Petroff Rebekah L, Dolinoy Dana C, Wang Kai, Montrose Luke, Padmanabhan Vasantha, Peterson Karen E, Ruden Douglas M, Sartor Maureen A, Svoboda Laurie K, Téllez-Rojo Martha M, Goodrich Jaclyn M
Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA.
Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA; Nutritional Sciences, University of Michigan, Ann Arbor, MI, USA.
Environ Int. 2024 Apr;186:108575. doi: 10.1016/j.envint.2024.108575. Epub 2024 Mar 11.
Although toxicology uses animal models to represent real-world human health scenarios, a critical translational gap between laboratory-based studies and epidemiology remains. In this study, we aimed to understand the toxicoepigenetic effects on DNA methylation after developmental exposure to two common toxicants, the phthalate di(2-ethylhexyl) phthalate (DEHP) and the metal lead (Pb), using a translational paradigm that selected candidate genes from a mouse study and assessed them in four human birth cohorts. Data from mouse offspring developmentally exposed to DEHP, Pb, or control were used to identify genes with sex-specific sites with differential DNA methylation at postnatal day 21. Associations of human infant DNA methylation in homologous mouse genes with prenatal DEHP or Pb were examined with a meta-analysis. Differential methylation was observed on 6 cytosines (adjusted-p < 0.05) and 90 regions (adjusted-p < 0.001). This translational approach offers a unique method that can detect conserved epigenetic differences that are developmentally susceptible to environmental toxicants.
尽管毒理学使用动物模型来代表现实世界中的人类健康情况，但基于实验室的研究与流行病学之间仍存在关键的转化差距。在本研究中，我们旨在利用一种转化范式，了解发育过程中暴露于两种常见毒物——邻苯二甲酸二（2-乙基己基）酯（DEHP）和金属铅（Pb）后对DNA甲基化的毒理表观遗传效应，该范式从小鼠研究中选择候选基因，并在四个人类出生队列中对其进行评估。将发育过程中暴露于DEHP、Pb或对照的小鼠后代的数据用于识别在出生后第21天具有性别特异性且DNA甲基化存在差异位点的基因。通过荟萃分析研究了人类婴儿同源小鼠基因中的DNA甲基化与产前DEHP或Pb的关联。在6个胞嘧啶（校正p<0.05）和90个区域（校正p<0.001）观察到了差异甲基化。这种转化方法提供了一种独特的方法，能够检测对环境毒物发育敏感的保守表观遗传差异。
