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Life (Basel, Switzerland) Mar 2022Background: Epigenetic factors including DNA methylation contribute to specific patterns of gene expression. Gene−environment interactions can change the methylation...
Background: Epigenetic factors including DNA methylation contribute to specific patterns of gene expression. Gene−environment interactions can change the methylation status in the brain, and accumulation of these epigenetic changes over a lifespan may be co-responsible for a neurodegenerative disease like Parkinson’s disease, which that is characterised by a late onset in life. Aims: To determine epigenetic modifications in the brains of Parkinson’s disease patients. Patients and Methods: DNA methylation patterns were compared in the cortex tissue of 14 male PD patients and 10 male healthy individuals using the Illumina Methylation 450 K chip. Subsequently, DNA methylation of candidate genes was evaluated using bisulphite pyrosequencing, and DNA methylation of cytochrome P450 2E1 (CYP2E1) was characterized in DNA from blood mononuclear cells (259 PD patients and 182 healthy controls) and skin fibroblasts (10 PD patients and 5 healthy controls). Protein levels of CYP2E1 were analysed using Western blot in human cortex and knock-out mice brain samples. Results: We found 35 hypomethylated and 22 hypermethylated genes with a methylation M-value difference >0.5. Decreased methylation of cytochrome P450 2E1 (CYP2E1) was associated with increased protein levels in PD brains, but in peripheral tissues, i.e., in blood cells and skin fibroblasts, DNA methylation of CYP2E1 was unchanged. In CYP2E1 knock-out mice brain alpha-synuclein (SNCA) protein levels were down-regulated compared to wild-type mice, whereas treatment with trichloroethylene (TCE) up-regulated CYP2E1 protein in a dose-dependent manner in cultured cells. We further identified an interconnected group of genes associated with oxidative stress, such as Methionine sulfoxide reductase A (MSRA) and tumour protein 73 (TP73) in the brain, which again were not paralleled in other tissues and appeared to indicate brain-specific changes. Conclusions: Our study revealed surprisingly few dysmethylated genes in a brain region less affected in PD. We confirmed hypomethylation of CYP2E1.
PubMed: 35454993
DOI: 10.3390/life12040502 -
Toxicology Jun 2021Trichloroethene (TCE) exposure is associated with the induction of autoimmune diseases (ADs). Although oxidative stress plays a major role in TCE-mediated autoimmunity,...
Trichloroethene (TCE) exposure is associated with the induction of autoimmune diseases (ADs). Although oxidative stress plays a major role in TCE-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Dysregulation of redox-sensitive nuclear factor (erythroid-derived 2)-like2 (Nrf2), resulting in uncontrolled antioxidant and cytoprotective genes, and pro-inflammatory MAPK signaling pathways could be critical in TCE-mediated disease progression. This study was, therefore, focused on establishing status and contribution of Nrf2 and MAPK signaling in TCE-mediated inflammatory and autoimmune responses, especially during disease progression. To achieve these objectives, time-response studies were conducted by treating female MRL+/+ mice with TCE (0.5 mg/mL, a dose relevant to human exposure) for 24, 36 and 52 wks. TCE exposure led to reduction in Nrf2 expression, but increased phos-NF-κB (p65) and iNOS along with increased phosphorylation of MAPKs (p38, ERK and JNK) and downstream pro-inflammatory cytokines IL-12, TNF-α and RANTES in the livers in a time-dependent manner. These changes were also associated with time-dependent increases in liver protein carbonyls and induction of serum anti-dsDNA antibodies (marker of systemic lupus erythematosus disease), further supporting the role of oxidative stress and Nrf2/MAPK signaling in TCE-mediated autoimmune response progression. The mechanistic role of MAPK in TCE-mediated autoimmunity was further established by treating MRL+/+ mice with sulforaphane (SFN; 8 mg/kg, i.p., every other day) along with TCE (10 mmol/kg, i.p., every 4th day) for 6 wks using an established protocol, and by in vitro treatment of T cells with dichloroacetyl chloride (a TCE metabolite) with/without p38 MAPK inhibitor. SFN treatment attenuated the TCE-mediated phosphorylation of p38 MAPK. More importantly, treatment with SFN or p38 inhibitor led to suppression of downstream pro-inflammatory cytokines IL-12 and TNF-α. These findings thus support the contribution of Nrf2 and MAPK signaling pathways and help in delineating novel potential therapeutic targets against TCE-mediated autoimmunity.
