebane, Dimakatso Alice; Thomford, Nicholas Ekow; Rowe, Arielle; Shipanga, Hendrina; Wonkam, Ambroise; Parker, M Iqbal; Mowla, Shaheen; Dandara, Collet

2018-04-17

Background: Environmental pollution such as exposure to pro-carcinogens including benzo-α-pyrene is becoming a major problem globally. Moreover, the effects of benzo-α-pyrene (BaP) on drug pharmacokinetics, pharmacodynamics, and drug resistance warrant further investigation, especially in cancer outpatient chemotherapy where exposure to environmental pollutants might occur. Method: We report here on the effects of benzo-α-pyrene on esophageal cancer cells in vitro, alone, or in combination with chemotherapeutic drugs cisplatin, 5-flurouracil, or paclitaxel. As the study endpoints, we employed expression of proteins involved in cell proliferation, drug metabolism, apoptosis, cell cycle analysis, colony formation, migration, and signaling cascades in the WHCO1 esophageal cancer cell line after 24 h of treatment. Results: Benzo-α-pyrene had no significant effect on WHCO1 cancer cell proliferation but reversed the effect of chemotherapeutic drugs by reducing drug-induced cell death and apoptosis by 30–40% compared to drug-treated cells. The three drugs significantly reduced WHCO1 cell migration by 40–50% compared to control and BaP-treated cells. Combined exposure to drugs was associated with significantly increased apoptosis and reduced colony formation. Evaluation of survival signaling cascades showed that although the MEK-ERK and Akt pathways were activated in the presence of drugs, BaP was a stronger activator of the MEK-ERK and Akt pathways than the drugs. Conclusion: The present study suggest that BaP can reverse the effects of drugs on cancer cells via the activation of survival signaling pathways and upregulation of anti-apoptotic proteins such as Bcl-2 and Bcl-xL. Our data show that BaP contribute to the development of chemoresistant cancer cells.

Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho-GTPase-dependent actin cytoskeletal signaling in fetal lungs.

PubMed

Unachukwu, Uchenna; Trischler, Jordis; Goldklang, Monica; Xiao, Rui; D'Armiento, Jeanine

2017-06-01

The present study tested the hypothesis that maternal smoke exposure results in fetal lung growth retardation due to dysregulation in various signaling pathways, including the Wnt (wingless-related integration site)/β-catenin pathway. Pregnant female C57BL/6J mice were exposed to cigarette smoke (100-150 mg/m 3 ) or room air, and offspring were humanely killed on 12.5, 14.5, 16.5, and 18.5 d post coitum (dpc). We assessed lung stereology with Cavalieri estimation; apoptosis with proliferating cell nuclear antigen, TUNEL, and caspase assays; and gene expression with quantitative PCR (qPCR) and RNA sequencing on lung epithelium and mesenchyme retrieved by laser capture microdissection. Results demonstrated a significant decrease in body weight and lung volume of smoke-exposed embryos. At 16.5 dpc, the reduction in lung volume was due to loss of lung mesenchymal tissue correlating with a decrease in cell proliferation ( n = 10; air: 61.65% vs. smoke: 44.21%, P < 0.05). RNA sequence analysis demonstrated an alteration in the Wnt pathway, and qPCR confirmed an increased expression of secreted frizzled-related protein 1 (sFRP-1) [ n = 12; relative quantification (RQ) 1 vs. 2.33, P < 0.05] and down-regulation of Cyclin D1 ( n = 7; RQ 1 vs. 0.61, P < 0.05) in mesenchymal tissue. Furthermore, genome expression studies revealed a smoke-induced up-regulation of Rho-GTPase-dependent actin cytoskeletal signaling that can lead to loss of tissue integrity.-Unachukwu, U., Trischler, J., Goldklang, M., Xiao, R., D'Armiento, J. Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho-GTPase-dependent actin cytoskeletal signaling in fetal lungs. © FASEB.

Transcriptomic Analysis of Lung Tissue from Cigarette Smoke-Induced Emphysema Murine Models and Human Chronic Obstructive Pulmonary Disease Show Shared and Distinct Pathways.

