氧苯酮通过调控KDM5B介导H3K4me3去甲基化修饰致卵子成熟障碍及生育力下降的机制研究

氧苯酮是护肤品主成分之一，因其过度使用已成为一类新型环境污染物，并在人类血浆中被检测到。流行病学研究发现氧苯酮与生殖细胞发育、生育力下降密切相关，但其作用机制还不清楚。申请人在前期明确了生理浓度下氧苯酮暴露会引起小鼠卵子体内和体外成熟率显著降低、氧化应激损伤、线粒体功能下降、纺锤体结构异常。进一步实验显示，氧苯酮暴露卵子的H3K4me3水平下降、KDM5B表达上调。由此，我们提出假设：氧苯酮可能通过破坏KDM5B介导的H3K4甲基化和去甲基化平衡，导致卵子成熟异常及生育力下降。本项目拟以氧苯酮诱导的卵子成熟障碍模型小鼠为研究对象，从离体和在体不同角度，系统阐明氧苯酮通过调控KDM5B-H3K4me3影响卵子成熟的分子机制，结合单细胞RNA-seq和低起始量ChIP-seq，筛选其他靶基因并验证，从而加深卵母细胞减数分裂的表观遗传调控机制的理解，为人类卵子成熟障碍疑难病例提供新的诊疗策略。

Oxybenzone, one of the main components of skin care products, has become a new type of environmental pollutants due to its overuse and has been detected in human plasma. Epidemiological studies have found that oxybenzone is closely related to germ cell development and fertility decline, but the molecular mechanism of its effect on oocyte maturation and fertility decline is still unclear. Recently, our group found that exposure to oxybenzone at physiological concentration significantly reduced the maturation rate of mouse oocytes in vivo and in vitro, increased oxidative stress, destroyed morphology, and decreased mitochondrial function. Further experiments showed that oxybenzone exposure decreased histone H3K4me3 levels and increased KDM5B expression in oocytes. Thus, we hypothesized that oxybenzone may eventually lead to oocyte maturation disorders by disrupting KDM5B-mediated histone H3K4 methylation and demethylation balance. In this project, the mechanism of oxybenzone-induced abnormal oogenesis and fertility decline was clarified by oxybenzone exposed oocyte maturation failure mouse models. To screen and verify other target genes, we would combine single cell RNA-seq and low input ChIP-seq. This project is helpful to deepen the understanding of the epigenetic regulation mechanism of oocyte maturation and provide a new diagnosis and treatment strategy for patients with oocyte maturation disorders.