Academic journal article Environmental Health Perspectives

An Emerging Role for Epigenetic Dysregulation in Arsenic Toxicity and Carcinogenesis

Academic journal article Environmental Health Perspectives

An Emerging Role for Epigenetic Dysregulation in Arsenic Toxicity and Carcinogenesis

Article excerpt

BACKGROUND: Exposure 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.

OBJECTIVE: We 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 SYNTHESIS: We 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.

CONCLUSIONS: Arsenic 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.

KEY WORDS: arsenic carcinogenesis, arsenical compounds, DNA methylation, epigenetics, histone modification, microRNA. Environ Health Perspect 119:11-19 (2011). doi:10.1289/ehp.1002114 [Online 2 August 2010]

The International Agency for Research on Cancer (IARC) classified arsenic, a toxic metalloid, as a group 1 carcinogen > 20 years ago (IARC 1987). It is widely accepted that exposure to arsenic is associated with lung, bladder, kidney, liver, and nonmelanoma skin cancers (IARC 2004; Pershagen 1981; Smith et al. 1992; Smith and Steinmaus 2009). High levels of arsenic have also been associated with the development of several other diseases and deleterious health effects in humans, such as skin lesions (dyspigmentation, keratosis), peripheral vascular diseases, reproductive toxicity, and neurological effects (Abernathy et al. 1999).

Exposure to arsenic typically results from either oral arsenic consumption through contaminated drinking water, soil, and food, or arsenic inhalation in an industrial work setting. Arsenic-contaminated drinking water has been associated with increased mortality of bladder and lung cancer in Chile (Marshall et al. 2007) and with increased mortality of both noncancerous causes and cancers in Bangladesh (Sohel et al. 2009). In the human arsenic metabolic pathway, inorganic pentavalent arsenic ([As.sup.V]) is converted to trivalent arsenic ([As.sup.III]), with subsequent methylation to monomethylated and dimethylated arsenicals (MMA, DMA, respectively) (Drobna et al. 2009). The general scheme is as follows:

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Methylated arsenicals, especially [MMA.sup.III], are considered more toxic than inorganic [As.sup.III] both in vivo (in animals) (Petrick et al. 2001) and in vitro (human cell lines) (Styblo et al. 2002). Several mechanisms by which arsenical compounds induce tumorigenesis have been proposed, including oxidative stress (Kitchin and Wallace 2008), genotoxic damage and chromosomal abnormalities (Moore et al. 1997a; Zhang et al. 2007a), and cocarcinogenesis with other environmental toxicants (Rossman et al. 2004); epigenetic mechanisms, in particular, have been reported to alter DNA methylation (Zhao et al. …

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