COH高雌激素状态通过ER-α介导TET2高表达影响卵母细胞“胎盘特异性母源甲基化”致子代低出生体重的机制研究

我们前期研究显示：COH高雌激素致新鲜周期试管婴儿低出生体重（LBW）的现象，在冻融胚胎移植周期依然存在，高雌激素是LBW的独立危险因素；COH小鼠卵子发育而来的胎盘组织形态异常、胎鼠低体重。以上均表明COH高雌激素影响卵子致胎盘发育异常是LBW的重要诱因。新近研究报道，卵子胎盘特异性母源甲基化在胎盘发育中具有重要作用；COH致卵子甲基化水平降低；雌激素通过ER-α介导TET2高表达致DNA低甲基化。我们小鼠实验发现，COH致卵子TET2表达水平显著升高。据此提出，COH高雌激素通过ER-α介导TET2高表达致卵子胎盘特异性母源甲基化水平下降，影响胎盘发育，致LBW的假说。本项目以小鼠为动物模型，结合细胞和分子生物学分析，揭示COH高雌激素致卵子胎盘特异性母源甲基化降低的机制，阐明其对胎盘功能的影响。项目的完成将可能发现COH致试管婴儿LBW的新机制，为临床干预提供新靶点，具有重要的意义。

We have revealed that the phenomenon of high estrogen in COH induced LBW of test tube infants in fresh cycle still existed in the frozen thawed embryo transfer cycle, and high estrogen was an independent risk factor of LBW. We also found that, in the mouse model, the weight of the fetus developed from the COH derived oocyte decreased significantly, and the placental morphology was abnormal. These findings indicated that the abnormal placental development resulted in affected mouse oocyte by the high estrogen of COH was an important cause of LBW. Recently, studies have been reported that oocyte’s placenta-specific maternal methylation played an important role in the development of placenta; the level of DNA methylation in oocyte was significantly reduced by COH; estrogen could promote the expression of the methylcytosine dioxygenase enzyme TET 2 to regulate DNA demethylation. We further found that the expression of TET2 in oocytes significantly increased by COH in mice. Therefore, the hypothesis is proposed that high estrogen in COH promotes the high expression of TET2 through ER - α, which can further affect the development of placenta and lead to LBW. In this project, the mouse is used as animal model, combined with cell and molecular biological analysis, to reveal the mechanism of reduction of oocyte’s placenta-specific maternal methylation caused by high estrogen of COH, and to clarify its effects on placenta development. The completion of the project will reveal the new mechanism of low birth weight induced by COH, and provide new targets for clinical intervention, which is of great clinical significance and value.