title: Association of AS3MT polymorphisms and the risk of premalignant arsenic skin lesions.
abstract: Exposure to naturally occurring inorganic arsenic (iAs), primarily from contaminated drinking water, is considered one of the top environmental health threats worldwide. Arsenic (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in the biotransformation pathway of iAs. AS3MT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to trivalent arsenicals, resulting in the production of methylated (MAs) and dimethylated arsenicals (DMAs). MAs is a susceptibility factor for iAs-induced toxicity. In this study, we evaluated the association of the polymorphism in AS3MT gene with iAs metabolism and with the presence of arsenic (As) premalignant skin lesions. This is a case-control study of 71 cases with skin lesions and 51 controls without skin lesions recruited from a iAs endemic area in Mexico. We measured urinary As metabolites, differentiating the trivalent and pentavalent arsenical species, using the hydride generation atomic absorption spectrometry. In addition, the study subjects were genotyped to analyze three single nucleotide polymorphisms (SNPs), A-477G, T14458C (nonsynonymus SNP; Met287Thr), and T35587C, in the AS3MT gene. We compared the frequencies of the AS3MT alleles, genotypes, and haplotypes in individuals with and without skin lesions. Marginal differences in the frequencies of the Met287Thr genotype were identified between individuals with and without premalignant skin lesions (p=0.055): individuals carrying the C (TC+CC) allele (Thr) were at risk [odds ratio=4.28; 95% confidence interval (1.0-18.5)]. Also, individuals with C allele of Met287Thr displayed greater percentage of MAs in urine and decrease in the percentage of DMAs. These findings indicate that Met287Thr influences the susceptibility to premalignant As skin lesions and might be at increased risk for other adverse health effects of iAs exposure.
authors.affiliation: Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politecnico Nacional (Cinvestav-IPN), Av. IPN 2508, San Pedro Zacatenco, México D. F., C. P. 07360, Mexico.
authors.forename: Olga L
authors.initials: OL
authors.lastname: Valenzuela
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Drobná
authors.forename: Erika
authors.initials: E
authors.lastname: Hernández-Castellanos
authors.forename: Luz C
authors.initials: LC
authors.lastname: Sánchez-Peña
authors.forename: Gonzalo G
authors.initials: GG
authors.lastname: García-Vargas
authors.forename: Víctor H
authors.initials: VH
authors.lastname: Borja-Aburto
authors.forename: Miroslav
authors.initials: M
authors.lastname: Stýblo
authors.forename: Luz M
authors.initials: LM
authors.lastname: Del Razo
mesh_terms: D000293:Adolescent; D000328:Adult; D001151:Arsenic / Q000633:toxicity* / Q000652:urine; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D004247:DNA / Q000235:genetics; D004781:Environmental Exposure / Q000009:adverse effects / Q000032:analysis; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008800:Mexico / Q000453:epidemiology; D008875:Middle Aged; D009061:Mouth Mucosa / Q000166:cytology; D020641:Polymorphism, Single Nucleotide; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D014874:Water Pollutants, Chemical / Q000633:toxicity* / Q000652:urine; D055815:Young Adult
chemical_list: D014874:Water Pollutants, Chemical; D004247:DNA; D008780:Methyltransferases; C505756:AS3MT protein, human; D001151:Arsenic