An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis.
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.


METHODS
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.
Ren
Xuefeng
X
Division of Environmental Health Sciences, School of Public Health, University of California–Berkeley, Berkeley, California 94720, USA. xfr@berkeley.edu
McHale
Cliona M
CM
Skibola
Christine F
CF
Smith
Allan H
AH
Smith
Martyn T
MT
Zhang
Luoping
L
D001151:Arsenic / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002274:Carcinogens, Environmental / Q000633:toxicity*; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000032:analysis; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D018384:Oxidative Stress
D002274:Carcinogens, Environmental; D006657:Histones; D035683:MicroRNAs; D001151:Arsenic