PDF(Pubmed)
Abstract：
Arsenic is a relatively abundant metalloid that impacts DNA methylation and has been implicated in various adverse health outcomes including several cancers and diabetes. However, uncertainty remains about the identity of genomic CpGs that are sensitive to arsenic exposure, in utero or otherwise. Here we identified a high confidence set of CpG sites whose methylation is sensitive to in utero arsenic exposure. To do so, we analyzed methylation of infant CpGs as a function of maternal urinary arsenic in cord blood and placenta from geographically and ancestrally distinct human populations. Independent analyses of these distinct populations were followed by combination of results across sexes and populations/tissue types. Following these analyses, we concluded that both sex and tissue type are important drivers of heterogeneity in methylation response at several CpGs. We also identified 17 high confidence CpGs that were hypermethylated across sex, tissue type and population; 11 of these were located within protein coding genes. This pattern is consistent with hypotheses that arsenic increases cancer risk by inducing the hypermethylation of genic regions. This study represents an opportunity to understand consistent, reproducible patterns of epigenomic responses after in utero arsenic exposure and may aid towards novel biomarkers or signatures of arsenic exposure. Identifying arsenic-responsive sites can also contribute to our understanding of the biological mechanisms by which arsenic exposure can affect biological function and increase risk of cancer and other age-related diseases.
摘要：
砷是一种相对丰富的类金属，会影响DNA甲基化，并与各种不良健康结果有关，包括几种癌症和糖尿病。然而,对砷暴露敏感的基因组CpG的身份仍然存在不确定性，在子宫内或以其他方式。在这里，我们确定了一组高置信度的CpG位点，其甲基化对子宫内砷暴露敏感。要做到这一点，我们分析了不同地理位置和祖先人群的脐带血和胎盘中婴儿CpGs甲基化与母体尿砷的关系.对这些不同群体的独立分析之后是跨性别和群体/组织类型的结果的组合。根据这些分析，我们得出的结论是,性别和组织类型都是几个CpG甲基化反应异质性的重要驱动因素.我们还确定了17个高置信度CpG，它们在性别上高度甲基化，组织类型和群体；其中11个位于蛋白质编码基因内。这种模式与砷通过诱导基因区域的超甲基化增加癌症风险的假设一致。这项研究代表了一个理解一致的机会，子宫内砷暴露后表观基因组反应的可重复模式，可能有助于砷暴露的新型生物标志物或特征。确定砷反应位点也有助于我们了解砷暴露会影响生物学功能并增加癌症和其他与年龄有关的疾病风险的生物学机制。