Topics: Animals; Autoimmune Diseases; Disease Progression; Female; Humans; Jurkat Cells; MAP Kinase Signaling System; Mice; Mice, Transgenic; NF-E2-Related Factor 2; Oxidation-Reduction; Solvents; Trichloroethylene
PubMed: 33930529
DOI: 10.1016/j.tox.2021.152804 -
Applied and Environmental Microbiology Nov 2022Acetylene (CH) is a molecule rarely found in nature, with very few known natural sources, but acetylenotrophic microorganisms can use acetylene as their primary carbon...
Acetylene (CH) is a molecule rarely found in nature, with very few known natural sources, but acetylenotrophic microorganisms can use acetylene as their primary carbon and energy source. As of 2018 there were 15 known strains of aerobic and anaerobic acetylenotrophs; however, we hypothesize there may yet be unrecognized diversity of acetylenotrophs in nature. This study expands the known diversity of acetylenotrophs by isolating the aerobic acetylenotroph, sp. strain I71, from trichloroethylene (TCE)-contaminated soils. Strain I71 is a member of the class and exhibits acetylenotrophic and diazotrophic activities, the only two enzymatic reactions known to transform acetylene. This unique capability in the isolated strain may increase the genus' economic impact beyond agriculture as acetylenotrophy is closely linked to bioremediation of chlorinated contaminants. Computational analyses indicate that the sp. strain I71 genome contains 522 unique genes compared to close relatives. Moreover, applying a novel hidden Markov model of known acetylene hydratase (AH) enzymes identified a putative AH enzyme. Protein annotation with I-TASSER software predicted the AH from the microbe Syntrophotalea acetylenica as the closest structural and functional analog. Furthermore, the putative AH was flanked by horizontal gene transfer (HGT) elements, like that of AH in anaerobic acetylenotrophs, suggesting an unknown source of acetylene or acetylenic substrate in the environment that is selecting for the presence of AH. The isolation of strain I71 expands the distribution of acetylene-consuming microbes to include a group of economically important microorganisms. Members of are well studied for their abilities to improve plant health and increase crop yields by providing bioavailable nitrogen. Additionally, acetylene-consuming microbes have been shown to work in tandem with other microbes to degrade soil contaminants. Based on genome, cultivation, and protein prediction analysis, the ability to consume acetylene is likely not widespread within the genus . These findings suggest that the suite of phenotypic capabilities of strain I71 may be unique and make it a good candidate for further study in several research avenues.
Topics: Bradyrhizobium; Trichloroethylene; Nitrogen Fixation; Soil; Acetylene; Phylogeny; Symbiosis; RNA, Ribosomal, 16S; Root Nodules, Plant; DNA, Bacterial; Sequence Analysis, DNA
PubMed: 36286524
DOI: 10.1128/aem.01219-22 -
International Journal of Environmental... Feb 2022A health risk assessment was carried out for the residents of Łęgnowo-Wieś settlement adjacent to a former Zachem Chemical Plant, Bydgoszcz, Poland. Due to the unique...
