Sex-specific cypermethrin-induced hippocampal neurotoxicity is associated with alterations in signaling molecules for antioxidant defense, membrane integrity, apoptosis, and GABAergic integrity.

Cypermethrin(CP), a widely used pesticide, is recognized for its neurotoxic potential. The hippocampus is particularly susceptible to such damage, and sex may influence susceptibility. We investigated sex-specific hippocampal neurotoxicity following short-term CP exposure in rats, focusing on oxidative stress, apoptosis, membrane integrity, and GABAergic interneuron function. Adult male and female Wistar rats (n = 8/group/sex) were orally exposed to corn oil (vehicle control), low (6.25 mg/kg), or high (12.5 mg/kg) doses of CP for 14 days. High-dose CP induced significant weight loss in both males (p = 0.0055) and females (p = 0.0025). CP caused dose-dependent and sex-dependent alterations: females showed greater vulnerability in Na⁺/K⁺-ATPase and COX-2 suppression (treatment × sex interaction, p < 0.05), while males exhibited reduced Nrf2 expression, indicating impaired antioxidant response. Apoptotic markers revealed a distinct pattern; females showed robust Caspase-3 activation alongside increased BCL-2, whereas males displayed a net reduction in BCL-2. Furthermore, CP disrupted parvalbumin-positive GABAergic interneurons, with males showing greater susceptibility to this effect. Collectively, these findings demonstrate that CP induces sex-dependent hippocampal neurotoxicity, with males more vulnerable to oxidative stress and neuronal loss, and females to apoptotic signaling and GABAergic disruption. Understanding such sex-specific vulnerabilities is crucial for risk assessment.