Bisphenol F impairs spermatogenesis via UCP2-related oxidative stress and autophagy dysregulation

Driven by the global restrictions on Bisphenol A (BPA), Bisphenol F (BPF) has emerged as a significant environmental toxicant widely detected in food containers, daily diet and traditional medicinal formulations. However, the mechanisms underlying BPF-induced male reproductive toxicity remain poorly defined. Here, we demonstrate that environmentally relevant BPF exposure (250 μg/kg/day for 35 days) leads to dose-dependent testicular BPF bioaccumulation, disrupts testicular architecture and impairs sperm quality in male mice. In vitro assays using GC-2 cells reveal that BPF significantly reduces cell viability in a dose- and time-dependent manner while inducing oxidative stress and autophagy. Mechanistically, we identified the mitochondrial uncoupling protein 2 (UCP2) as the primary target of BPF toxicity. BPF suppresses UCP2 expression, which subsequently inactivates the AMPK/NRF2 signaling axis, restricting the nuclear translocation of NRF2 and downregulating HO-1. Notably, pharmacological intervention with N-acetyl-L-cysteine (NAC) or UCP2 overexpression successfully reactivates the AMPK/NRF2 pathway and mitigates BPF-induced autophagy. In conclusion, these findings establish a comprehensive adverse outcome pathway wherein UCP2-mediated oxidative stress act as the core driver of BPF-induced male reproductive toxicity, providing crucial hazard identification data for international regulatory agencies to reassess the global safety profiles and worldwide substitution policies of bisphenol analogs.