School of Public Health, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China; School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA.
Environ Int. 2018 Oct;119:250-263. doi: 10.1016/j.envint.2018.06.024. Epub 2018 Jul 5.
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.
作为一种非致突变的人类致癌物质，砷（As）的致癌活性可能是表观遗传变化的结果，特别是 DNA 甲基化的改变。虽然越来越多的研究表明，As 暴露的时间对 DNA 甲基化模式和随后的 As 毒性和致癌风险有潜在的重要作用，但缺乏针对这些关键问题的研究，特别是在基于人群的研究中。在这里，我们报告了一项基于家庭的研究，包括三代人，每一代人都生活在同一个家庭，具有独特的 As 暴露时间：成年人、胎儿期和幼儿期，以及分别为祖父母、父母和孙辈的生殖系暴露。我们为 18 个 As 暴露家庭、9 个对照家庭以及 18 个砷性皮肤损伤患者生成了全基因组 DNA 甲基化数据。我们的分析表明，即使暴露发生在几十年前，As 暴露也可能留下可检测的 DNA 甲基化变化，而且在患有砷性皮肤损伤的患者中观察到的全基因组 DNA 甲基化变化最为显著。尽管每一代人的暴露时间都不同，但跨代的 As 暴露共享共同的差异甲基化 DNA 位点和区域（744 个 DML 和 15 个 DMRs）。重要的是，基于这些 DML，聚类分析将皮肤损伤患者与暴露家庭中的祖父母聚集在同一组中，与对照家庭中的祖父母分开。进一步的分析确定了一些 DML 和几个分子途径，这些 DML 在对照组、暴露人群以及皮肤损伤患者之间有显著区别。最后，我们的探索性分析表明，As 暴露改变的一些 DML 可能具有遗传潜力，不仅影响直接暴露的个体，还影响后代。总之，我们的研究结果表明，无论一生中何时暴露于 As，都可以识别与疾病发展风险增加相关的常见 DML 和/或 DMR，因此可能能够作为识别砷诱导皮肤损伤和可能癌症风险个体的生物标志物。
