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

Guangyu Liu, Jing Lv, Jueshun Zhang, Kaikai Sun, Ziqi Wang, Xiaoya Li, Yuanyou Li, Dmitry Il, Tiantian Lian, Shayakhmetova Altyn

1 more author

Zhongliang Jiang

2026

Full text Open access: Gold Metadata (CSL-JSON)
DOI 10.1016/j.ecoenv.2026.120113
Data confidence 70 medium
How this score is calculated

It is built from checkable properties of the record itself: whether the article has a DOI, how many independent sources confirmed its data, whether the required fields are filled in, and how recent the latest confirmation is. Disagreement between sources and a missing identifier lower it. A value of 80 or above means the record was published without further checking; 60 to 79 means it is published at reduced confidence, with a manual check advisable. A record verified by an editor by hand is never pushed below 90 by a recalculation. This scores our data about the article, not the article itself.

Abstract

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. • BPF exposure impairs sperm quality and induces male reproductive toxicity. • BPF specifically targets and suppresses mitochondrial UCP2 in spermatocytes. • BPF-induced severe oxidative stress triggers autophagic dysregulation. • UCP2 overexpression or NAC intervention rescues BPF-induced testicular damage.