地塞米松所致子代卵巢低功能发育跨代遗传的宫内编程机制

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.

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。

地塞米松（DEX）被广泛用于多种妊娠期早产相关疾病治疗，但治疗量可引起子代卵巢发育毒性。我们前期发现，孕期DEX暴露的雌性子代大鼠卵巢雌激素合成抑制并具有跨代遗传效应，但机制不清。通过本项目研究，我们证实孕期DEX暴露可激活GR,通过抑制miRNA320a-3p表达，靶向上调RUNX2，并通过下调胎儿卵巢P450arom，进一步抑制雌激素合成功能。子代卵巢miRNA320a-3p抑制可通过F1代卵母细胞影响F2代，由于其遗传稳定性，间接暴露于DEX的F2代卵母细胞也表现出miRNA320a-3p的抑制，并遗传到F3代。miRNA320a-3p/RUNX2/P450arom级联效应最终导致了卵巢雌激素合成功能抑制的跨代遗传效应。除影响子代卵巢雌激素合成功能外，我们还观察到孕期DEX暴露可致子代卵巢储备功能下降并存在跨代遗传效应，孕期DEX暴露通过激活胎鼠卵巢GR，上调miR-17-5p并靶向抑制FOXL2/CDKN1B信号引起卵巢储备降低。卵巢miR-17-5p表达上调也可通过F1代的生殖细胞影响F2代，致F2代生殖细胞也出现miR-17-5p表达上调并传递至F3代，经过miR-17-5p/FOXL2/CDKN1B的级联效应，最终介导子代卵巢储备功能降低的跨代遗传。本研究对于深刻理解卵巢发育毒性的宫内起源，为孕期DEX暴露所致的获得性性状的跨代遗传提供实验证据，为探寻DEX致子代卵巢发育毒性的防治靶标提供理论依据。本项目在毒理、发育等权威杂志Arch Toxicol、Pharmacol Res、Food Chem Toxicol等发表第一/通讯作者SCI论文15篇，中文核心1篇，参加国内外学术会议15次，授权/申请专利6项。获湖北省科技进步一等奖（排名3/15），中国出生缺陷干预救助基金会科技成果奖二等奖（排名4/15）、2018中国药理学青年药理学家奖以及论文奖多项。