College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, People's Republic of China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Yangling, Shaanxi, People's Republic of China.
College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, People's Republic of China; Key Laboratory of Animal Biotechnology, Ministry of Agriculture, Yangling, Shaanxi, People's Republic of China.
Redox Biol. 2022 Feb;49:102215. doi: 10.1016/j.redox.2021.102215. Epub 2021 Dec 17.
In mammalian ovaries, oocytes are physically coupled to somatic granulosa cells, and this coupling is crucial for the growth and development of competent oocytes as it mediates the transfer of metabolic support molecules. However, aging-mediated dysregulation in communication between the oocytes and granulosa cells affects the oocyte quality. In the present study, we examined the defected germline-soma communication and reduced mRNA levels encoding key structural components of transzonal projections (TZPs) in maternally aged oocytes. Oral administration of melatonin to aged mice substantially increased TZPs and maintained the cumulus cells-oocyte communication, which played a central role in the production of adequate oocyte ATP levels and reducing the accumulation of reactive oxygen species (ROS), apoptosis, DNA damage, endoplasmic reticulum (ER) stress and spindle/chromosomal defects. This beneficial effect of melatonin was inhibited by carbenoxolone (CBX), a gap junctional uncoupler, which disrupts bidirectional communications between oocyte and somatic cells. Simultaneously, melatonin significantly increased the mRNA and protein levels corresponding to genes associated with TZPs and prevented TZP retraction in in vitro-cultured cumulus-oocyte complex (COCs). Furthermore, we infused melatonin and CBX into the COCs in vitro culture system and monitored the levels of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) in cumulus cells and oocytes. Notably, COCs treated with melatonin demonstrated improved NADPH and GSH levels. Of note, CBX was capable of reducing NADPH and GSH levels, aggravated the ROS accumulation and ER stress. Collectively, our data demonstrate the role of melatonin in preventing age-associated germline-soma communication defects, aiding the relay of antioxidant metabolic molecules for the maintenance of oocyte quality from cumulus cells, which have important potential for improving deficient phenotypes of maternally aged oocytes and the treatment of woman infertility.
在哺乳动物的卵巢中，卵母细胞与体颗粒细胞在物理上相连接，这种连接对于有能力的卵母细胞的生长和发育至关重要，因为它介导了代谢支持分子的转移。然而，衰老引起的卵母细胞和颗粒细胞之间的通讯失调会影响卵母细胞的质量。在本研究中，我们检查了母体衰老卵母细胞中缺陷的生殖-体通讯和编码透明带突起（TZPs）关键结构成分的 mRNA 水平降低。褪黑素的口服给予可显著增加 TZPs，并维持卵丘细胞-卵母细胞的通讯，这在产生足够的卵母细胞 ATP 水平和减少活性氧（ROS）积累、凋亡、DNA 损伤、内质网（ER）应激和纺锤体/染色体缺陷中发挥了核心作用。缝隙连接解偶联剂 carbenoxolone（CBX）抑制了褪黑素的这种有益作用，它破坏了卵母细胞和体细胞之间的双向通讯。同时，褪黑素显著增加了与 TZPs 相关的基因的 mRNA 和蛋白水平，并防止了体外培养的卵丘-卵母细胞复合体（COCs）中 TZP 的回缩。此外，我们在体外 COC 培养系统中注入褪黑素和 CBX，并监测卵丘细胞和卵母细胞中烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和谷胱甘肽（GSH）的水平。值得注意的是，用褪黑素处理的 COCs 表现出改善的 NADPH 和 GSH 水平。值得注意的是，CBX 能够降低 NADPH 和 GSH 水平，加剧 ROS 积累和 ER 应激。总的来说，我们的数据表明褪黑素在预防与年龄相关的生殖-体通讯缺陷方面发挥作用，有助于从卵丘细胞传递抗氧化代谢分子，以维持卵母细胞的质量，这对改善母体衰老卵母细胞的缺陷表型和治疗女性不育症具有重要的潜在意义。
