Environmental arsenic exposure and DNA methylation of the tumor suppressor gene p16 and the DNA repair gene MLH1: effect of arsenic metabolism and genotype.
Arsenic is carcinogenic, possibly partly through epigenetic mechanisms. We evaluated the effects of arsenic exposure and metabolism on DNA methylation. Arsenic exposure and methylation efficiency in 202 women in the Argentinean Andes were assessed from concentrations of arsenic metabolites in urine (inorganic arsenic, methylarsonic acid [MMA], and dimethylarsinic acid [DMA]), measured by HPLC-ICPMS. Methylation of CpGs of the tumor suppressor gene p16, the DNA repair gene MLH1, and the repetitive elements LINE1 was measured by PCR pyrosequencing of blood DNA. Genotyping (N = 172) for AS3MT was performed using Sequenom™, and gene expression (N = 90) using Illumina DirectHyb HumanHT-12 v3.0. Median arsenic concentration in urine was 230 μg L(-1) (range 10.1-1251). In linear regression analysis, log(2)-transformed urinary arsenic concentrations were positively associated with methylation of p16 (β = 0.14, P = 0.0028) and MLH1 (β = 0.28, P = 0.0011), but not with LINE1. Arsenic concentrations were of borderline significance negatively correlated with expression of p16 (r(s) = -0.20; P = 0.066)), but not with MLH1. The fraction of inorganic arsenic was positively (β = 0.026; P = 0.010) and DMA was negatively (β = -0.017, P = 0.043) associated with p16 methylation with no effect of MMA. Carriers of the slow-metabolizing AS3MT haplotype were associated with more p16 methylation (P = 0.022). Arsenic exposure was correlated with increased methylation, in blood, of genes encoding enzymes that suppress carcinogenesis, and the arsenic metabolism efficiency modified the degree of epigenetic alterations.
Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, Lund, SE-22185, Sweden.
Mohammad Bakhtiar
MB
Hossain
Marie
M
Vahter
Gabriela
G
Concha
Karin
K
Broberg
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D001118:Argentina; D001151:Arsenic / Q000032:analysis*; D020261:Arsenic Poisoning / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000652:urine; D019175:DNA Methylation / Q000187:drug effects*; D004781:Environmental Exposure / Q000032:analysis*; D005260:Female; D019942:Genes, p16 / Q000187:drug effects*; D005819:Genetic Markers / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008780:Methyltransferases / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D018709:Statistics, Nonparametric; D014881:Water Supply
D048868:Adaptor Proteins, Signal Transducing; D005819:Genetic Markers; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D008780:Methyltransferases; C505756:AS3MT protein, human; D000070957:MutL Protein Homolog 1; D001151:Arsenic