Sperm Epimutation Biomarkers of Obesity and Pathologies following DDT Induced Epigenetic Transgenerational Inheritance of Disease

Gestating F0 generational female rats were transiently exposed to DDT during fetal gonadal sex determination and the incidence of adult onset pathologies was assessed in the subsequent F1, F2, and F3 generations. In addition, sperm differential DNA methylation regions (DMRs) that were associated with specific pathologies in the F3 generation males were investigated. No pathology was observed in the F1 generation DDT lineage males or females compared with F1 generation controls (vehicle exposure). There was an increase of testis disease and early onset puberty in the F2 generation DDT lineage males. The F3 generation DDT males had significant increases in testis disease, prostate disease, and late onset puberty. The F3 generation DDT females had significant increases in ovarian and kidney disease. Both the F3 generation males and females had significant increases in the frequency of obesity and multiple disease. The F3 generation sperm was collected to examine DMRs for the ancestrally exposed DDT male population. Unique sets of DMRs were associated with late onset puberty, kidney disease, and multiple disease pathologies.将妊娠的F0代雌性大鼠在胎儿性腺性别决定期短暂暴露于滴滴涕（DDT），随后评估后续F1、F2及F3代的成年发病病症发生率。此外，本研究还针对F3代雄性个体中与特定病症相关的精子差异DNA甲基化区域（DMRs）展开了探究。与F1代赋形剂暴露对照组相比，F1代滴滴涕暴露谱系的雌雄大鼠均未观察到任何病理异常。F2代滴滴涕暴露谱系的雄性个体出现睾丸疾病与青春期早发的比例有所升高。F3代滴滴涕暴露谱系的雄性个体的睾丸疾病、前列腺疾病及青春期迟发的发生率显著上升；F3代滴滴涕暴露谱系的雌性个体则出现卵巢疾病与肾脏疾病的风险显著提升。无论雌雄，F3代个体的肥胖症与多种病症的发生频率均显著升高。本研究采集了F3代大鼠的精子，以检测祖辈暴露于滴滴涕的雄性种群的DMRs，结果发现不同的DMR集合分别与青春期迟发、肾脏疾病及多种病症相关联。