Bisphenol F Exposure Induces Ovarian Ferroptosis via the ERβ–ATM–Ferritinophagy Axis

Abstract

Bisphenol F (BPF) has rapidly emerged as a primary substitute for bisphenol A (BPA) and a ubiquitous environmental contaminant, yet its reproductive toxicity remains poorly understood, particularly at low doses. Here, we demonstrate that oral exposure to BPF (as low as 250 μg/kg) induces ovarian hypertrophy, disrupted follicular architecture and cumulus-oocyte communication, and reduced serum estradiol and progesterone in mice by triggering ferroptosis. Integrating multiomics approaches, we identified NCOA4-mediated ferritinophagy as the central cellular driver of this process. In granulosa cells, pharmacologic inhibition of autophagy and gene silencing blocked NCOA4 phosphorylation, ferritin degradation, iron overload, and ferroptosis. Mechanistically, we reveal a new signaling axis wherein BPF promotes the physical interaction between membrane-associated ERβ and the kinase ATM. This interaction triggers ATM activation and subsequent phosphorylation of NCOA4, thereby accelerating ferritin degradation and iron overload. Structural analysis identifies G2296 as the critical interface residue; importantly, an ATM–G2296A point mutation disrupts the ERβ–ATM interaction and abolishes BPF-induced ferroptosis. These findings elucidate a distinct molecular mechanism of ovarian injury driven by low-dose BPF exposure, underscoring the urgent need to reassess the safety profiles of BPF-containing materials.