Relationships among Inorganic Arsenic, Nutritional Status CpG Methylation and microRNAs: A Review of the Literature

Abstract

Inorganic arsenic is a naturally occurring toxicant that poses a significant and persistent challenge to public health. The World Health Organization has identified many geographical regions where inorganic arsenic levels exceed safe limits in drinking water. Numerous epidemiological studies have associated exposure to inorganic arsenic with increased risk of adverse health outcomes. Randomized clinical trials have shown that nutritional supplementation can mitigate or reduce exacerbation of exposure-related effects. Although a growing body of evidence suggests that epigenetic status influences toxicity, the relationships among environmental exposure to arsenic, nutrition, and the epigenome are not well detailed. This review provides a comprehensive summary of findings from human, rodent, and in vitro studies highlighting these interactive relationships.

The Role of the Nuclear Receptor FXR in Arsenic-Induced Glucose Intolerance in Mice

“…Our observation that arsenic exposure reduced hepatic CYP7B1 is consistent with previous studies with various arsenic doses in mice [45][46][47]. CYP7B1 is one of the cytochrome P450 (CYP) monooxygenases that is involved in the biosynthesis of bile acids, oxysterols, and steroid hormones by consuming cholesterol.…”

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…Despite the abundant literature on the toxicity of arsenic [273][274][275] and the existing regulatory measures taken by numerous agencies (e.g., maximum drinking water contamination level of 10 µg/L (10 ppb or 0.13 µM) set by the World Health Organization and US-EPA [276]), the toxicity of this metal is still an important risk assessment research topic. This is because: (1) it is present naturally in the environment and as waste in mining industries [277], (2) inorganic arsenic levels exceed safe limits in drinking water in more than 50 countries [278], (3) reasons for interindividual disease susceptibility to arsenic must be understood [278], (4) mitigation [278] or remediation nutritional supports are required for the exposed population [273], and (5), understanding the extent of genotoxic and non-genotoxic mechanisms contributing to its carcinogenic mode of action is important given that this might influence regulatory measures and treatment intervention for correctable non-genotoxic epigenetic anomalies. Finally, numerous epigenetic anomalies described in the following paragraphs and in the Supplementary Tables S2 and S3 occur at physiologically relevant concentrations (human whole-blood levels of total arsenic range from 0 to 46.5 µg/L or 0.6 µM) [279].…”

“…There are sex differences in the one-carbon metabolism pathway generating SAM necessary to methylate arsenicals [321], such that men are at a higher risk of developing skin lesions due to the lower methylation rate of MMA to DMA [322]. Differences in arsenic metabolism, nutrition and micronutrients (e.g., methionine, choline, folate, betaine, and vitamin B12) are known to affect DNAm [273,321]. Timing of sampling relative to exposure and disease status may also influence detection of associations.…”