Gestational fluoride exposure compromises ovarian function via SIRT1-ATF4 axis in female offspring

Fluoride exposure is linked to impaired reproductive capacity in female mammals. Ovarian reserve is established during fetal development. Maternal exposure to adverse environmental factors during pregnancy can impair offspring ovarian function, with prenatal fluoride exposure potentially contributing to ovarian dysfunction, though underlying mechanisms remain unclear. We established a model with C57BL/6 J mice that were given 100 mg/L sodium fluoride (NaF) from the 1st day of pregnancy to the 20th day. NaF exposure impaired ovarian function in female offspring, manifested as reduced ovarian reserve, disrupted follicular maturation, and increased follicular atresia. Molecular analyses demonstrated elevated ATF4 expression, decreased SIRT1 levels, upregulated CHOP, and activation of the BAX/BCL-2 apoptotic pathway in offspring ovaries, indicating ovarian apoptosis as the primary mechanism of ovarian dysfunction. Chromatin immunoprecipitation (ChIP) revealed that NaF exposure increased H3K9ac binding at the Atf4 promoter region, suggesting SIRT1-mediated regulation enhances -Atf4 acetylation and transcription. Consistently, NaF-treated KGN cells showed reduced SIRT1 and increased ATF4. Critically, resveratrol, a specific SIRT1 activator, effectively upregulated SIRT1 expression in both fluoride-exposed animal models and KGN cells. This intervention ameliorated ovarian dysfunction phenotypes and inhibited granulosa cell apoptosis. These results establish SIRT1-ATF4 signaling as the mechanistic core of fluoride-induced ovotoxicity and validate its targeting with Resveratrol as a therapeutic strategy against environmental ovarian dysfunction.