Tissue and sex-specific programming of DNA methylation by perinatal lead exposure: implications for environmental epigenetics studies

Early developmental environment can influence long-term health through reprogramming of the epigenome. Human environmental epigenetics studies rely on surrogate tissues, such as blood, to assess the effects of environment on disease-relevant but inaccessible target tissues. However, the extent to which environment-induced epigenetic changes are conserved between these tissues is unclear. A better understanding of this conservation is imperative for effective design and interpretation of human environmental epigenetics studies. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues. We and others have recently reported that perinatal exposure to lead (Pb) is associated with adverse metabolic outcomes. Here, we investigated the sex-specific effects of perinatal exposure to a human environmentally relevant level of Pb on DNA methylation in paired liver and blood samples from adult mice using enhanced reduced-representation bisulphite sequencing. Although Pb exposure ceased at 3 weeks of age, we observed thousands of sex-specific differentially methylated cytosines in the blood and liver of Pb-exposed animals at 5 months of age, including 44 genomically imprinted loci. We observed significant tissue overlap in the genes mapping to differentially methylated cytosines. A small but significant subset of Pb-altered genes exhibit basal sex differences in gene expression in the mouse liver. Collectively, these data identify potential molecular targets for Pb-induced metabolic diseases, and inform the design of more robust human environmental epigenomics studies.

早期发育环境可通过表观基因组（epigenome）重编程影响机体长期健康。人类环境表观遗传学研究通常依托血液等替代组织，以评估环境对与疾病相关但难以获取的靶组织的影响。然而，环境诱导的表观遗传改变在这些组织间的保守程度仍未明确。深入阐明该保守性，对于合理设计与解读人类环境表观遗传学研究至关重要。美国国家环境卫生科学研究所组建了转录的基因组与表观基因组调控因子介导的毒物暴露与应答（TaRGET II）联盟，旨在评估替代组织作为靶组织中毒物诱导表观遗传改变替代物的应用价值。我们与其他团队近期已报道，围产期暴露于铅（Pb）与不良代谢结局存在关联。本研究采用增强型简化代表性亚硫酸氢盐测序（enhanced reduced-representation bisulphite sequencing）技术，对成年小鼠的配对肝脏与血液样本展开分析，探究围产期暴露于人类环境相关剂量铅（Pb）对DNA甲基化的性别特异性影响。尽管铅暴露在小鼠3周龄时即已终止，但在暴露小鼠5月龄的血液与肝脏组织中，我们仍检测到数千个性别特异性差异甲基化胞嘧啶（differentially methylated cytosines），其中包含44个基因组印记位点（genomically imprinted loci）。我们发现，差异甲基化胞嘧啶所关联的基因在两类组织间存在显著重叠。一小部分但具有统计学意义的铅暴露调控基因，在小鼠肝脏中存在基础的表达性别差异。综上，本研究数据明确了铅诱导代谢疾病的潜在分子靶点，并为设计更严谨的人类环境表观基因组学研究提供了参考依据。