PubMed

Yun, Jeong H; Morrow, Jarrett; Owen, Caroline A; Qiu, Weiliang; Glass, Kimberly; Lao, Taotao; Jiang, Zhiqiang; Perrella, Mark A; Silverman, Edwin K; Zhou, Xiaobo; Hersh, Craig P

2017-07-01

Although cigarette smoke (CS) is the primary risk factor for chronic obstructive pulmonary disease (COPD), the underlying molecular mechanisms for the significant variability in developing COPD in response to CS are incompletely understood. We performed lung gene expression profiling of two different wild-type murine strains (C57BL/6 and NZW/LacJ) and two genetic models with mutations in COPD genome-wide association study genes (HHIP and FAM13A) after 6 months of chronic CS exposure and compared the results to human COPD lung tissues. We identified gene expression patterns that correlate with severity of emphysema in murine and human lungs. Xenobiotic metabolism and nuclear erythroid 2-related factor 2-mediated oxidative stress response were commonly regulated molecular response patterns in C57BL/6, Hhip +/- , and Fam13a -/- murine strains exposed chronically to CS. The CS-resistant Fam13a -/- mouse and NZW/LacJ strain revealed gene expression response pattern differences. The Fam13a -/- strain diverged in gene expression compared with C57BL/6 control only after CS exposure. However, the NZW/LacJ strain had a unique baseline expression pattern, enriched for nuclear erythroid 2-related factor 2-mediated oxidative stress response and xenobiotic metabolism, and converged to a gene expression pattern similar to the more susceptible wild-type C57BL/6 after CS exposure. These results suggest that distinct molecular pathways may account for resistance to emphysema. Surprisingly, there were few genes commonly modulated in mice and humans. Our study suggests that gene expression responses to CS may be largely species and model dependent, yet shared pathways could provide biologically significant insights underlying individual susceptibility to CS.

Tissue distribution, excretion, and the metabolic pathway of 2,2',4,4',5-penta-chlorinated diphenylsulfide (CDPS-99) in ICR mice.

PubMed

Zeng, Xiaolan; Zhang, Xuesheng; Qin, Li; Wang, Zunyao

2015-09-15

The tissue distribution, excretion, and metabolic pathway of 2,2',4,4',5-penta-chlorinated diphenylsulfide (CDPS-99) in ICR mice were investigated after oral perfusion at 10mg/kg body weight (b.w.). Biological samples were extracted and separated and, for the first time, were determined by a novel, sensitive, and specific GC-MS method under the full scan and selected ion monitoring (SIM) modes. The results showed that the concentrations of CDPS-99 in the liver, kidneys, and serum reached a maximum after a one-day exposure and that the CDPS-99 concentration in the liver was the highest (3.43μg/g). The increase in the concentration of CDPS-99 in muscle, skin, and adipose tissue was slower, and the concentrations of CDPS-99 achieved their highest levels after 3 days of exposure. It was observed that the CDPS-99 concentration in adipose tissue was still very high (0.71μg/g) after 21 days of exposure, which suggested that CDPS-99 was able to accumulate in adipose tissue. In addition, mouse feces accounted for approximately 75% of the total gavage dose, indicating that CDPS-99 was mainly excreted via mouse feces. Metabolism analysis demonstrated that there were three possible metabolic pathways of CDPS-99 in mice: dechlorination reactions with the formation of tetra-CDPS and hydroxylation and oxidation reactions with the formation of OH-CDPS-99 and chlorinated diphenylsulfone. The present study will help to develop a better understanding of mammalian metabolism of CDPS-99. Copyright © 2015 Elsevier B.V. All rights reserved.

In vitro expression of hard metal dust (WC-Co) - responsive genes in human peripheral blood mononucleated cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lombaert, Nooemi; Lison, Dominique; Van Hummelen, Paul

Hard metals consist of tungsten carbide (WC) and metallic cobalt (Co) particles and are important industrial materials produced for their extreme hardness and high wear resistance properties. While occupational exposure to metallic Co alone is apparently not associated with an increased risk of cancer, the WC-Co particle mixture was shown to be carcinogenic in exposed workers. The in vitro mutagenic/apoptogenic potential of WC-Co in human peripheral blood mononucleated cells was previously demonstrated by us. This study aimed at obtaining a broader view of the pathways responsible for WC-Co induced carcinogenicity, and in particular genotoxicity and apoptosis. We analyzed the profilemore » of gene expression induced in vitro by WC-Co versus control (24 h treatment) in human PBMC and monocytes using microarrays. The most significantly up-regulated pathways for WC-Co treated PBMC were apoptosis and stress/defense response; the most down-regulated was immune response. For WC-Co treated monocytes the most significantly up- and down-regulated pathways were nucleosome/chromatin assembly and immune response respectively. Quantitative RT-PCR data for a selection of the most strongly modulated genes (HMOX1, HSPA1A, HSPA1L, BNIP3, BNIP3L, ADORA2B, MT3, PLA2G7, TNFAIP6), and some additionally chosen apoptosis related genes (BCL2, BAX, FAS, FASL, TNF{alpha}), confirmed the microarray data after WC-Co exposure and demonstrated limited differences between the Co-containing compounds. Overall, this study provides the first analysis of gene expression induced by the WC-Co mixture showing a large profile of gene modulation and giving a preliminary indication for a hypoxia mimicking environment induced by WC-Co exposure.« less

