Bisphenol H exposure disrupts Leydig cell function in adult rats via oxidative stress-mediated m6A modifications: Implications for reproductive toxicity

• Published in: Ecotoxicology and environmental safety Vol. 285; p. 117061
• Main Authors: Wang, Shaowei, Lu, Han, Su, Ming, He, Jiayi, Tang, Yunbing, Ying, Yingfen, Chen, Zhuoqi, Zhu, Qiqi, Ge, Ren-Shan, Li, Huitao, Li, Xiaoheng
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.10.2024; Elsevier
• Subjects: BPH; Leydig cells; M6A modification; Testosterone; YTHDF3; Testosterone; BPH; YTHDF3; M6A modification; Leydig cells
• ISSN: 0147-6513; 1090-2414; 1090-2414
• DOI: 10.1016/j.ecoenv.2024.117061

Bisphenol H (BPH) has emerged as a potential alternative to bisphenol A (BPA), which has been curtailed for use due to concerns over its reproductive and endocrine toxicity. This study investigates whether BPH exerts antiandrogenic effects by impairing Leydig cell function, a critical component in testosterone production. We administered orally BPH to adult male rats at doses of 0, 1, 10, and 100 mg/kg/day for 7 days. Notably, BPH treatment resulted in a dose-dependent reduction in testicular testosterone levels, with significant decreases observed at ≥ 1 mg/kg/day. Additionally, BPH affected the expression of key genes involved in steroidogenesis and cholesterol metabolism, including Nr5a1, Nr3c4, Lhcgr, Scarb1, and Star, at higher doses (10 and/or 100 mg/kg/day). The study also revealed alterations in antioxidant gene expression (Sod2 and Cat) and modulation of m6A-related genes (Ythdf1–3 and Foxo3) and their proteins. Through MeRIP-qPCR analysis, we identified increased m6A modifications in Scarb1 and Star genes following BPH exposure. In vitro experiments with primary Leydig cells confirmed that BPH enhanced oxidative stress and diminished testosterone production, which were partially mitigated by antioxidant vitamin E supplementation and Ythdf3 knockdown. Meanwhile, simultaneous administration of BPH and vitamin E to primary Leydig cells partially counteracted BPH-induced alterations in the Ythdf3 expression. Our findings underscore a novel mechanism by which BPH disrupts Leydig cell function through the oxidative stress-m6A modification-autophagy pathway, raising concerns about its potential reproductive toxicity. [Display omitted] •BPH significantly reduces testicular testosterone levels.•BPH downregulates the expression of steroidogenesis-related genes.•BPH induces an increase in m6A levels of Scarb1 and Star genes in Leydig cells.•BPH increases oxidative stress and autophagy levels in Leydig cells.