Abstract
Arsenic is a very potent toxicant. One major susceptibility factor for arsenic-related toxicity is the efficiency of arsenic metabolism. The efficiency, in turn, is associated with non-coding single nucleotide polymorphisms (SNPs) in the arsenic methyltransferase AS3MT on chromosome 10q24. However, the mechanism of action for these SNPs is not yet clarified. Here, we assessed the influence of genetic variation in AS3MT on DNA methylation and gene expression within 10q24, in people exposed to arsenic in drinking water. DNA was extracted from peripheral blood from women in the Argentinean Andes (N = 103) and from cord blood from new-borns in Bangladesh (N = 127). AS3MT SNPs were analyzed with Sequenom or Taqman assays. Whole genome epigenetic analysis with Infinium HumanMethylation450 BeadChip was performed on bisulphite-treated DNA. Whole genome gene expression analysis was performed with Illumina DirectHyb HumanHT-12 v4.0 on RNA from peripheral blood. Arsenic exposure was assessed by HPLC-ICPMS. In the Argentinean women, the major AS3MT haplotype, associated with more efficient arsenic metabolism, showed increased methylation of AS3MT (p = 10−6) and also differential methylation of several other genes within about 800 kilobasepairs: CNNM2 (p<10−16), NT5C2 (p<10−16), C10orf26 (p = 10−8), USMG5 (p = 10−5), TRIM8 (p = 10−4), and CALHM2 (p = 0.038) (adjusted for multiple comparisons). Similar, but weaker, associations between AS3MT haplotype and DNA methylation in 10q24 were observed in cord blood (Bangladesh). The haplotype-associated altered CpG methylation was correlated with reduced expression of AS3MT and CNNM2 (rs = −0.22 to −0.54), and with increased expression of NT5C2 and USMG5 (rs = 0.25 to 0.58). Taking other possibly influential variables into account in multivariable linear models did only to a minor extent alter the strength of the associations. In conclusion, the AS3MT haplotype status strongly predicted DNA methylation and gene expression of AS3MT as well as several genes in 10q24. This raises the possibility that several genes in this region are important for arsenic metabolism.
Highlights
Arsenic is a widespread environmental pollutant with strong adverse effects in humans, including increased incidence of cancer and effects on skin, respiratory tract, liver, and immune function [1], [2], [3], [4], [5]
One potential effect of single nucleotide polymorphisms (SNPs) on DNA methylation may come from sequence changes that introduce or remove methylation sites; we examined the SNPs associated with the arsenic (+3 oxidation state) methyltransferase (AS3MT) haplotype to determine whether these SNPs altered methylation sites and whether these sites were in CpG islands or shores
We evaluated if the correlation in DNA methylation of genes around AS3MT was strong compared to other regions on chromosome 10, by analyzing windows of 20 consecutive genes and the fraction of CpGs that were correlated between the genes with Pearson correlation
Summary
Arsenic is a widespread environmental pollutant with strong adverse effects in humans, including increased incidence of cancer and effects on skin, respiratory tract, liver, and immune function [1], [2], [3], [4], [5]. Inorganic arsenic is efficiently absorbed in the gastrointestinal tract and is metabolized in the body by a series of reduction and methylation reactions, producing methylarsonic acid (MMA) and dimethylarsinic acid (DMA), both of which are excreted in the urine [6]. Incomplete arsenic metabolism, with higher urinary inorganic arsenic and MMA, but lower DMA, seems to be a marker of increased susceptibility to arsenic-related diseases, including cancer [7], [8]. Real time-polymerase chain reaction (PCR) analysis of mature rat tissues detected AS3MT expression in the heart, adrenal gland, urinary bladder, brain, kidney, lung, and liver [9]
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