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. 2013 Feb;27(2):106-15.
doi: 10.1002/jbt.21462. Epub 2013 Jan 11.

Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation

Kathryn A Bailey  1 , Michael C Wu, William O Ward, Lisa Smeester, Julia E Rager, Gonzalo García-Vargas, Luz-Maria Del Razo, Zuzana Drobná, Miroslav Stýblo, Rebecca C Fry
Affiliations

Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation

Kathryn A Bailey et al. J Biochem Mol Toxicol. 2013 Feb.

Abstract

Biotransformation of inorganic arsenic (iAs) is one of the factors that determines the character and magnitude of the diverse detrimental health effects associated with chronic iAs exposure, but it is unknown how iAs biotransformation may impact the epigenome. Here, we integrated analyses of genome-wide, gene-specific promoter DNA methylation levels of peripheral blood leukocytes with urinary arsenical concentrations of subjects from a region of Mexico with high levels of iAs in drinking water. These analyses revealed dramatic differences in DNA methylation profiles associated with concentrations of specific urinary metabolites of arsenic (As). The majority of individuals in this study had positive indicators of As-related disease, namely pre-diabetes mellitus or diabetes mellitus (DM). Methylation patterns of genes with known associations with DM were associated with urinary concentrations of specific iAs metabolites. Future studies will determine whether these DNA methylation profiles provide mechanistic insight into the development of iAs-associated disease, predict disease risk, and/or serve as biomarkers of iAs exposure in humans.

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Figures

FIGURE 1
FIGURE 1
Venn diagram illustrating the number of genes that have a statistically significant association between promoter DNA methylation levels and urinary concentrations of iAs, MMAs and/or DMAs. The five most significant canonical pathways associated with the genes in each group are displayed. Major functions associated with these pathways include: 1cellular growth and development, 2inflammatory response/immune response; 3nuclear receptor signaling, 4cellular stress/injury, 5carbohydrate metabolism, 6intercellular/intracellular signaling, and 7apoptosis.
FIGURE 2
FIGURE 2
Hierarchical clustering of the association coefficients of 812 unique genes that had a statistically significant association between promoter DNA methylation status and concentrations of iAs, MMAs, and/or DMAs in urine. The number of genes that were positively and negatively correlated with concentrations of arsenical is indicated (# positive/# negative) and represented by red and blue tones, respectively.
FIGURE 3
FIGURE 3
Promoter DNA methylation levels of diabetes mellitus (DM)-associated genes correlated with urinary concentrations (ng/ml) of iAs, MMAs, and/or DMAs. DM-associated genes include those involved in (A) pancreatic β-cell apoptosis particularly related to T1DM and (B) insulin signaling/insulin resistance in peripheral tissues that are primarily associated with T2DM. Genes with promoter DNA methylation levels that had a positive or negative association with urinary arsenical concentrations are shaded in red and green, respectively.
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