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Environmental arsenic exposure and DNA methylation of the tumor suppressor gene p16 and the DNA repair gene MLH1: effect of arsenic metabolism and genotype.

Hossain, Bakhtiar LU ; Vahter, Marie; Concha, Gabriela and Broberg Palmgren, Karin LU (2012) In Metallomics 4(11). p.1167-1175
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
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type
Contribution to journal
publication status
published
subject
in
Metallomics
volume
4
issue
11
pages
1167 - 1175
publisher
Royal Society of Chemistry
external identifiers
  • wos:000311186400006
  • pmid:23073540
  • scopus:84867890206
ISSN
1756-5901
DOI
10.1039/c2mt20120h
language
English
LU publication?
yes
id
a0c4b51d-889e-4dcf-8044-e303d0bf712b (old id 3160627)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23073540?dopt=Abstract
date added to LUP
2012-11-01 13:17:13
date last changed
2017-11-19 03:18:16
@article{a0c4b51d-889e-4dcf-8044-e303d0bf712b,
  abstract     = {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.},
  author       = {Hossain, Bakhtiar and Vahter, Marie and Concha, Gabriela and Broberg Palmgren, Karin},
  issn         = {1756-5901},
  language     = {eng},
  number       = {11},
  pages        = {1167--1175},
  publisher    = {Royal Society of Chemistry},
  series       = {Metallomics},
  title        = {Environmental arsenic exposure and DNA methylation of the tumor suppressor gene p16 and the DNA repair gene MLH1: effect of arsenic metabolism and genotype.},
  url          = {http://dx.doi.org/10.1039/c2mt20120h},
  volume       = {4},
  year         = {2012},
}