Bisphenol AF induces overactivation of primordial follicles via Hippo signaling and causes premature ovarian insufficiency in mice

Premature depletion of ovarian reserve is a cause of female infertility. Plasticizer Bisphenol AF (BPAF) residues have been found in human reproductive-related samples. However, little is known about its influence on the ovarian reserve. Here, we demonstrate that BPAF exposure causes excessive activation of primordial follicles through Hippo signaling in young females, resulting in rapid exhaustion of the ovarian reserve and, ultimately, premature ovarian insufficiency. We found that oral ingestion of BPAF disrupts normal estrous cyclicity and induces constant estrus in a dose-dependent manner. BPAF can upregulate the expression of YAP transcriptional coactivator. Intriguingly, only the high dose of BPAF inhibits Hippo signaling by eliciting a substantial decrease in phospho-YAP levels. Through such regulatory effects, BPAF causes YAP translocation into the nucleus and triggers the overactivation of primordial follicles. Collectively, this study proposes a novel toxicological mechanism explaining the negative impact of BPAF on the ovarian health of young females.