Abstract：
Increasing evidence shows that an adverse environment during the early fetal development can affect the epigenetic modifications on a wide range of diabetes-related genes, leading to an increased diabetic susceptibility in adulthood or even in subsequent generations. p,p\'-Dichlorodiphenoxydichloroethylene (p,p\'-DDE) is a break-down product of the pesticide dichlorodiphenyltrichloroethane (DDT). p,p\'-DDE has been associated with various health concerns, such as diabetogenic effect. However, the precise molecular mechanism remains unclear. In this study, p,p\'-DDE was given by gavage to pregnant rat dams from gestational day (GD) 8 to GD15 to generate male germline to investiagate the transgenerational effects. We found that early-life p,p\'-DDE exposure increased the transgenerational diabetic susceptibility through male germline inheritance. In utero exposure to p,p\'-DDE altered the sperm DNA methylome in F1 progeny, and a significant number of those differentially methylated genes could be inherited by F2 progeny. Furthermore, early-life p,p\'-DDE exposure altered DNA methylation in glucose metabolic genes Gck and G6pc in sperm and the methylation modification were also found in liver of the next generation. Our study demonstrate that DNA methylation plays a critical role in mediating transgenerational diabetogenic effect induced by early-life p,p\'-DDE exposure.
摘要：
越来越多的证据表明，胎儿早期发育的不良环境会影响广泛的糖尿病相关基因的表观遗传修饰。导致成年甚至后代的糖尿病易感性增加。p,p'-二氯二苯氧基二氯乙烯(p,p'-DDE）是农药二氯二苯基三氯乙烷（DDT）的分解产物。p,p\'-DDE与各种健康问题有关，如致糖尿病作用。然而,确切的分子机制尚不清楚。在这项研究中,p,从妊娠日（GD）8至GD15，通过管饲法对怀孕的大鼠大坝进行p'-DDE，以产生雄性种系，以研究跨代效应。我们发现生命早期的P,p'-DDE暴露通过男性种系遗传增加了跨代糖尿病易感性。在子宫内暴露于p，p'-DDE改变了F1后代的精子DNA甲基化，F2后代可以遗传大量的差异甲基化基因。此外，生命早期p,p'-DDE暴露改变了精子中葡萄糖代谢基因Gck和G6pc的DNA甲基化，并且在下一代肝脏中也发现了甲基化修饰。我们的研究表明，DNA甲基化在介导由生命早期p，p\'-DDE暴露。
