Abstract：
Follicular ovarian cysts (FOCs) are characterized by follicles in the ovaries that are >20 mm in diameter and persist for >10 days without the corpus luteum, leading to anovulation, dysregulation of folliculogenesis and subfertility in humans and livestock species. Despite their clinical significance, the precise impact of FOCs on oocyte reserve, maturation, and quality still needs to be explored. While FOCs are observed in both human and livestock populations, they are notably prevalent in livestock species. Consequently, livestock species serve as valuable models for investigating the molecular intricacies of FOCs. Thus, in this study, using goat FOCs, we performed integrated proteomic, metabolomic and functional analyses to demonstrate that oocyte maturation is hampered due to increased reactive oxygen species (ROS) in FOCs follicular fluid (FF) via downregulation of glutathione peroxidase (GPX1), a critical antioxidant seleno enzyme required to negate oxidative stress. Notably, GPX1 reduction was positively correlated with the FF\'s decline of free selenium and selenocysteine metabolic enzymes, O-phosphoryl-tRNA (Sec) selenium transferase (SEPSECS) and selenocysteine lyase (SCLY) levels. Adding GPX1, selenocysteine, or selenium to the culture media rescued the oocyte maturation abnormalities caused by FOCs FF by down-regulating the ROS. Additionally, we demonstrate that substituting GPX1 regulator, Insulin-like growth factor-I (IGF-1) in the in vitro maturation media improved the oocyte maturation in the cystic FF by down-regulating the ROS activity via suppressing Non-sense-mediated decay (NMD) of GPX1. In contrast, inhibition of IGF-1R and the target of rapamycin complex 1 (mTORC1) hampered the oocyte maturation via NMD up-regulation. These findings imply that the GPX1 regulation via selenocysteine metabolism and the IGF-1-mediated NMD may be critical for the redox homeostasis of FF. We propose that GPX1 enhancers hold promise as therapeutics for enhancing the competence of FOCs oocytes. However, further in vivo studies are necessary to validate these findings observed in vitro.
摘要：
卵泡性卵巢囊肿（FOCs）的特征是卵巢中的卵泡直径>20毫米，并且在没有黄体的情况下持续>10天，导致无排卵,人类和家畜的卵泡发育和不育失调。尽管它们具有临床意义，FOCs对卵母细胞储备的精确影响，成熟,质量还有待探索。虽然在人类和牲畜种群中都观察到FOCs，它们在牲畜物种中尤为普遍。因此,家畜物种是研究FOCs分子复杂性的有价值的模型。因此，在这项研究中，使用山羊FOCs，我们进行了整合的蛋白质组学，代谢组学和功能分析表明，由于谷胱甘肽过氧化物酶（GPX1）的下调，FOCs卵泡液（FF）中活性氧（ROS）的增加，卵母细胞成熟受到阻碍，消除氧化应激所需的关键抗氧化剂硒酶。值得注意的是,GPX1的减少与游离硒和硒代半胱氨酸代谢酶的FF下降呈正相关,O-磷酰基-tRNA(Sec)硒转移酶(SEPSECS)和硒代半胱氨酸裂解酶(SCLY)水平。添加GPX1、硒代半胱氨酸、或培养基中的硒通过下调ROS来挽救由FOCsFF引起的卵母细胞成熟异常。此外,我们证明了用GPX1调节器代替，体外成熟培养基中的胰岛素样生长因子-I（IGF-1）通过抑制GPX1的无义介导的衰变（NMD）来下调ROS活性，从而改善了囊性FF中的卵母细胞成熟。相比之下,抑制IGF-1R和雷帕霉素复合物1（mTORC1）的靶标通过NMD上调阻碍了卵母细胞的成熟。这些发现暗示通过硒代半胱氨酸代谢和IGF-1介导的NMD的GPX1调节可能对于FF的氧化还原稳态至关重要。我们建议GPX1增强剂有望作为增强FOCs卵母细胞能力的治疗剂。然而,需要进一步的体内研究来验证这些在体外观察到的发现。
