miRNA320a-3p/RUNX2 signal programming mediates the transgenerational inheritance of inhibited ovarian estrogen synthesis in female offspring rats induced by prenatal dexamethasone exposure
miRNA320a-3p/RUNX2 signal programming mediates the transgenerational inheritance of inhibited ovarian estrogen synthesis in female offspring rats induced by prenatal dexamethasone exposure
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DOI：
10.1016/j.phrs.2021.105435
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发表时间：
2021-03-16
影响因子：
9.3
通讯作者：
Xu, Dan
中科院分区：
文献类型：
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作者：
Gong, Xiaohan;Zhang, Jinzhi;Xu, Dan
我们前期的研究发现，产前地塞米松暴露可导致胎鼠卵泡发育异常。本研究旨在观察地塞米松（0.2 mg/kg）暴露对子代卵巢雌激素抑制的跨代遗传效应。d）Wistar大鼠妊娠第9天（GD 9）至GD 20，探讨宫内程序化机制。产前地塞米松暴露可降低F1代大鼠卵巢细胞色素P450芳香化酶（P450 arom）的表达，降低血清雌二醇（E-2）水平，减少原始卵泡数，增加出生前后闭锁卵泡数。同时，F1代卵巢中miRNA 320 a-3 p的表达下调，RUNX 2的表达显著增加。这些变化持续到F2和F3代，伴随着F1和F2成年后代卵母细胞中miRNA 320 a-3 p表达的持续下调。在体外，用地塞米松处理胎鼠卵巢和KGN人卵巢颗粒细胞。结果表明，地塞米松降低了miRNA 320 a-3 p和P450 arom的表达，降低了E-2的合成，增加了RUNX 2的表达。GR拮抗剂RU 486可逆转上述作用。体外过表达miRNA 320 a-3 p也可逆转地塞米松对RUNX 2、P450 arom和E-2水平的影响。双荧光素酶报告基因实验进一步证实了miRNA 320 a-3 p对RUNX 2的直接靶向调控。这些结果表明，产前地塞米松暴露可通过GR/miRNA 320 a-3 p/RUNX 2/P450 arom级联信号介导抑制胎鼠卵巢E-2合成，并具有跨代遗传效应，可能与抑制卵母细胞miRNA 320 a-3 p表达有关。
Our previous studies found that prenatal dexamethasone exposure could cause abnormal follicular development in fetal rats. This study intends to observe the transgenerational inheritance effects of ovarian estrogen inhibition in offspring exposed to dexamethasone (0.2 mg/kg . d) from gestational day 9 (GD9) to GD20 in Wistar rats, and explore the intrauterine programming mechanisms. Prenatal dexamethasone exposure reduced the expression of ovarian cytochrome P450 aromatase (P450arom), the level of serum estradiol (E-2) and the number of primordial follicles, while increased the number of atresia follicles before and after birth in F1 offspring rats. At the same time, the expression of miRNA320a-3p in F1 ovaries was down-regulated, and RUNX2 expression increased significantly. These changes were continued to F2 and F3 generations, accompanied by consistently down-regulated miRNA320a-3p expression in oocyte of F1 and F2 adult offspring. In vitro, fetal rat ovaries and KGN human ovarian granulosa cells were treated with dexamethasone. It showed that dexamethasone decreased miRNA320a-3p and P450arom expression, as well as E-2 synthesis, and increased RUNX2 expression. All these effects could be reversed by the GR antagonist RU486. The overexpression of miRNA320a-3p in vitro could also reverse the effects of dexamethasone on RUNX2, P450arom, and E-2 levels. The dual-luciferase reporter gene experiment further confirmed the direct targeted regulation of miRNA320a-3p on RUNX2. These results indicate that prenatal dexamethasone exposure induces ovarian E-2 synthesis inhibition mediated by the GR/miRNA320a-3p/RUNX2/P450arom cascade signal in fetal rat ovary, which has transgenerational inheritance effects and may related to the inhibited miRNA320a-3p expression in oocyte.