Nifuroxazide attenuates bisphenol A-induced male reproductive toxicity by modulating oxidative stress, inflammation, and Nrf2/HO-1 and necroptosis pathways.

Bisphenol A (BPA) is a widely used industrial chemical with endocrine-disrupting properties. BPA is linked to male reproductive dysfunction through oxidative stress and cell death pathways. The intestinal antimicrobial nifuroxazide (NFZ) has recently been reported to possess antioxidant and anti-inflammatory activities. This study investigated whether NFZ protects against BPA-induced testicular dysfunction in rats, with a focus on redox imbalance, inflammatory signaling, and necroptosis. Adult male Wistar rats were divided into four groups: control, NFZ, BPA, and BPA + NFZ. Animals received daily oral NFZ, BPA, or both for 28 days, and samples were collected. BPA exposure induced pronounced testicular injury characterized by degenerative changes in seminiferous tubules, thickened basement membrane, collagen accumulation, and impaired sperm parameters. Hormonal analysis showed significant reductions in FSH, LH, and testosterone, along with downregulation of steroidogenic genes (StAR, 3β-HSD, 17β-HSD, and CYP17A1). BPA also increased lipid peroxidation, decreased antioxidant defenses, and upregulated NF-κB p65 and proinflammatory cytokines. Furthermore, BPA promoted necroptosis by elevating testicular RIP1, RIP3, MLKL, and caspase-8, while disrupting the Keap1/Nrf2/HO-1 pathway. NFZ markedly counteracted these effects, restoring testicular histoarchitecture, improving sperm quality, normalizing hormone levels, suppressing oxidative and inflammatory responses, attenuating necroptotic signaling, and activating Nrf2/HO-1-mediated cytoprotection. In conclusion, NFZ provides significant protection against BPA-induced testicular toxicity by targeting oxidative stress, inflammatory signaling, and necroptosis, in part through activation of the Keap1/Nrf2/HO-1 axis. These findings suggest NFZ as a promising candidate for preserving male reproductive health in the context of environmental toxicant exposure.