As a nonmutagenic human carcinogen, arsenic (As)'s carcinogenic activity is likely the result of epigenetic changes, particularly alterations in DNA methylation. While increasing studies indicate a potentially important role for timing of As exposure on DNA methylation patterns and the subsequent differential risks for As toxicity and carcinogenesis, there is a lack of research that tackles these critical questions, particularly in human based populations. Here we reported a family-based study including three generations, in which each generation living in the same household had a distinctive timing of As exposure: in adulthood, in utero and during early childhood, and in germlines exposure for grandparents, parents, and grandchildren, respectively. We generated genome-wide DNA methylation data for 18 As-exposed families, nine control families, as well as 18 arsenical skin lesion patients. Our analysis showed that As exposure may leave detectable DNA methylation changes even though exposure occurred decades ago, and the most significant changes of global DNA methylation were observed among patients afflicted with arsenical skin lesions. As exposure across generations shared common differentially methylated DNA loci and regions (744 DML and 15 DMRs) despite the distinctive exposure timing in each generation. Importantly, based on these DML, clustering analysis grouped skin lesion patients together with grandparents in exposed families in the same cluster, separated from grandparents in control families. Further analysis identified a number of DML and several molecular pathways that were significantly distinguished between controls, exposed populations, as well as skin lesion patients. Finally, our exploratory analysis suggested that some of these DML altered by As exposure, may have the potential to be inherited affecting not only those directly exposed but also later generations. Together, our results suggest that common DML and/or DMRs associated with an increased risk for disease development could be identified regardless of when exposure to As occurred during their life span, and thus may be able to serve as biomarkers for identifying individuals at risk for As-induced skin lesions and possible cancers.

作为一种非致突变性人类致癌物，砷（As）的致癌活性可能是表观遗传变化的结果，尤其是DNA甲基化的改变。虽然越来越多的研究表明，砷暴露在DNA甲基化模式上的时间安排以及随后的砷毒性和致癌风险的潜在潜在重要作用，但仍缺乏解决这些关键问题的研究，尤其是在人类人群中。在这里，我们报告了一项基于家庭的研究，包括三代人，其中生活在同一家庭中的每一代人都有不同的砷暴露时间：成年期，子宫内和幼儿期，以及祖父母，父母和孙子的生殖系暴露时间， 分别。我们生成了18个暴露水平的家族，9个对照家族的全基因组DNA甲基化数据，以及18名砷中毒皮肤病患者。我们的分析表明，即使暴露发生在几十年前，由于暴露仍可能导致可检测的DNA甲基化变化，并且在患有砷性皮肤病变的患者中观察到了最重要的总体DNA甲基化变化。尽管每个世代都有不同的暴露时间，但世代之间的暴露共享着共同的差异甲基化DNA位点和区域（744 DML和15 DMR）。重要的是，基于这些DML，在同一个集群中暴露的家庭祖父母聚类分析分组皮损患者一起，从控制家庭祖父母分开。进一步的分析确定了在对照，暴露人群以及皮肤病变患者之间明显地区分的许多DML和几种分子途径。最后，我们的探索性分析表明，这些DML可能会因砷暴露而改变，它们有可能被遗传，不仅影响那些直接暴露的人，还会影响后代。总之，我们的结果表明，与疾病发展风险增加相关的常见DML和/或DMR，无论其一生中何时暴露于As都可以被识别，因此可以作为生物标记物，用于识别有感染风险的个体。 As诱发的皮肤病变和可能的癌症。