ABSTRACT

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.

摘要

早期发育环境可以通过表观基因组的重新编程影响长期健康。人类环境表观遗传学研究依赖于替代组织（例如血液）来评估环境对与疾病相关但无法接近的靶组织的影响。然而，环境诱导的表观遗传变化在这些组织之间的保守程度尚不清楚。更好地理解这种保护对于有效设计和解释人类环境表观遗传学研究至关重要。基因组和表观基因组转录调节因子 (TaRGET II) 的毒物暴露和反应联盟由国家环境健康科学研究所建立，旨在解决替代组织作为靶组织毒物诱导的表观遗传变化代理的效用。我们和其他人最近报道说，围产期铅 (Pb) 暴露与不良代谢结果有关。在这里，我们使用增强的还原代表性亚硫酸氢盐测序研究了围产期暴露于人类环境相关水平的铅对成年小鼠成对肝脏和血液样本中 DNA 甲基化的性别特异性影响。尽管铅暴露在 3 周龄时停止，但我们在 5 个月大时在铅暴露动物的血液和肝脏中观察到数千个性别特异性差异甲基化胞嘧啶，包括 44 个基因组印记位点。我们在映射到差异甲基化胞嘧啶的基因中观察到显着的组织重叠。铅改变基因的一个小但重要的子集在小鼠肝脏中表现出基因表达的基础性别差异。总的来说，