DNA甲基化重编程介导生命早期p,p'-DDE暴露诱导的跨代糖尿病效应,Chemosphere

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DNA甲基化重编程介导生命早期p,p'-DDE暴露诱导的跨代糖尿病效应
Chemosphere ( IF 8.1 ) Pub Date : 2023-12-11 , DOI: 10.1016/j.chemosphere.2023.140907
Shuo Wang , Jingjing Wu , Zhong Chen , Wei Wu , Liping Lu , Yuzhou Cheng , Shuqi Li , Liangjing Chen , Xiaohua Tan , Lei Yang , Charles Wang , Yang Song

越来越多的证据表明，胎儿早期发育期间的不利环境会影响多种糖尿病相关基因的表观遗传修饰，导致成年期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，例如导致糖尿病的作用。然而，确切的分子机制仍不清楚。在这项研究中，从妊娠第 8 天到第 15 天，通过强饲法给怀孕母鼠注射 p,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。暴露于 p,p'-DDE 改变了 F1 后代的精子 DNA 甲基化组，并且 F2 后代可以遗传大量这些差异甲基化基因。此外，生命早期的p,p'-DDE暴露改变了葡萄糖代谢基因和精子中的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 甲基化在介导生命早期 p,p'-DDE 暴露诱导的跨代糖尿病效应中发挥着关键作用。

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DNA methylation reprogramming mediates transgenerational diabetogenic effect induced by early-life p,p’-DDE exposure

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. 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 and 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.

更新日期：2023-12-11

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