Respiratory exposure to polymethyl methacrylate nanoplastics impairs female fertility via ovarian accumulation and oocyte quality deterioration in mice.

Respiratory exposure to airborne polymethyl methacrylate (PMMA) nanoplastics (NPs) represents a critical, yet poorly mechanistically defined, hazard to female reproductive physiology. Here, we investigated the reproductive toxicity of PMMA NPs (average diameter ∼55 nm; negative surface charge) following intratracheal instillation in mice (0.2-100 μg/day for 7 days). Fluorescently labeled PMMA NPs translocated systemically and accumulated in ovarian tissue. Exposure disrupted the estrous cycle and suppressed the pituitary-ovarian endocrine axis, characterized by marked reductions in circulating follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone. Histological analysis revealed selective depletion of secondary follicles accompanied by increased follicular atresia. Transcriptomic and protein-level analyses identified widespread downregulation of genes essential for ovarian function, including Esr1, Angpt1, Cftr, and Cd36. Specifically, we confirmed the suppression of the local CYP19A1-estradiol-ESR1-AKT survival signaling axis, accompanied by reduced expression of CFTR and CD36, which are associated with follicular growth and maturation. In vitro maturation assays further indicated impaired oocyte developmental competence following exposure to PMMA NPs. In reproductive outcome assessments, pre-pregnancy exposure alone did not significantly affect initial pregnancy rates, whereas continuous exposure extending into early gestation resulted in reduced pregnancy success. Collectively, these findings demonstrate that respiratory exposure to PMMA NPs compromises female fertility by disrupting both systemic gonadotropin support and localized intraovarian networks.