Single-Nucleotide Polymorphisms Associated with Skin Naphthyl–Keratin Adduct Levels in Workers Exposed to Naphthalene

PubMed Central

Jiang, Rong; French, John E.; Stober, Vandy P.; Kang-Sickel, Juei-Chuan C.; Zou, Fei

2012-01-01

Background: Individual genetic variation that results in differences in systemic response to xenobiotic exposure is not accounted for as a predictor of outcome in current exposure assessment models. Objective: We developed a strategy to investigate individual differences in single-nucleotide polymorphisms (SNPs) as genetic markers associated with naphthyl–keratin adduct (NKA) levels measured in the skin of workers exposed to naphthalene. Methods: The SNP-association analysis was conducted in PLINK using candidate-gene analysis and genome-wide analysis. We identified significant SNP–NKA associations and investigated the potential impact of these SNPs along with personal and workplace factors on NKA levels using a multiple linear regression model and the Pratt index. Results: In candidate-gene analysis, a SNP (rs4852279) located near the CYP26B1 gene contributed to the 2-naphthyl–keratin adduct (2NKA) level. In the multiple linear regression model, the SNP rs4852279, dermal exposure, exposure time, task replacing foam, age, and ethnicity all were significant predictors of 2NKA level. In genome-wide analysis, no single SNP reached genome-wide significance for NKA levels (all p ≥ 1.05 × 10–5). Pathway and network analyses of SNPs associated with NKA levels were predicted to be involved in the regulation of cellular processes and homeostasis. Conclusions: These results provide evidence that a quantitative biomarker can be used as an intermediate phenotype when investigating the association between genetic markers and exposure–dose relationship in a small, well-characterized exposed worker population. PMID:22391508

Genome-wide methylation profiling and the PI3K-AKT pathway analysis associated with smoking in urothelial cell carcinoma.

PubMed

Brait, Mariana; Munari, Enrico; LeBron, Cynthia; Noordhuis, Maartje G; Begum, Shahnaz; Michailidi, Christina; Gonzalez-Roibon, Nilda; Maldonado, Leonel; Sen, Tanusree; Guerrero-Preston, Rafael; Cope, Leslie; Parrella, Paola; Fazio, Vito Michele; Ha, Patrick K; Netto, George J; Sidransky, David; Hoque, Mohammad O

2013-04-01

Urothelial cell carcinoma (UCC) is the second most common genitourinary malignant disease in the USA, and tobacco smoking is the major known risk factor for UCC development. Exposure to carcinogens, such as those contained in tobacco smoke, is known to directly or indirectly damage DNA, causing mutations, chromosomal deletion events and epigenetic alterations in UCC. Molecular studies have shown that chromosome 9 alterations and P53, RAS, RB and PTEN mutations are among the most frequent events in UCC. Recent studies suggested that continuous tobacco carcinogen exposure drives and enhances the selection of epigenetically altered cells in UCC, predominantly in the invasive form of the disease. However, the sequence of molecular events that leads to UCC after exposure to tobacco smoke is not well understood. To elucidate molecular events that lead to UCC oncogenesis and progression after tobacco exposure, we developed an in vitro cellular model for smoking-induced UCC. SV-40 immortalized normal HUC1 human bladder epithelial cells were continuously exposed to 0.1% cigarette smoke extract (CSE) until transformation occurred. Morphological alterations and increased cell proliferation of non-malignant urothelial cells were observed after 4 months (mo) of treatment with CSE. Anchorage-independent growth assessed by soft agar assay and increase in the migratory and invasive potential was observed in urothelial cells after 6 mo of CSE treatment. By performing a PCR mRNA expression array specific to the PI3K-AKT pathway, we found that 26 genes were upregulated and 22 genes were downregulated after 6 mo of CSE exposure of HUC1 cells. Among the altered genes, PTEN, FOXO1, MAPK1 and PDK1 were downregulated in the transformed cells, while AKT1, AKT2, HRAS, RAC1 were upregulated. Validation by RT-PCR and western blot analysis was then performed. Furthermore, genome-wide methylation analysis revealed MCAM, DCC and HIC1 are hypermethylated in CSE-treated urothelial cells when compared with non-CSE exposed cells. The methylation status of these genes was validated using quantitative methylation-specific PCR (QMSP), confirming an increase in methylation of CSE-treated urothelial cells compared to untreated controls. Therefore, our findings suggest that a tobacco signature could emerge from distinctive patterns of genetic and epigenetic alterations and can be identified using an in vitro cellular model for the development of smoking-induced cancer.

