Micronutrient antioxidant supplementation alleviates valproic acid-induced oxidative stress and male infertility via the NRF2/HO-1 pathway

作者：Muhammad Arif Asghar, Bing Wan, Lu Li, Jie Zhang, Shixin Tang, Hang Han, Yuanyuan Yang, Long Chu, Qian Zhang, Xiao Zhang, Qinjian Zhao · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103685 · 被引用次数：16 · 研究领域：Pharmacological Effects and Toxicity Studies、Sperm and Testicular Function、Histone Deacetylase Inhibitors Research

BACKGROUND: Valproic Acid (VPA), a widely used anticonvulsant, is known to induce oxidative stress, contributing to male infertility. This study explores the potential of micronutrient antioxidants to improve fertility in VPA-treated individuals. METHODS: Six-week-old male mice were treated with VPA and supplemented with antioxidants, including l-Arginine (120 mg/kg), N-Acetylcysteine (NAC) (2 mg/kg), Taurine (200 mg/kg), L-Tryptophan (0.5 mg/kg), Zinc chloride (ZnCl2) (1.5 mg/kg), and Selenium (0.5 mg/kg). The dosing regimen lasted for 34 days. Sperm quality, oxidative stress, and inflammatory biomarkers were assessed through gene expression analysis, western blotting, histological assessments, TUNEL assays, and immunohistochemistry. Additionally, GC-2spd(ts) and HepG2 cell lines were used to examine the testicular and systemic effects of VPA and antioxidants. Network pharmacology was applied to identify key molecular targets and pathways. RESULTS: Antioxidant supplementation significantly improved sperm count, with l-Arginine showing an approximately 296.1 % increase, NAC a 270.7 % increase, and Taurine a 255.9 % increase compared to the VPA-only group. Furthermore, antioxidants enhanced semen volume, testosterone levels, sperm motility, morphology, and viability. Gene expression analysis revealed significant upregulation of key oxidative stress-related proteins such as SOD1, HO-1, NRF2, and NQO1. Western blot and histological analyses showed a reversal of oxidative stress ...