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首页> 外文OA文献 >Environmental arsenic exposure and DNA methylation of the tumor suppressor gene p16 and the DNA repair gene MLH1: effect of arsenic metabolism and genotype.
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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.

机译：环境砷暴露和肿瘤抑制基因p16的DNa甲基化和DNa修复基因mLH1：砷代谢和基因型的影响。

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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.
机译：砷可能致癌，可能部分是通过表观遗传机制。我们评估了砷暴露和代谢对DNA甲基化的影响。根据HPLC-ICPMS测定的尿液中砷的代谢产物（无机砷，甲基砷酸[MMA]和二甲基砷酸[DMA]）的浓度评估了阿根廷安第斯山脉中202名妇女的砷暴露和甲基化效率。通过血液DNA的PCR焦磷酸测序法测定肿瘤抑制基因p16，DNA修复基因MLH1和重复元件LINE1的CpG的甲基化。使用Sequenom™进行AS3MT的基因分型（N = 172），并使用Illumina DirectHyb HumanHT-12 v3.0进行基因表达（N = 90）。尿中砷的中位浓度为230μgL（-1）（范围10.1-1251）。在线性回归分析中，log（2）转化的尿砷浓度与p16（β= 0.14，P = 0.0028）和MLH1（β= 0.28，P = 0.0011）的甲基化呈正相关，而与LINE1则不相关。砷的浓度与p16的表达呈负相关（r（s）= -0.20; P = 0.066）），与MLH1无关。与p16甲基化相关的无机砷分数为正（β= 0.026； P = 0.010），而DMA则为负（β= -0.017，P = 0.043），而没有MMA影响。慢代谢AS3MT单倍型的携带者与更多的p16甲基化有关（P = 0.022）。砷的暴露与血液中抑制癌变的酶编码基因的甲基化增加有关，并且砷的代谢效率改变了表观遗传学改变的程度。

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