Mechanisms of Arsenic Toxicity in Humans: Interplay of Arsenic, Glutathione, and DNA Methylation in Bangladeshi Adults

摘要: Mechanisms of Arsenic Toxicity in Humans: Interplay Arsenic, Glutathione, and DNA Methylation Bangladeshi Adults Megan Marie Niedzwiecki Background: Over 200 million individuals worldwide are chronically exposed to arsenic (As) drinking water at concentrations above the World Health Organization (WHO) guideline 10 μg/L. exposure is particular concern Bangladesh, where it estimated that 35-77 people As well WHO guideline. Chronic associated with neurological impairments, respiratory disease, cardiovascular skin lesions, cancers skin, liver, lung bladder. The mechanisms toxicity humans not well-characterized: there considerable interspecies differences toxicokinetics, until recently, were no animal models study carcinogenesis. However, two several proposed pathways involve methylation oxidative stress. metabolism, methylation, glutathione (GSH) metabolically connected through one-carbon metabolism transsulfuration pathways, their interactions remarkably complex. epidemiologic studies this dissertation designed address overarching hypothesis pathway interact influence susceptibility toxicity. Introduction: methylated liver monomethyl (MMA) dimethyl (DMA) arsenical species by arsenic(III)-methyltransferase (AS3MT), which requires a methyl group from S-adenosylmethionine (SAM) presence reductant, such as (GSH). SAM universal donor for transmethylation reactions, including product folate-dependent metabolism. GSH primary endogenous antioxidant determinant intracellular redox state, rate-limiting precursor synthesis, cysteine (Cys), pathway. One-carbon homocysteine (Hcys). In humans, aberrant stress, hyperhomocysteinemia (HHcys), impaired capacity have been identified risk factors As-related conditions, As-induced lesions. knowledge gaps regarding relationships among these namely (1) dose-response relationship between chronic global over wide range concentrations, on newly-discovered epigenetic modification, 5-hydroxymethylcytosine (5hmC); (2) whether an oxidized state impairs methylate DNA; (3) variants genes HHcys Methods: We addressed questions five self-contained epidemiological Asexposed adults, employed cross-sectional (Chapters 3-6) nested casecontrol (Chapter 7) designs. First, we examined peripheral blood mononuclear cell (PBMC) 3). Second, optimized high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay measure 5-methylcytosine (5mC) 5hmC content human samples, associations %mC %hmC independent samples As-exposed adults 4). Third, measured its “oxidized” form, disulfide (GSSG) plasma, interaction plasma folate nutritional status 5). Fourth, redox, SAM, PBMC 6). Fifth, conducted case-control determine nonsynonymous single nucleotide polymorphisms (SNPs) methylene-tetrahydrofolate reductase (MTHFR) other precancerous exploratory genome-wide association (GWAS) Hcys subset participants. Results: was increased 3), but gender-specific, positive males negative females found both decreased 5) hypomethylation Finally, nested-case control study, confirmed previous findings serum factor gene MTHFR explain substantial proportion variance 7). did find GWAS one genomewide significant SNP pregnane X receptor (PXR) gene, along SNPs involved signaling establishment epithelial polarity. Taken together, our suggest indices pathway—DNA methylation—interact another humans. addition, knowledge, first report 5hmC.