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

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

  • Ecotoxicol Environ Saf. 2024 Oct 15:285:117061. doi: 10.1016/j.ecoenv.2024.117061.
Shaowei Wang 1,  Han Lu 2,  Ming Su 3,  Jiayi He 3,  Yunbing Tang 2,  Yingfen Ying 2,  Zhuoqi Chen 2,  Qiqi Zhu 3,  Ren-Shan Ge 4,  Huitao Li 3,  Xiaoheng Li 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University; Key Laboratory of Pediatric Anesthesiology, Ministry of Education,Wenzhou Medical University; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University; Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China.
  • 2 Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China.
  • 3 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University; Key Laboratory of Pediatric Anesthesiology, Ministry of Education,Wenzhou Medical University; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University.
  • 4 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University; Key Laboratory of Pediatric Anesthesiology, Ministry of Education,Wenzhou Medical University; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University; Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, People's Republic of China. Electronic address: renshan_ge@wmu.edu.cn.
  • 5 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University; Key Laboratory of Pediatric Anesthesiology, Ministry of Education,Wenzhou Medical University; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University. Electronic address: lixiaoheng8611@wmu.edu.cn.
PMID: 39303633 DOI: 10.1016/j.ecoenv.2024.117061
Abstract

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.

Keywords

BPH; Leydig cells; M6A modification; Testosterone; YTHDF3.

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