title: Differential methylation of the arsenic (III) methyltransferase promoter according to arsenic exposure.
abstract: Inorganic arsenic is methylated in the body by arsenic (III) methyltransferase (AS3MT). Arsenic methylation is thought to play a role in arsenic-related epigenetic phenomena, including aberrant DNA and histone methylation. However, it is unclear whether the promoter of the AS3MT gene, which codes for AS3MT, is differentially methylated as a function of arsenic exposure. In this study, we evaluated AS3MT promoter methylation according to exposure, assessed by urinary arsenic excretion in a stratified random sample of 48 participants from the Strong Heart Study who had urine arsenic measured at baseline and DNA available from 1989 to 1991 and 1998-1999. For this study, all data are from the 1989-1991 visit. We measured AS3MT promoter methylation at its 48 CpG loci by bisulphite sequencing. We compared mean  % methylation at each CpG locus by arsenic exposure group using linear regression adjusted for study centre, age and sex. A hypomethylated region in the AS3MT promoter was associated with higher arsenic exposure. In vitro, arsenic induced AS3MT promoter hypomethylation, and it increased AS3MT expression in human peripheral blood mononuclear cells. These findings may suggest that arsenic exposure influences the epigenetic regulation of a major arsenic metabolism gene.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Matthew O
authors.initials: MO
authors.lastname: Gribble
authors.forename: Wan-Yee
authors.initials: WY
authors.lastname: Tang
authors.forename: Yan
authors.initials: Y
authors.lastname: Shang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pollak
authors.forename: Jason G
authors.initials: JG
authors.lastname: Umans
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Francesconi
authors.forename: Walter
authors.initials: W
authors.lastname: Goessler
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Silbergeld
authors.forename: Eliseo
authors.initials: E
authors.lastname: Guallar
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.forename: M Daniele
authors.initials: MD
authors.lastname: Fallin
authors.forename: Ana
authors.initials: A
authors.lastname: Navas-Acien
mesh_terms: D000368:Aged; D001151:Arsenic / Q000633:toxicity* / Q000652:urine*; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000187:drug effects*
chemical_list: D008780:Methyltransferases; C505756:AS3MT protein, human; D001151:Arsenic