Metabolic interactions between arsenic, folate, and selenium and their impact on genomic DNA methylation

Introduction. Chronic arsenic (As) exposure currently affects more than 100 million people worldwide. The studies reported in this dissertation focus primarily on determining if arsenic (As) exposure is associated with genomic DNA methylation and if this association is modified by folate nutritional status among Bangladeshi adults. Furthermore, this thesis investigates if folate and homocysteine concentrations and/or genomic DNA methylation serve as risk factors for As-induced premalignant skin lesions. Additional analyses investigate if plasma selenium concentrations are associated with As concentrations, its metabolites and/or genomic DNA methylation.;Methods. To investigate these questions, three epidemiological studies were employed. First, a cross-sectional study was conducted to determine if As exposure was associated with genomic DNA methylation, and if this association was modified by folate and/or selenium nutritional status (Chapters II and III). Next, we conducted a 12 week randomized, double-blind, placebo-controlled trial of folic acid supplementation to folate-deficient Bangladeshi adults to determine if folic acid increased genomic DNA methylation (Chapter IV). Finally, a nested-case control study was employed to determine if plasma folate or homocysteine concentrations and/or genomic methylation of peripheral blood leukocytes (PBL) DNA were associated with the risk for subsequent development of As-induced premalignant skin lesions (Chapter V).;Results. The work presented in the cross-sectional study indicates that As exposure is positively associated with genomic methylation of PBL DNA in a dose-dependent manner, and furthermore that this association is modified by folate nutritional status. Our data also suggests that plasma selenium plays a role in facilitating the secondary methylation step in As biotransformation. Plasma selenium was also found to be inversely related to (a) the extent of genomic methylation of PBL DNA and (b) to plasma folate concentrations. Our folic acid supplementation trial revealed that folic acid treatment to individuals with marginal folate nutritional status appears to prevent further declines in genomic DNA methylation over time that were observed in the placebo group. Finally, the findings in this thesis suggest that, for a given As exposure, folate deficiency, hyperhomocysteinemia, and hypomethylation of genomic PBL DNA are risk factors for; whereas urinary creatinine is protective against, the subsequent development of As-induced skin lesions.;Taken together, the findings in this thesis demonstrate the importance of folate and selenium nutritional status in regard to the methylation of As and DNA among Bangladeshi adults chronically exposed to As in drinking water. Further, the results from this thesis suggest that indices of one-carbon metabolism and genomic methylation of PBL DNA may be modifiable risk factors for As-induced skin lesions. Collectively, the implication of these findings is that FA has enormous therapeutic potential for ameliorating the long-term health consequences of As exposure for the many populations at risk.;Background. Arsenic contamination of drinking water in Bangladesh is considered by the World Health Organization to be the largest mass poisoning in history. It is estimated that in Bangladesh alone, 30-36 million people are chronically exposed to As concentrations exceeding 50 mug/L, the current standard for As in Bangladesh. Clinical manifestations of chronic As exposure include cancers of the skin, liver, lung and bladder as well as cardiovascular disease and diabetes. Despite well known clinical outcomes, the mechanism(s) of As-induced toxicity still remain unclear and are likely multifactorial. Aberrations in genomic DNA methylation, resulting in loss of genomic stability and inactivation of tumor-suppressor genes, play an integral role in carcinogenesis. Folate, a B vitamin, is an essential component of the one-carbon metabolic pathway, which provides carbon groups for nucleic acid synthesis and for numerous methylation reactions including As and DNA methylation. Animal and in vitro studies have indicated that As exposure induces genomic hypomethylation of DNA, which is exacerbated by folate deficiency. The biotransformation of selenium and InAs involves reduction and methylation reactions. The former is thought to be mediated by glutathione and/or thioredoxin; the latter are mediated by folate-dependent one-carbon metabolism. Animal studies indicate that selenium deficiency causes genomic DNA hypomethylation. To date, however, the influence of As exposure on genomic DNA methylation, and the potential modification by folate and/or selenium nutritional status, have not been investigated in human populations. Furthermore, it has not been determined if these factors influence the risk for As-induced health outcomes.