Genome-wide methylation profiling and the PI3K-AKT pathway analysis associated with smoking in urothelial cell carcinoma

PubMed Central

Brait, Mariana; Munari, Enrico; LeBron, Cynthia; Noordhuis, Maartje G.; Begum, Shahnaz; Michailidi, Christina; Gonzalez-Roibon, Nilda; Maldonado, Leonel; Sen, Tanusree; Guerrero-Preston, Rafael; Cope, Leslie; Parrella, Paola; Fazio, Vito Michele; Ha, Patrick K.; Netto, George J.; Sidransky, David; Hoque, Mohammad O.

2013-01-01

Urothelial cell carcinoma (UCC) is the second most common genitourinary malignant disease in the USA, and tobacco smoking is the major known risk factor for UCC development. Exposure to carcinogens, such as those contained in tobacco smoke, is known to directly or indirectly damage DNA, causing mutations, chromosomal deletion events and epigenetic alterations in UCC. Molecular studies have shown that chromosome 9 alterations and P53, RAS, RB and PTEN mutations are among the most frequent events in UCC. Recent studies suggested that continuous tobacco carcinogen exposure drives and enhances the selection of epigenetically altered cells in UCC, predominantly in the invasive form of the disease. However, the sequence of molecular events that leads to UCC after exposure to tobacco smoke is not well understood. To elucidate molecular events that lead to UCC oncogenesis and progression after tobacco exposure, we developed an in vitro cellular model for smoking-induced UCC. SV-40 immortalized normal HUC1 human bladder epithelial cells were continuously exposed to 0.1% cigarette smoke extract (CSE) until transformation occurred. Morphological alterations and increased cell proliferation of non-malignant urothelial cells were observed after 4 months (mo) of treatment with CSE. Anchorage-independent growth assessed by soft agar assay and increase in the migratory and invasive potential was observed in urothelial cells after 6 mo of CSE treatment. By performing a PCR mRNA expression array specific to the PI3K-AKT pathway, we found that 26 genes were upregulated and 22 genes were downregulated after 6 mo of CSE exposure of HUC1 cells. Among the altered genes, PTEN, FOXO1, MAPK1 and PDK1 were downregulated in the transformed cells, while AKT1, AKT2, HRAS, RAC1 were upregulated. Validation by RT-PCR and western blot analysis was then performed. Furthermore, genome-wide methylation analysis revealed MCAM, DCC and HIC1 are hypermethylated in CSE-treated urothelial cells when compared with non-CSE exposed cells. The methylation status of these genes was validated using quantitative methylation-specific PCR (QMSP), confirming an increase in methylation of CSE-treated urothelial cells compared to untreated controls. Therefore, our findings suggest that a tobacco signature could emerge from distinctive patterns of genetic and epigenetic alterations and can be identified using an in vitro cellular model for the development of smoking-induced cancer. PMID:23435205

EPA's SHEDS-multimedia model: children's cumulative pyrethroid exposure estimates and evaluation against NHANES biomarker data.

