Investigation of Thymoquinone's Effects on Bisphenol A-Induced Neurotoxicity, Keap-1/Nrf-2 Signalling, Oxidative Stress, and Behavior in Rats

Abstract

Chronic low-dose exposure to bisphenol A (BPA), a widely used environmental endocrine disruptor, has been increasingly associated with oxidative stress-mediated neurotoxicity. Thymoquinone (TQ), a bioactive constituent of Nigella sativa, exhibits potent antioxidant properties; however, its neuroprotective potential against BPA-induced toxicity remains incompletely understood. Given the pervasive nature of BPA exposure, identifying effective and accessible neuroprotective strategies is of growing importance. This study investigated the effects of TQ on oxidative stress, Keap-1/ Nrf-2 signaling, behavior, and histopathological alterations in rats exposed to BPA. A total of 24 adult male Wistar Albino rats were randomly assigned to four groups (n = 6/group): control, BPA, BPA + 10 mg/kg TQ (BPA+TQ I), and BPA + 20 mg/ kg TQ (BPA+TQ II). BPA (50 µg/kg) and TQ were administered intragastrically for 30 days. BPA exposure induced significant behavioral impairments, oxidative stress, disruption of Keap-1/Nrf-2 signaling, and marked histopathological damage in the hippocampus and cerebral cortex. TQ treatment significantly improved locomotor activity and depression-like behavior, reduced lipid peroxidation and nitric oxide levels, restored glutathione-related antioxidant capacity, and normalized Keap-1 and Nrf-2 expression (p < 0.001). These protective effects were more pronounced at the higher TQ dose. Taken together, these findings demonstrate that thymoquinone mitigates BPA-induced neurotoxicity through modulation of oxidative stress and the Keap-1/ Nrf-2 signaling pathway, highlighting its potential as a neuroprotective agent against environmentally relevant BPA exposure.