肥胖妇女生殖系统细胞脂毒性反应—卵泡微环境及子宫内膜

Oocytes (or eggs) are exceptional cells which are the foundation for generating new life. Compelling evidence shows that the earliest foundations of oocyte quality and embryo growth potential are established by peri-conception metabolic and nutritional signals from the mother. Regulation of lipid homeostasis is essential for ovulation, oocyte quality and early embryo growth. Our previous study having demonstrated that obesity influences female fertility even before conception by causing profound changes in the ovary that affect the release of the egg and its capacity to form an embryo. Oocyte and embryos from obese mice showed significant lipotoxcity reaction, which lead to final apoptosis. Further step forward would answer three major outstanding questions: 1. Do follicle microenvironment and endometrium of obese women got more disturbed lipid profile than those of moderate weight women? Especially for fatty acid metabolism; 2. Are ER stress, lipotoxicity and apoptosis occurring in ovarian cells and endometrium of obese women? Do these defects correlate with poor reproductive outcomes? 3. Are these defects most severe in ovarian cells or endometrium of women with PCOS, in whom both obesity and androgens contribute to dyslipidemia? The completion of the proposed research will allow a global view of lipid metabolism profile in human ovarian environment. A giant step forward in understanding the mechanism of obesity affect female fertility.

卵子是孕育新生命的始基，母体孕前代谢及营养状态奠定了卵子质量及胚胎发育的基础。肥胖在孕前可通过对卵巢的影响而改变排卵，受精及胚胎发育潜能。肥胖的影响从卵泡液微环境开始，动物实验中，肥胖小鼠卵子内含有显著增加的脂肪含量，进而诱导小鼠卵子及胚胎内的细胞脂毒性反应，降低胚胎质量。本课题以此基础深入以下研究内容：1.了解肥胖以何种程度影响了卵巢及子宫内膜脂代谢生理状态？ 2. 重点明确肥胖是否通过引发人类卵泡液微环境及子宫内膜组织中的细胞脂毒性反应进而导致肥胖者生育力下降；3. PCOS是否会加重肥胖患者卵泡液微环境内异常脂肪酸代谢状态及细胞脂毒性反应的严重程度。这些科学问题的解答可以辅助探索肥胖导致女性生育力下降的潜在分子学机制，具有重要社会意义。

课题主要按照计划书的内容分为三大部分内容：在前两部分中侧重肥胖患者卵子-卵丘复合物及子宫内膜组织这两类对于卵子发育，胚胎着床等女性生育力至为重要的环节进行细胞脂毒性反应的深入研究。肥胖人类卵子所生长的内环境（卵泡液，颗粒细胞）及胚胎着床的土壤（内膜）在脂代谢方面存在显著的共性：肥胖患者颗粒细胞及子宫内膜组织中普遍存在高于正常者的脂肪储备；生长及着床内环境中炎症性细胞因子高表达；脂质代谢基因表达异常；内质网应激基因表达增强，并出现PERK,eIF2A凋亡通路中关键因子的蛋白表达量异常；TUNEL染色提示凋亡信号增加，但无论在颗粒细胞中抑或是子宫内膜组织中，本研究并未检测到显著增加的DNA碎片化程度。但各类异常均提示为细胞内脂质含量增加而诱发出细胞脂毒性反应，这类变化与炎症性细胞因子密切相关。.第三部分针对PCOS患者的研究我们发现，PCOS患者外周血测定可见PCOS患者群体具有典型的性激素紊乱及高脂血症，慢性亚急性炎症反应的血清特点。与此相伴随的是卵泡液中脂质代谢及炎症性细胞因子水平显著增加，卵巢组织颗粒细胞内脂代谢及炎症性细胞因子基因表达。这些变化在普通肥胖患者的基础上更为凸显了内分泌紊乱的状态及炎症性细胞因子高度存在。推测具有加重细胞脂毒性反应的可能性。.此外，我们还进一步深入了既往发现肥胖对于玻璃化冷冻损伤的影响的分子学研究。.本课题研究明晰了肥胖患者自然生育力下降及流产率增加可能的细胞学机制。提示在辅助生育助孕治疗中更多的关注代谢对于卵子发育及胚胎着床微环境的不利影响，有针对性的对这类患者进行助孕治疗前的基础脂质状态调整，增加辅助生育技术助孕成功率，降低流产率，减少肥胖患者各类不良并发症的发生，减轻患者的精神，经济，身体负担。在胚胎的玻璃化冷冻保存过程也可更进一步的探索可能的损伤预防性措施，增加助孕治疗的疗效。