Guarding the ovarian reserve: Maternal methyl donor supplementation protects against propylparaben-induced ovarian aging in offspring

Prenatal exposure to endocrine-disrupting chemicals is increasingly recognized as a contributing factor to female reproductive aging. Propylparaben (PRP), a widely used preservative with estrogenic activity, is ubiquitously detected in human biological samples, raising concern regarding gestational exposure. However, how prenatal PRP exposure affects ovarian development and whether nutritional interventions confer protection remain unclear. Here, pregnant mice were exposed to PRP from embryonic day 7.5 to E13.5, with or without maternal methyl donor (MD) supplementation. Prenatal PRP exposure was associated with impaired primordial follicle pool establishment as early as postnatal day 7 and reduced ovarian reserve and fertility in adult offspring. These effects were associated with increased oxidative stress, inflammation, fibrotic remodeling, hyperactivation of PI3K/AKT/mTOR signaling, and aberrant DNA methylation, collectively contributing to premature follicle activation and depletion. Maternal MD supplementation partially mitigated PRP-induced ovarian injury, helped preserve follicle homeostasis, and improved reproductive outcomes, accompanied by partial restoration of DNA methylation and moderation of aberrant pathway activation. These findings suggest that maternal MD intake may offer a potential nutritional approach to mitigating long-term reproductive risks associated with prenatal PRP exposure. • Prenatal propylparaben exposure accelerates offspring ovarian aging. • PRP induces oxidative stress, inflammation, fibrosis, and PI3K/AKT/mTOR activation. • PRP alters DNA methylation of key genes regulating primordial follicle activation. • Maternal methyl donor supplementation alleviates PRP-induced ovarian injury. • Methyl donors restore DNA methylation and improve fertility outcomes.