Introduction

Arsenic exposure and its adverse health outcome, including the association with cancer risk are well established from several studies across the globe. The present study aims to analyze the epigenetic regulation of key mismatch repair (MMR) genes in the arsenic-exposed population.

Method

A case-control study was conducted involving two hundred twenty four (N=224) arsenic exposed [with skin lesion (WSL=110) and without skin lesion (WOSL=114)] and one hundred and two (N=102) unexposed individuals. The methylation status of key MMR genes i.e. MLH1, MSH2, and PMS2 were analyzed using methylation-specific PCR (MSP). The gene expression was studied by qRTPCR. The expression of H3K36me3, which was earlier reported to be an important regulator of MMR pathway, was assessed using ELISA.

Results

Arsenic-exposed individuals showed significant promoter hypermethylation (p < 0.0001) of MLH1 and MSH2 compared to those unexposed with consequent down-regulation in their gene expression [MLH1 (p=0.001) and MSH2 (p<0.05)]. However, no significant association was found in expression and methylation of PMS2 with arsenic exposure. We found significant down-regulation of H3K36me3 in the arsenic-exposed group, most significantly in the WSL group (p<0.0001). The expression of SETD2, the methyltransferase of an H3K36me3 moiety was found to be unaltered in arsenic exposure, suggesting the involvement of other regulatory factors yet to be identified.

Discussion

In summary, the epigenetic repression of DNA damage repair genes due to promoter hypermethylation of MLH1 and MSH2 and inefficient recruitment of MMR complex at the site of DNA damage owing to the reduced level of H3K36me3 impairs the mismatch repair pathway that might render the arsenic-exposed individuals more susceptible towards DNA damage and associated cancer risk.

中文翻译：

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印度西孟加拉邦长期暴露于砷的人群中错配修复基因的表观遗传改变

介绍

砷的暴露及其对健康的不良后果，包括与癌症风险的关系，在全球范围内的多项研究中都得到了很好的证实。本研究旨在分析砷暴露人群中关键错配修复（MMR）基因的表观遗传调控。

方法

进行了一项病例对照研究，涉及暴露的二十二十四（N = 224）砷[有皮肤病变（WSL = 110）和无皮肤病变（WOSL = 114）]和一百零二（N = 102）未暴露的个体。使用甲基化特异性PCR（MSP）分析了关键MMR基因（即MLH1，MSH2和PMS2）的甲基化状态。通过qRTPCR研究基因表达。使用ELISA评估了H3K36me3的表达，该表达先前被报道是MMR通路的重要调节因子。

结果

暴露于砷的个体与未暴露于其基因表达而因此下调的那些相比，显示出MLH1和MSH2的启动子高度甲基化（p <0.0001）[ MLH1（p = 0.001）和MSH2（p < 0.05）]。但是，没有发现PMS2的表达和甲基化与砷接触之间存在显着关联。我们发现在砷暴露组中H3K36me3明显下调，在WSL组中最显着下调（p < 0.0001）。SETD2的表达， H3K36me3部分的甲基转移酶被发现在砷暴露中没有改变，这暗示了尚待确定的其他调控因素的参与。

讨论

总之，由于H3K36me3水平降低，MLH1和MSH2启动子过度甲基化以及DNA损伤部位MMR复合物的无效募集引起的DNA损伤修复基因的表观遗传抑制削弱了错配修复途径，该途径可能使砷暴露个体更容易受到DNA损伤和相关癌症风险的影响。