Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School Palmer Commons, Ann Arbor, MI, USA.
Epigenetics. 2021 Oct;16(10):1102-1122. doi: 10.1080/15592294.2020.1841872. Epub 2020 Nov 8.
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.
早期发育环境可以通过表观基因组重编程影响长期健康。人类环境表观遗传学研究依赖于替代组织（如血液）来评估环境对疾病相关但无法触及的靶组织的影响。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。更好地了解这种保守性对于有效设计和解释人类环境表观遗传学研究至关重要。毒代动力学暴露和转录调控基因组和表观基因组调节剂的反应（TaRGET II）联盟由美国国家环境卫生科学研究所成立，旨在解决替代组织作为靶组织中有毒物诱导的表观遗传变化的替代物的效用。我们和其他人最近报道，围产期暴露于铅（Pb）与不良代谢结局有关。在这里，我们使用增强的简化重亚硫酸盐测序技术，研究了围产期暴露于人类环境相关水平的 Pb 对成年小鼠配对肝脏和血液样本中 DNA 甲基化的性别特异性影响。尽管 Pb 暴露在 3 周龄时停止，但我们在 5 月龄时观察到 Pb 暴露动物的血液和肝脏中存在数千个性别特异性差异甲基化胞嘧啶，包括 44 个基因组印迹基因座。我们观察到映射到差异甲基化胞嘧啶的基因在组织上具有显著的重叠。一小部分 Pb 改变的基因在小鼠肝脏中表现出基础的性别差异表达。总的来说，这些数据确定了 Pb 诱导的代谢疾病的潜在分子靶标，并为更稳健的人类环境表观基因组学研究提供了信息。
