Modulation of Redox Homeostasis, Inflammation, and Necroptosis by Carbocisteine Protects Against Bisphenol A-Induced Male Reproductive Toxicity

Abstract

The widely used industrial compound, bisphenol A (BPA), has been implicated in male reproductive impairment and other endocrine-disrupting effects. Carbocisteine (S-carboxymethylcysteine (SCMC)) is a thiol-based mucolytic with antioxidant and cytoprotective properties. This study evaluated SCMC for its potential to mitigate BPA-induced reproductive toxicity in male rats. Wistar rats were assigned to four experimental groups: control, SCMC, BPA, and BPA + SCMC, and received daily oral treatments for 28 consecutive days. BPA administration elicited testicular damage, evidenced by degeneration of seminiferous tubules, thickening of the basement membrane, collagen deposition, and marked deterioration of sperm parameters. Significant suppression of circulating gonadotropins and testosterone, concomitant with suppression of key steroidogenic genes were reported in BPA-administered rats. BPA exposure elevated lipid peroxidation, suppressed antioxidant defenses, and triggered inflammatory cascades through NF-κB and cytokine upregulation. Moreover, BPA induced necroptotic cell death, as reflected by increased expression of RIP1, RIP3, and MLKL, alongside impairment of Nrf2/HO-1 signaling. SCMC supplementation alleviated these pathological alterations, preserved tissue structure, enhanced sperm quality, restored hormonal profiles, and suppressed oxidative stress, inflammation, and necroptotic mediators. These effects were associated with upregulation of testicular Nrf2/HO-1 pathway and antioxidant defenses. In conclusion, SCMC confers protection against BPA-mediated testicular dysfunction by mitigating oxidative injury, inflammation, and necroptosis, and modulating Keap-1/Nrf2/HO-1 axis. This highlights SCMC as a potential therapeutic strategy for protecting male reproductive health in individuals at risk of BPA exposure.