An Emerging Role for Epigenetic Dysregulation in Arsenic Toxicity and Carcinogenesis

Abstract

BackgroundExposure to arsenic, an established human carcinogen, through consumption of highly contaminated drinking water is a worldwide public health concern. Several mechanisms by which arsenical compounds induce tumorigenesis have been proposed, including oxidative stress, genotoxic damage, and chromosomal abnormalities. Recent studies have suggested that epigenetic mechanisms may also mediate toxicity and carcinogenicity resulting from arsenic exposure.ObjectiveWe examined the evidence supporting the roles of the three major epigenetic mechanisms—DNA methylation, histone modification, and microRNA (miRNA) expression—in arsenic toxicity and, in particular, carcinogenicity. We also investigated future research directions necessary to clarify epigenetic and other mechanisms in humans.Data sources and synthesisWe conducted a PubMed search of arsenic exposure and epigenetic modification through April 2010 and summarized the in vitro and in vivo research findings, from both our group and others, on arsenic-associated epigenetic alteration and its potential role in toxicity and carcinogenicity.ConclusionsArsenic exposure has been shown to alter methylation levels of both global DNA and gene promoters; histone acetylation, methylation, and phosphorylation; and miRNA expression, in studies analyzing mainly a limited number of epigenetic end points. Systematic epigenomic studies in human populations exposed to arsenic or in patients with arsenic-associated cancer have not yet been performed. Such studies would help to elucidate the relationship between arsenic exposure, epigenetic dysregulation, and carcinogenesis and are becoming feasible because of recent technological advancements.

Diurnal expression ofDnmt3bmRNA in mouse liver is regulated by feeding and hepatic clockwork

“…56 Aberrant DNA methylation levels have been found to be associated with the onset and progression of adult-onset metabolic diseases. 3,4,13,56,57 Thus, we can speculate that the higher Dnmt3b expression and the temporarily higher DNA methylation state, as that Dnmt3b mRNA receives posttranscriptional regulation along with the time of day. Further study based on these hypotheses will be required to unveil the mechanism of diurnal variation of Dnmt3b transcription.…”

“…3 Some agents are known to alter the DNA methylation state by changing the level of expression of Dnmt and/or by modifying the enzymatic activity of DNMT. 3,13 Transcription of Dnmt3a and Dnmt3b is reported to be regulated by the ubiquitous transcription factors specific protein 1 (Sp1) and Sp3.…”

Dietary methyl-consuming compounds and metabolic syndrome

“…The mechanism underlying arsenic toxicity is believed to be due to methyl depletion-induced aberrant DNA methylation, and excessive ROS generation and subsequent oxidative cell injury. [40][41][42]45 Niacin Niacin (nicotinic acid and nicotinamide) is a water-soluble vitamin and a common methyl consumer. 46 Dietary nicotinic acid is derived from plant foods, while nicotinamide is derived from animal foods and typically used for food fortification.…”

“…Excessive methyl consumer-induced methyl depletion may affect DNA methylation status, as observed in arsenic exposure. 45 Moreover, some secondary factors may contribute substantially to the development of the disease. These factors include: (1) other ROS-generating xenobiotics or compounds, such as alcohol, (2) chronic mental stress and (3) lifestyle-related factors such as high fat intake, low vegetable intake and decreased skin functions (primarily sweat elimination) (Figure 1).…”

Quantitative Mass Spectrometry Reveals Changes in Histone H2B Variants as Cells Undergo Inorganic Arsenic-Mediated Cellular Transformation

“…A number of studies have demonstrated that iAs exposure induces global and gene-specific post-translational histone modifications such as reduction of acetylation in histone H3 and H4: loss of H4Lys 16 10 and H2AX phosphorylation, and decreases in H2B ubiquitination (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”