A health risk assessment was carried out for the residents of Łęgnowo-Wieś settlement adjacent to a former Zachem Chemical Plant, Bydgoszcz, Poland. Due to the unique Zachem site history and contamination profile, an innovative strategy for soil sampling and contaminant selection was applied. The novelty in the developed strategy consisted of selecting substances for the health risk assessment, taking into consideration the location and boundaries of the groundwater contamination plumes in relation to contamination sources. This allowed limiting the number of the analysed contaminants. The risk assessment focused on the surface soil of a residential area, which was divided into 20 sampling sectors and 6 backyards with wells from which water was used for watering edible plants. A total of 80 inorganic and organic substances were determined, including metals, phenol, aniline, BTEX, diphenyl sulphone, chloroaniline, epichlorohydrin, hydroxybiphenyl, nitrobenzene, octylphenols, toluenediamine, toluidine, 16 polycyclic aromatic hydrocarbons, tetrachloroethylene and trichloroethylene. For the health risk assessment, the United States Environmental Protection Agency's deterministic method was applied. This applies conservative assumptions to obtain risk estimates protective for most of the potential receptors. Three exposure pathways were analysed: (1) incidental soil ingestion, (2) dermal contact with soil and (3) inhalation of fugitive soil particles and volatiles. In all sampling sectors and backyards, the total non-cancer risks (hazard index) were significantly lower than the acceptable level of 1. The acceptable cancer risk level for the single carcinogen of 1 × 10 was only insignificantly exceeded in the case of benzo(a)pyrene in three sectors and one backyard. The total cancer risks were lower than the acceptable level of 1 × 10 in all sampling sectors and all backyards. The findings show that the soil in the entire residential area is safe for the residents' health and no remedial actions are required. However, since not all possible exposure pathways were analysed in this study, further research focused on assessing the health risk resulting from the consumption of locally grown food is strongly recommended.
Topics: Environmental Monitoring; Polycyclic Aromatic Hydrocarbons; Risk Assessment; Soil; Soil Pollutants
PubMed: 35270282
DOI: 10.3390/ijerph19052590 -
International Journal of Occupational... Aug 2022The etiology of exocrine pancreatic cancer (EPC) remains unknown except for family history and smoking. Despite recent medical advances, rates of pancreatic cancer...
OBJECTIVES
The etiology of exocrine pancreatic cancer (EPC) remains unknown except for family history and smoking. Despite recent medical advances, rates of pancreatic cancer incidence and mortality are increasing. Although existing evidence suggests a potentially causal relationship between environmental chemical exposures and pancreatic cancer, whether residential exposure impacts pancreatic cancer rates remains unknown.
MATERIAL AND METHODS
The authors identified 28 941 patients diagnosed with exocrine pancreatic cancer in New York State exclusive of New York City for the years 1996-2013. Descriptive statistics and negative binomial regression were used in this ecological study to compare pancreatic cancer hospitalization rates among patients who lived in zip codes with hazardous waste sites (HWSs) containing persistent organic pollutants (POPs) and volatile organic pollutants (VOCs) compared with clean zip codes with no identified hazardous waste sites. The authors assessed the effect of selected known and suspected human carcinogens on the EPC hospitalization rates by subgroup analyses.
RESULTS
Compared with the clean sites, the pancreatic cancer hospital discharge rate in the "VOCs without POPs" and "VOCs and POPs" sites, after adjustment for potential confounders were 1.06 (95% CI: 1.03-1.09) and 1.05 (95% CI: 1.01-1.08), respectively. In the analysis by specific chemicals, rate ratios (RR) for the benzene (RR = 1.12) and ethylbenzene (RR = 1.34) in the non-chlorinated VOCs group, trichloroethylene (RR = 1.07) and tetrachloroethylene (RR = 1.11) in the chlorinated VOCs group, chlorinated pesticides (RR = 1.11) and PCBs (RR = 1.05) in the POPs groups were statistically significant (p-values <0.05) compared with clean sites.
CONCLUSIONS
Compared with the clean sites, the pancreatic cancer hospital discharge rate in the "VOCs without POPs" and "VOCs and POPs" sites, after adjustment for potential confounders were 1.06 (95% CI: 1.03-1.09) and 1.05 (95% CI: 1.01-1.08), respectively. In the analysis by specific chemicals, rate ratios (RR) for the benzene (RR = 1.12) and ethylbenzene (RR = 1.34) in the non-chlorinated VOCs group, trichloroethylene (RR = 1.07) and tetrachloroethylene (RR = 1.11) in the chlorinated VOCs group, chlorinated pesticides (RR = 1.11) and PCBs (RR = 1.05) in the POPs groups were statistically significant (p-values <0.05) compared with clean sites. Int J Occup Med Environ Health. 2022;35(4):459-71.
