环境水平双酚A通过母胎界面EphA2/ephrinA1反向信号转导影响胚胎着床的分子机制研究

Bisphenol A (BPA) is one of the most important environmental endocrine disruptors harmful to human reproductive health. Chronic exposure to BPA at environmental level is associated with decreased trophoblast invasion and embryo implantation rate, but the molecular mechanism is still unrevealed. Epithelial-mesenchymal transition (EMT) of trophoblast is one of the crucial processes of successful embryo implantation, which occurs not before embryo attachment. Therefore, cell-cell attachment might be essential to EMT, and Eph/ephrin family , which is expressed at the cell interface, is likely to play an important role in regulating embryo implantation. Our previous study indicated that the expression level of EphA2 significantly decreased in patients with higher urinary BPA concentration, and ectogenic EphA2 could increase trophoblast invasion with activating MAPK pathway and inducing EMT related molecules. Consequently, we hypothesized that BPA might interfere trophoblast EMT by EphA2/eprhinA1 reverse signaling pathway at the feto-maternal interface, and finally lead to implantation failure. In this research, using clinical materials, animal and cell-line models, we will investigate the effect of environmental BPA on EphA2/ephrinA1 expression at the feto-maternal interface and on the EMT of trophoblast. It is hoped that a better understanding of the pathogenesis of hazardous environmental factors on human reproductive health will provide us new insights on clinical therapy.

双酚A（BPA）是影响人类生殖健康的环境内分泌干扰物之一，环境水平BPA长期暴露可影响胚胎滋养细胞侵袭而降低着床率，但具体机制不清。滋养细胞上皮-间充质转化（EMT）是成功着床的关键，始于胚胎稳定粘附于子宫内膜时。推测母胎界面细胞间的接触可能是EMT的重要条件，而表达于细胞界面的Eph/ephrin家族很可能对胚胎EMT具有重要的调控作用。前期研究发现，BPA高暴露者子宫内膜EphA2表达显著下调；而外源性EphA2可促进滋养细胞侵袭，并激活MAPK通路和上调EMT指标。由此猜想：BPA可能通过母胎界面EphA2/ephrinA1介导反向信号转导影响滋养细胞EMT，最终导致胚胎着床异常。本项目拟利用人类临床资源、小鼠与细胞模型，在整体、细胞及分子水平探索环境水平BPA对母胎界面EphA2/ephrinA1表达及其对滋养细胞EMT的影响，为认识不良环境因素导致生殖健康受损的机制奠定基础。

本项目采用用人类临床资源、小鼠与细胞模型，在整体、细胞及分子水平探索环境水平BPA对母胎界面EphA2/ephrinA1表达及其对滋养细胞EMT的影响。研究发现BPA可以影响子宫内膜EphA2的表达水平，而后者可以通过作用在胚胎滋养细胞表面的ephrinA1引起细胞凋亡增加、迁移力降低。首先双酚A高暴露的小鼠呈现胚胎着床率降低，同时，在临床样本中，再次证实BPA高暴露的个体在围着床期子宫内膜中EphA2表达水平降低。体外细胞实验结果显示，EphA2水平降低可以使滋养细胞迁移力降低，而ephrinA1可能通过影响m6A的写入与擦除（相关研究还有待深入），最终引起细胞EMT发生改变。此外本研究还同时发现，BPA暴露可以使小鼠卵巢功能发生改变，导致其呈现多囊样改变，以及卵泡发育异常。而BPA导致小鼠卵巢功能异常的途径，可能使通过AMPK通路导致细胞自噬-凋亡平衡出现紊乱所致。本研究的意义在于，初步阐明了BPA导致胚胎种植失败以及卵巢功能异常的分子机制，并为深入研究奠定了基础。