PubMed

Xue, Jianping; Zartarian, Valerie; Tornero-Velez, Rogelio; Tulve, Nicolle S

2014-12-01

The U.S. EPA's SHEDS-Multimedia model was applied to enhance the understanding of children's exposures and doses to multiple pyrethroid pesticides, including major contributing chemicals and pathways. This paper presents combined dietary and residential exposure estimates and cumulative doses for seven commonly used pyrethroids, and comparisons of model evaluation results with NHANES biomarker data for 3-PBA and DCCA metabolites. Model input distributions were fit to publicly available pesticide usage survey data, NHANES, and other studies, then SHEDS-Multimedia was applied to estimate total pyrethroid exposures and doses for 3-5 year olds for one year variability simulations. For dose estimations we used a pharmacokinetic model and two approaches for simulating dermal absorption. SHEDS-Multimedia predictions compared well to NHANES biomarker data: ratios of 3-PBA observed data to SHEDS-Multimedia modeled results were 0.88, 0.51, 0.54 and 1.02 for mean, median, 95th, and 99th percentiles, respectively; for DCCA, the ratios were 0.82, 0.53, 0.56, and 0.94. Modeled time-averaged cumulative absorbed dose of the seven pyrethroids was 3.1 nmol/day (versus 8.4 nmol/day for adults) in the general population (residential pyrethroid use and non-use homes) and 6.7 nmol/day (versus 10.5 nmol/day for adults) in the simulated residential pyrethroid use population. For the general population, contributions to modeled cumulative dose by chemical were permethrin (60%), cypermethrin (22%), and cyfluthrin (16%); for residential use homes, contributions were cypermethrin (49%), permethrin (29%), and cyfluthrin (17%). The primary exposure route for 3-5 year olds in the simulated residential use population was non-dietary ingestion exposure; whereas for the simulated general population, dietary exposure was the primary exposure route. Below the 95th percentile, the major exposure pathway was dietary for the general population; non-dietary ingestion was the major pathway starting below the 70th percentile for the residential use population. The new dermal absorption methodology considering surface loading had some impact, but did not change the order of key pathways. Published by Elsevier Ltd.

Children’s Phthalate Intakes and Resultant Cumulative Exposures Estimated from Urine Compared with Estimates from Dust Ingestion, Inhalation and Dermal Absorption in Their Homes and Daycare Centers

PubMed Central

Bekö, Gabriel; Weschler, Charles J.; Langer, Sarka; Callesen, Michael; Toftum, Jørn; Clausen, Geo

2013-01-01

Total daily intakes of diethyl phthalate (DEP), di(n-butyl) phthalate (DnBP), di(isobutyl) phthalate (DiBP), butyl benzyl phthalate (BBzP) and di(2-ethylhexyl) phthalate (DEHP) were calculated from phthalate metabolite levels measured in the urine of 431 Danish children between 3 and 6 years of age. For each child the intake attributable to exposures in the indoor environment via dust ingestion, inhalation and dermal absorption were estimated from the phthalate levels in the dust collected from the child’s home and daycare center. Based on the urine samples, DEHP had the highest total daily intake (median: 4.42 µg/d/kg-bw) and BBzP the lowest (median: 0.49 µg/d/kg-bw). For DEP, DnBP and DiBP, exposures to air and dust in the indoor environment accounted for approximately 100%, 15% and 50% of the total intake, respectively, with dermal absorption from the gas-phase being the major exposure pathway. More than 90% of the total intake of BBzP and DEHP came from sources other than indoor air and dust. Daily intake of DnBP and DiBP from all exposure pathways, based on levels of metabolites in urine samples, exceeded the Tolerable Daily Intake (TDI) for 22 and 23 children, respectively. Indoor exposures resulted in an average daily DiBP intake that exceeded the TDI for 14 children. Using the concept of relative cumulative Tolerable Daily Intake (TDIcum), which is applicable for phthalates that have established TDIs based on the same health endpoint, we examined the cumulative total exposure to DnBP, DiBP and DEHP from all pathways; it exceeded the tolerable levels for 30% of the children. From the three indoor pathways alone, several children had a cumulative intake that exceeded TDIcum. Exposures to phthalates present in the air and dust indoors meaningfully contribute to a child’s total intake of certain phthalates. Such exposures, by themselves, may lead to intakes exceeding current limit values. PMID:23626820

Identification of Putative Cardiovascular System Developmental Toxicants using a Classification Model based on Signaling Pathway-Adverse Outcome Pathways

EPA Science Inventory

An important challenge for an integrative approach to developmental systems toxicology is associating putative molecular initiating events (MIEs), cell signaling pathways, cell function and modeled fetal exposure kinetics. We have developed a chemical classification model based o...

Reducing the Take-Home Pathway of Pesticide Exposure: Behavioral Outcomes from the ¡Para Niños Saludables! Study

PubMed Central

Strong, Larkin L.; Thompson, Beti; Koepsell, Thomas D.; Meischke, Hendrika; Coronado, Gloria D.