Topics: Benzene; Environmental Pollutants; Hazardous Substances; Hazardous Waste; Humans; New York; Pancreatic Neoplasms; Pesticides; Polychlorinated Biphenyls; Tetrachloroethylene; Trichloroethylene
PubMed: 35876351
DOI: 10.13075/ijomeh.1896.01886 -
Toxicological Sciences : An Official... Dec 2019Context-specific GEnome-scale metabolic Network REconstructions (GENREs) provide a means to understand cellular metabolism at a deeper level of physiological detail....
Context-specific GEnome-scale metabolic Network REconstructions (GENREs) provide a means to understand cellular metabolism at a deeper level of physiological detail. Here, we use transcriptomics data from chemically-exposed rat hepatocytes to constrain a GENRE of rat hepatocyte metabolism and predict biomarkers of liver toxicity using the Transcriptionally Inferred Metabolic Biomarker Response algorithm. We profiled alterations in cellular hepatocyte metabolism following in vitro exposure to four toxicants (acetaminophen, carbon tetrachloride, 2,3,7,8-tetrachlorodibenzodioxin, and trichloroethylene) for six hour. TIMBR predictions were compared with paired fresh and spent media metabolomics data from the same exposure conditions. Agreement between computational model predictions and experimental data led to the identification of specific metabolites and thus metabolic pathways associated with toxicant exposure. Here, we identified changes in the TCA metabolites citrate and alpha-ketoglutarate along with changes in carbohydrate metabolism and interruptions in ATP production and the TCA Cycle. Where predictions and experimental data disagreed, we identified testable hypotheses to reconcile differences between the model predictions and experimental data. The presented pipeline for using paired transcriptomics and metabolomics data provides a framework for interrogating multiple omics datasets to generate mechanistic insight of metabolic changes associated with toxicological responses.
Topics: Acetaminophen; Activation, Metabolic; Animals; Biomarkers; Carbon Tetrachloride; Cells, Cultured; Computational Biology; Gene Expression Profiling; Hepatocytes; Male; Metabolic Networks and Pathways; Metabolomics; Polychlorinated Dibenzodioxins; Primary Cell Culture; Rats, Sprague-Dawley; Transcriptome; Trichloroethylene
PubMed: 31501904
DOI: 10.1093/toxsci/kfz197 -
Sangyo Eiseigaku Zasshi = Journal of... Jul 2023To provide an overview of the pathogenesis of pneumatosis cystoides intestinalis (PCI) and hypersensitivity syndrome (HS) caused by trichloroethylene (TCE) and the basic... (Review)
Review
OBJECTIVE
To provide an overview of the pathogenesis of pneumatosis cystoides intestinalis (PCI) and hypersensitivity syndrome (HS) caused by trichloroethylene (TCE) and the basic research into their toxicity.
SUBJECTS AND METHODS
We reviewed previously published research articles.
RESULTS
PCI clustered in Japan in the 1980s is a rare disease characterized by cyst-like distention of gas in the intestinal wall, which can be secondary or primary. No TCE users were found in the former group, whereas approximately 71% of the latter group were TCE users, suggesting the involvement of TCE exposure in primary PCI. However, the pathogenesis was unclear. TCE is metabolized by the drug-metabolizing enzyme CYP2E1, and intermediate immunocomplexes with CYP2E1 may be involved in hepatotoxicity. HS clustered in the southern part of China since early 2000 is a systemic skin-liver disorder involving anti-CYP2E1 autoantibodies and HLA-B*13:01 polymorphisms, with elevated cytokines and reactivation of Human Herpesvirus 6.
