地塞米松（Dex）被广泛用于多种妊娠子代相关疾病治疗，但治疗剂量可引起子代卵巢发育改变，其机制尚未阐明。近期我们发现，孕期Dex暴露的雌性子代大鼠卵巢雌激素合成抑制、性发育异常并跨代遗传；进一步发现，胎卵巢胰岛素样生长因子1（IGF1）信号通路、多代子代类固醇生成因子1（SF-1）及甾体合成酶系统表达抑制。综合文献我们推测：Dex通过激活1型11ß羟类固醇脱氢酶/糖皮质激素受体（11ßHSD1/GR）系统下调IGF1/Akt通路，引起SF-1表观遗传修饰异常/表达抑制，进而下调甾体合成酶表达及雌激素合成并跨代传递。本项目拟确证11ßHSD1/GR/IGF1改变所致SF-1表观遗传修饰异常/表达抑制介导了Dex所致子代卵巢低功能发育的跨代遗传效应，进一步探讨SF-1表达抑制的表观遗传调控机制。本项目对深刻理解卵巢发育异常的宫内起源，进一步探寻早期预警标志物，均具有重要的理论价值和现实意义。

Dexamethasone (Dex) is widely used for the treatment of a variety of pregnancy-related diseases in offspring, but therapeutic doses of Dex can cause alteration of ovarian development in offspring, while the mechanism is not yet clear. Recently we found that prenatal Dex exposure can cause the transgenerational transmission of estrogen synthesis inhibition in ovarian, abnormal sexual maturity in offspring rats. We further found that the insulin-like growth factor 1 (IGF1) signaling pathway in fetal rats as well as the expression of steroidogenic factor 1 (SF-1) and steroidal synthetase in multiple generation offspring rats were all decreased. Based on literatures, we hypothesized that Dex can decrease the IGF1/Akt signaling pathway and induce the abnormal epigenetic modification and decrease expression of SF-1, by activating the 11ß hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor (11ßHSD1/GR) system, which will further decrease steroidal synthetase and estrogen synthesis and show a transgenerational transmission effect. In this project, we will confirm the abnormal epigenetic modification/decreased expression of SF-1 mediated transgenerational transmission of ovarian low-functional development, induced by 11ßHSD1/GR/IGF1 cascade alteration. Meanwhile, we will further investigate the epigenetic regulation mechanism of the decreased expression of SF-1. It has important theory value and practical significance for understanding the intrauterine origin of abnormal ovarian development and further exploring early-warning markers.