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Blood methylomics in response to arsenic exposure in a low-exposed US population.

ABSTRACT: Exposure to arsenic (As) has been associated with a number of diseases such as cancers, cardiovascular diseases (CVD), and neurological disorders. To explore the possible underlying epigenetic mechanisms, a nested case-control study was conducted within the Coronary Artery Risk Development in Young Adults (CARDIA) study by randomly selecting 46 non-smoker and non-diabetic White participants with low (N=23) and high (N=23) As exposure based on toenail total As measures at examination year 2. We conducted methylomic profiling of white blood cell (WBC) DNA collected at examination year 15 using the Illumina HumanMethylation450 BeadChip, and performed association tests using multiple linear regression models adjusting for age, sex, and estimated WBC proportions. We observed 22 CpG sites with methylation levels associated with high As exposure at a nominal significance level of 10(-4). However, the statistical significance disappeared after correction for multiple testing. Some genes annotated by these 22 CpG sites are known to be involved in As-associated diseases. Replication in larger samples of individuals with low levels of As exposure will be required.

SUBMITTER: Liu X

PROVIDER: S-EPMC4167014 | biostudies-literature | 2014 Mar-Apr

REPOSITORIES: biostudies-literature

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Blood methylomics in response to arsenic exposure in a low-exposed US population.

Liu Xin X Zheng Yinan Y Zhang Wei W Zhang Xiao X Lioyd-Jones Donald M DM Baccarelli Andrea A AA Ning Hongyan H Fornage Myriam M He Ka K Liu Kiang K Hou Lifang L

Journal of exposure science & environmental epidemiology 20131225 2

Exposure to arsenic (As) has been associated with a number of diseases such as cancers, cardiovascular diseases (CVD), and neurological disorders. To explore the possible underlying epigenetic mechanisms, a nested case-control study was conducted within the Coronary Artery Risk Development in Young Adults (CARDIA) study by randomly selecting 46 non-smoker and non-diabetic White participants with low (N=23) and high (N=23) As exposure based on toenail total As measures at examination year 2. We c ...[more]

PMID: 24368509

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Project description:Arsenic, a carcinogen with immunotoxic effects, is a common contaminant of drinking water and certain food worldwide. We hypothesized that chronic arsenic exposure alters gene expression, potentially by altering DNA methylation of genes encoding central components of the immune system. We therefore analyzed the transcriptomes (by RNA sequencing) and methylomes (by target-enrichment next-generation sequencing) of primary CD4-positive T cells from matched groups of four women each in the Argentinean Andes, with fivefold differences in urinary arsenic concentrations (median concentrations of urinary arsenic in the lower- and high-arsenic groups: 65 and 276 μg/l, respectively). Arsenic exposure was associated with genome-wide alterations of gene expression; principal component analysis indicated that the exposure explained 53% of the variance in gene expression among the top variable genes and 19% of 28,351 genes were differentially expressed (false discovery rate <0.05) between the exposure groups. Key genes regulating the immune system, such as tumor necrosis factor alpha and interferon gamma, as well as genes related to the NF-kappa-beta complex, were significantly downregulated in the high-arsenic group. Arsenic exposure was associated with genome-wide DNA methylation; the high-arsenic group had 3% points higher genome-wide full methylation (>80% methylation) than the lower-arsenic group. Differentially methylated regions that were hyper-methylated in the high-arsenic group showed enrichment for immune-related gene ontologies that constitute the basic functions of CD4-positive T cells, such as isotype switching and lymphocyte activation and differentiation. In conclusion, chronic arsenic exposure from drinking water was related to changes in the transcriptome and methylome of CD4-positive T cells, both genome wide and in specific genes, supporting the hypothesis that arsenic causes immunotoxicity by interfering with gene expression and regulation.

Project description:BackgroundChronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes.ObjectivesWe investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, mean (±SD) μg/g creatinine: 11.7 (10.6)].MethodsDNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species.ResultsIn adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (FDR< 0.05). After Bonferroni correction, 5 CpGs remained associated with total urinary As (pBonferroni<0.05), located in SLC7A11, ANKS3, LINGO3, CSNK1D, ADAMTSL4. We identified one DMR on chromosome 11 (chr11:2,322,050-2,323,247), annotated to C11orf2; TSPAN32 genes.DiscussionThis is one of the first epigenome-wide association studies to investigate As exposure and locus-specific DNA methylation using the Illumina MethylationEPIC array and the largest epigenome-wide study of As exposure. The top DMP was located in SLC7A11A, a gene involved in cystine/glutamate transport and the biosynthesis of glutathione, an antioxidant that may protect against As-induced oxidative stress. Additional DMPs were located in genes associated with tumor development and glucose metabolism. Further research is needed, including research in more diverse populations, to investigate whether As-related DNA methylation signatures are associated with gene expression or may serve as biomarkers of disease development. https://doi.org/10.1289/EHP6263.

Project description:BackgroundArsenicals (roxarsone and nitarsone) used in poultry production likely increase inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and roxarsone or nitarsone concentrations in poultry meat. However, the association between poultry intake and exposure to these arsenic species, as reflected in elevated urinary arsenic concentrations, is unknown.ObjectivesOur aim was to evaluate the association between 24-hr dietary recall of poultry consumption and arsenic exposure in the U.S. population. We hypothesized first, that poultry intake would be associated with higher urine arsenic concentrations and second, that the association between turkey intake and increased urine arsenic concentrations would be modified by season, reflecting seasonal use of nitarsone.MethodsWe evaluated 3,329 participants ? 6 years old from the 2003-2010 National Health and Nutrition Examination Survey (NHANES) with urine arsenic available and undetectable urine arsenobetaine levels. Geometric mean ratios (GMR) of urine total arsenic and DMA were compared across increasing levels of poultry intake.ResultsAfter adjustment, participants in the highest quartile of poultry consumption had urine total arsenic 1.12 (95% CI: 1.04, 1.22) and DMA 1.13 (95% CI: 1.06, 1.20) times higher than nonconsumers. During the fall/winter, participants in the highest quartile of turkey intake had urine total arsenic and DMA 1.17 (95% CI: 0.99, 1.39; p-trend = 0.02) and 1.13 (95% CI: 0.99, 1.30; p-trend = 0.03) times higher, respectively, than nonconsumers. Consumption of turkey during the past 24 hr was not associated with total arsenic or DMA during the spring/summer.ConclusionsPoultry intake was associated with increased urine total arsenic and DMA in NHANES 2003-2010, reflecting arsenic exposure. Seasonally stratified analyses by poultry type provide strong suggestive evidence that the historical use of arsenic-based poultry drugs contributed to arsenic exposure in the U.S.CitationNigra AE, Nachman KE, Love DC, Grau-Perez M, Navas-Acien A. 2017. Poultry consumption and arsenic exposure in the U.S. Environ Health Perspect 125:370-377; http://dx.doi.org/10.1289/EHP351.

Dataset Information

Blood methylomics in response to arsenic exposure in a low-exposed US population.

Publications

Blood methylomics in response to arsenic exposure in a low-exposed US population.

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