DISCUSSION AND CONCLUSION
PCI and HS, occupational diseases caused by TCE, were clustered in Japan and southern China, respectively. HS was mediated by immune system disorders and genetic polymorphisms, whereas their relevance to PCI occurrence remained unknown.
Topics: Humans; Trichloroethylene; Occupational Diseases; Drug Hypersensitivity Syndrome; Skin Diseases; Liver
PubMed: 37211415
DOI: 10.1539/sangyoeisei.2023-010-A -
Environmental Epidemiology... Apr 2021Environmental pollutants have been associated with hypertensive disorders in pregnancy including gestational hypertension, preeclampsia, and eclampsia, though few have...
UNLABELLED
Environmental pollutants have been associated with hypertensive disorders in pregnancy including gestational hypertension, preeclampsia, and eclampsia, though few have focused on drinking water contamination. Water pollution can be an important source of exposures that may contribute to adverse pregnancy outcomes.
METHODS
We linked water quality data on 13 contaminants and two violations from the California Communities Environmental Health Screening Tool to birth records from vital statistics and hospital discharge records (2007-2012) to examine the relationship between drinking water contamination and hypertensive disorders in pregnancy. We examined contaminants in single- and multipollutant models. Additionally, we examined if the relationship between water contamination and hypertensive disorders in pregnancy differed by neighborhood poverty, individual socioeconomic status, and race/ethnicity.
RESULTS
Arsenic, nitrate, trihalomethane, hexavalent chromium, and uranium were detected in a majority of water systems. Increased risk of hypertensive disorders in pregnancy was modestly associated with exposure to cadmium, lead, trihalomethane, and hexavalent chromium in drinking water after adjusting for covariates in single pollutant models with odds ratios ranging from 1.01 to 1.08. In multipollutant models, cadmium was consistent, lead and trihalomethane were stronger, and additional contaminants were associated with hypertensive disorders in pregnancy including trichloroethylene, 1,2-Dibromo-3-chloropropane, nitrate, and tetrachloroethylene. Other contaminants either showed null results or modest inverse associations. The relationship between water contaminants and hypertensive disorders in pregnancy did not differ by neighborhood poverty.
CONCLUSIONS
We found increased risk of hypertensive disorders in pregnancy associated with exposure to several contaminants in drinking water in California. Results for cadmium, lead, trihalomethane, and hexavalent chromium were robust in multipollutant models.
PubMed: 33870020
DOI: 10.1097/EE9.0000000000000149 -
International Journal of Environmental... Apr 2021Non-Hodgkin lymphoma (NHL), multiple myeloma and chronic lymphocytic leukemia are possibly related to environmental and/or occupational exposure. The primary objective...
Non-Hodgkin lymphoma (NHL), multiple myeloma and chronic lymphocytic leukemia are possibly related to environmental and/or occupational exposure. The primary objective of this study was to develop a questionnaire for screening patients with these blood disorders who might benefit from a specialized consultation for possible recognition of the disease as an occupational disease. The study included 205 subjects (male gender, 67.3%; mean age, 60 years; NHL, 78.5%). The questionnaire performed very satisfactorily in identifying the exposures most frequently retained by experts for their potential involvement in the occurrence of NHL. Its sensitivity and specificity in relation to the final expertise were 96% and 96% for trichloroethylene, 85% and 82% for benzene, 78% and 87% for solvents other than trichloroethylene and dichloromethane, 87% and 95% for pesticides, respectively. Overall, 15% of the subjects were invited to ask National Social Insurance for compensation as occupational disease. These declarations concerned exposure to pesticides (64%), solvents (trichloroethylene: 29%; benzene: 18%; other than chlorinated solvents: 18%) and sometimes multiple exposures. In conclusion, this questionnaire appears as a useful tool to identify NHL patients for a specialized consultation, in order to ask for compensation for occupational disease.
Topics: Case-Control Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Occupational Diseases; Occupational Exposure; Risk Factors; Surveys and Questionnaires
PubMed: 33920383
DOI: 10.3390/ijerph18084008