Manfei Si, Xianglei Xiong, Chuyu Yun, Yongyan Chen, Hongyu Niu, Yi Qu, Mengyu Liu, Yuqian Wang, Lixuan Huang, Xiaoyu Long, Wei Wang, Rui Yang, Rui Liu, Y J Pang, Xiumei Zhen, Rong Li, Tian Tian, Xinyu Qi, Jie Qiao
• We identified a significant association between the presence of specific MNP polymers (especially polyamide 66) in human follicular fluid and diminished ovarian reserve (DOR), building upon prior reports of MNP detection in follicular fluid. • Exposure to MNPs can induce DOR-like phenotypes in mice by disrupting the intestinal barrier and reducing the abundance of P. goldesteini. • MNPs activated the PI3K/AKT/mTOR signaling pathway, leading to granulosa cell dysfunction and subsequently diminished ovarian reserve. Ovarian aging is a significant concern, yet the influencing factors remain unclear. Environmental factors are crucial determinants of diminished ovarian reserve (DOR). Microplastics and nanoplastics (MNPs) are widespread in the environment and pose health risks. The effect of MNPs on ovarian function remains uncertain. The study aims to investigate whether exposure to MNPs negatively affects ovarian function. In particular, the research focuses on elucidating the association between MNPs—especially polyamide 66—and DOR, and validating Parabacteroides goldsteinii (P. goldsteinii) as a potential intervention. We conducted a case-control study analyzing MNPs in follicular fluid from 110 DOR patients and 110 age-matched controls. A mouse MNPs-exposure model assessed ovarian function and intestinal barrier integrity. Gut microbiota alterations were analyzed by metagenomic sequencing of fecal samples from MNPs-exposed mice. P. goldsteinii was identified and selected for microbial intervention, administered via oral gavage. The human granulosa cell line (KGN) was treated with MNPs for 48 h, followed by transcriptomic sequencing to examine PI3K/AKT/mTOR pathway alterations. Human follicular fluid contained multiple MNPs, with polyamide 66 (PA66) levels significantly linked to DOR. Polystyrene (PS) and polyvinyl chloride (PVC) concentrations were also higher in the DOR group. MNPs induced DOR-like phenotypes in mice, causing hormonal imbalances, disrupted estrous cycles, and increased atretic follicles, alongside intestinal barrier damage and gut microbiota dysbiosis. Notably, the abundance of P. goldsteinii and its key metabolite 7-keto-lithocholic acid was significantly reduced following MNPs exposure. Supplementation with P. goldsteinii effectively reversed MNPs-induced DOR-like phenotypes, restored hormonal homeostasis, normalized estrous cyclicity, reduced follicular atresia, and elevated 7-keto-LCA levels. Mechanistically, MNPs triggered the PI3K/AKT/mTOR pathway, impairing granulosa cell function and ovarian reserve. These findings elucidate how exposure to MNPs may harm female ovarian function and provide potential new strategies for ameliorating reproductive disorders through the environment‒gut‒ovarian axis.