2011-01-01

Objective To evaluate the effectiveness of a community intervention in promoting adoption of behaviors to reduce the take-home pathway of pesticide exposure in farmworker households. Methods Using two cross-sectional samples of farmworker households in 11 intervention and 12 comparison communities in Washington State, we examined whether differences over time in reported pesticide safety practices varied by community intervention status. Results Pesticide safety practices increased in both intervention and comparison communities over time. Changes were significantly greater in intervention communities for removing work shoes before entering the home (p=0.003) and marginally significantly greater for changing out of work clothes within one hour of arriving home (p=0.05). Conclusions The intervention was associated with modest effects in certain behaviors among farmworkers. Further research is needed to identify successful strategies for reducing the take-home pathway of pesticide exposure. PMID:19620892

Theorising and testing environmental pathways to behaviour change: natural experimental study of the perception and use of new infrastructure to promote walking and cycling in local communities

PubMed Central

Panter, Jenna; Ogilvie, David

2015-01-01

Objective Some studies have assessed the effectiveness of environmental interventions to promote physical activity, but few have examined how such interventions work. We investigated the environmental mechanisms linking an infrastructural intervention with behaviour change. Design Natural experimental study. Setting Three UK municipalities (Southampton, Cardiff and Kenilworth). Participants Adults living within 5 km of new walking and cycling infrastructure. Intervention Construction or improvement of walking and cycling routes. Exposure to the intervention was defined in terms of residential proximity. Outcome measures Questionnaires at baseline and 2-year follow-up assessed perceptions of the supportiveness of the environment, use of the new infrastructure, and walking and cycling behaviours. Analysis proceeded via factor analysis of perceptions of the physical environment (step 1) and regression analysis to identify plausible pathways involving physical and social environmental mediators and refine the intervention theory (step 2) to a final path analysis to test the model (step 3). Results Participants who lived near and used the new routes reported improvements in their perceptions of provision and safety. However, path analysis (step 3, n=967) showed that the effects of the intervention on changes in time spent walking and cycling were largely (90%) explained by a simple causal pathway involving use of the new routes, and other pathways involving changes in environmental cognitions explained only a small proportion of the effect. Conclusions Physical improvement of the environment itself was the key to the effectiveness of the intervention, and seeking to change people's perceptions may be of limited value. Studies of how interventions lead to population behaviour change should complement those concerned with estimating their effects in supporting valid causal inference. PMID:26338837

Dynamic imaging of adaptive stress response pathway activation for prediction of drug induced liver injury.

PubMed

Wink, Steven; Hiemstra, Steven W; Huppelschoten, Suzanne; Klip, Janna E; van de Water, Bob

2018-05-01

Drug-induced liver injury remains a concern during drug treatment and development. There is an urgent need for improved mechanistic understanding and prediction of DILI liabilities using in vitro approaches. We have established and characterized a panel of liver cell models containing mechanism-based fluorescent protein toxicity pathway reporters to quantitatively assess the dynamics of cellular stress response pathway activation at the single cell level using automated live cell imaging. We have systematically evaluated the application of four key adaptive stress pathway reporters for the prediction of DILI liability: SRXN1-GFP (oxidative stress), CHOP-GFP (ER stress/UPR response), p21 (p53-mediated DNA damage-related response) and ICAM1 (NF-κB-mediated inflammatory signaling). 118 FDA-labeled drugs in five human exposure relevant concentrations were evaluated for reporter activation using live cell confocal imaging. Quantitative data analysis revealed activation of single or multiple reporters by most drugs in a concentration and time dependent manner. Hierarchical clustering of time course dynamics and refined single cell analysis allowed the allusion of key events in DILI liability. Concentration response modeling was performed to calculate benchmark concentrations (BMCs). Extracted temporal dynamic parameters and BMCs were used to assess the predictive power of sub-lethal adaptive stress pathway activation. Although cellular adaptive responses were activated by non-DILI and severe-DILI compounds alike, dynamic behavior and lower BMCs of pathway activation were sufficiently distinct between these compound classes. The high-level detailed temporal- and concentration-dependent evaluation of the dynamics of adaptive stress pathway activation adds to the overall understanding and prediction of drug-induced liver liabilities.

DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors.

PubMed

Amatruda, James F; Ross, Julie A; Christensen, Brock; Fustino, Nicholas J; Chen, Kenneth S; Hooten, Anthony J; Nelson, Heather; Kuriger, Jacquelyn K; Rakheja, Dinesh; Frazier, A Lindsay; Poynter, Jenny N

2013-06-27

Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development. We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing. Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location. Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy.

Data Sources for Prioritizing Human Exposure to Chemicals

EPA Science Inventory

Humans may be exposed to thousands of chemicals through contact in the workplace, home, and via air, water, food, and soil. A major challenge is estimating chemical exposures, which requires understanding potential exposure pathways directly related to how chemicals are used. Wit...