Sex-Specific Associations of Arsenic Exposure with Global DNA Methylation and Hydroxymethylation in Leukocytes: Results from Two Studies in Bangladesh

Background: Depletion of global 5-hydroxymethylcytosine (5-hmC) is observed in human cancers and is strongly implicated in skin cancer development. Although arsenic (As)—a class I human carcinogen linked to skin lesion and cancer risk—is known to be associated with changes in global %5-methylcytosine (%5-mC), its influence on 5-hmC has not been widely studied. Methods: We evaluated associations of As in drinking water, urine, and blood with global %5-mC and %5-hmC in two studies of Bangladeshi adults: (i) leukocyte DNA in the Nutritional Influences on Arsenic Toxicity study (n = 196; 49% male, 19–66 years); and (ii) peripheral blood mononuclear cell DNA in the Folate and Oxidative Stress study (n = 375; 49% male, 30–63 years). Results: Overall, As was not associated with global %5-mC or %5-hmC. Sex-specific analyses showed that associations of As exposure with global %5-hmC were positive in males and negative in females (P for interaction < 0.01). Analyses examining interactions by elevated plasma total homocysteine (tHcys), an indicator of B-vitamin deficiency, found that tHcys also modified the association between As and global %5-hmC (P for interaction < 0.10). Conclusion: In two samples, we observed associations between As exposure and global %5-hmC in blood DNA that were modified by sex and tHcys. Impact: Our findings suggest that As induces sex-specific changes in 5-hmC, an epigenetic mark that has been associated with cancer. Future research should explore whether altered %5-hmC is a mechanism underlying the sex-specific influences of As on skin lesion and cancer outcomes. Cancer Epidemiol Biomarkers Prev; 24(11); 1748–57. ©2015 AACR.