Kaempferol alleviates cypermethrin induced reproductive toxicity in rats via Nrf2-mediated antioxidant and apoptotic regulation with histopathological evidence: in vivo and in silico study.

Cypermethrin (CYP), a common synthetic pyrethroid pesticide, is associated with oxidative stress-mediated female reproductive toxicity. With increasing concern over reproductive failures, exploring natural alternatives to mitigate this problem is crucial. For this purpose, thirty-six female SD rats were divided into six different (n = 6) groups such as negative control (group I), while disease control (group II) was treated to CYP-induced toxicity. Group III received 5 mg/kg Clomiphene Citrate, a standard drug, and groups IV, V, and VI were subjected with Kaempferol (KAE) dosage of 25, 50 and 100 mg/kg, respectively, for 14 days after induction of toxicity. CYP exposure significantly impaired the fertility status of female rats, disrupted the estrous cycle, altered ovarian and uterine coefficients. It also reduced antioxidant enzyme activity while elevating malondialdehyde levels. KAE supplementation effectively reversed these changes by restoring fertility status, normalizing antioxidant enzyme activity and reducing MDA levels, and improving ovarian and uterine coefficients. Histopathological analysis revealed preserved uterine and ovarian integrity in KAE-treated groups. Furthermore, KAE regulated the mRNA expression of key apoptotic and oxidative stress markers including Bcl2, Bax, caspase-3, caspase-9, and Nrf2. Further, gene ontological study revealed that these genes are involved in apoptotic signaling, immune homeostasis and neuronal regulation due to strong enrichment in mitochondrial and protease related function. Molecular docking analysis demonstrated that KAE exhibited significantly, inhibit Nrf2-KEAP1 bonding compared to Clomiphene citrate, indicated by well docking score. It is concluded that KAE holds therapeutic potential as a safe, natural alternative to combat CYP induced oxidative stress, apoptosis, and reproductive toxicity.