Arsenic-Associated Changes to the Epigenome: What Are the Functional Consequences?

Abstract

Inorganic arsenic (iAs) poses a major threat to worldwide human health, and yet the molecular mechanisms underlying the toxic effects associated with iAs exposure are not well understood. There is increasing experimental evidence indicating that epigenetic modifications may play a major role in the development of diseases associated with exposure to environmental toxicants. Research in the field has firmly established that iAs exposure is associated with epigenetic alterations including changes in DNA methylation, miRNA abundance, and post-translational histone modifications. Here, we summarize recent studies that have expanded the current knowledge of these relationships. These studies have pinpointed specific regions of the genome and genes that are targets of arsenical-induced epigenetic changes, including those associated with in utero iAs exposure. The recent literature indicates that iAs biotransformation likely plays an important role in the relationship between iAs exposure and the epigenome, in addition to the sex and genetic background of individuals. The research also shows that relatively low to moderate exposure to iAs is associated with epigenetic effects. However, while it is well established that arsenicals can alter components of the epigenome, in many cases, the biological significance of these alterations remains unknown. The manner by which these and future studies may help inform the role of epigenetic modifications in the development of iAs-associated disease is evaluated and the need for functional validation emphasized.

Keywords: Arsenic; DNA methylation; Epigenetic reprogramming; Epigenome; Histone post-translational modifications; MicroRNAs; Prenatal exposure.

Fig. 1

Arsenic biotransformation in humans. Worldwide, the most prevalent source of arsenic exposure in humans is drinking water contaminated with inorganic arsenic (iAs), which exists in two oxidation states, namely pentavalent arsenate (iAs^V) and trivalent arsenite (iAs^III). IAs^V is reduced to iAs^III mainly in the blood or liver by one of several mammalian enzymes that utilize glutathione (GSSH) or dithiothreitol (DTT) as reductants. The remaining steps of iAs biotransformation, which involve alternating oxidative methylation and reduction steps, occur mainly in the liver. In this process, iAs^III undergoes an oxidative methylation step catalyzed by arsenic (+3 oxidation state) methyltransferase (AS3MT) to produce monomethylarsonic acid (MMA^V). MMA^V is subsequently reduced to monomethylarsonous acid (MMA^III), which is the substrate for another round of oxidative methylation and reduction in which dimethylarsinic acid (DMA^V) and dimethylarsinous acid (DMA^III), respectively, are produced. AS3MT has been shown to catalyze both the oxidative methylation and successive reduction reactions using s-adenosyl methionine (SAM) as a methyl donor and various molecules such as nicotinamide adenine dinucleotide phosphate (NADPH), thioredoxin, DTT, or GSH as reductants (2e^-) [43, 45]. In general, total urinary arsenic in iAs-exposed individuals is composed of 10–20 % total (i.e. trivalent + pentavalent) iAs, 10–20 % total MMAs, and 60–80 % total DMAs [44]. (Modified from: Bailey KA and Fry RC, Arsenic-induced Changes to the Epigenome, in Toxicology and Epigenetics, S.C. Sahu, Editor. 2012, John Wiley & Sons, Ltd.: Chichester, UK) [22]