Kabeer Fahad, Anjum Shaista, Behan Atique Ahmed, Usman Muhammad, Khan Nazima Yousaf, Azeem Muhammad, Din Hafiz Misbah Ud, Arshad Muhammad Adeel, Nazir Sadaf, Cheng Shiping, Buzdar Jameel Ahmed
Department of Surgery, International Education College, Jiangxi University of Chinese Medicine, Nanchang, 33000, China.
Department of Botany, University of Balochistan, Quetta, 87300, Pakistan.
J Mol Histol. 2025 Aug 23;56(5):278. doi: 10.1007/s10735-025-10554-9.
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.
氯氰菊酯（CYP）是一种常见的合成拟除虫菊酯类农药，与氧化应激介导的雌性生殖毒性有关。随着对生殖失败的关注度不断提高，探索天然替代品来缓解这一问题至关重要。为此，将36只雌性SD大鼠分为六个不同的组（每组n = 6），如阴性对照组（I组），而疾病对照组（II组）接受CYP诱导的毒性处理。III组接受5 mg/kg的标准药物枸橼酸氯米芬，IV、V和VI组在诱导毒性后分别给予25、50和100 mg/kg的山奈酚（KAE），持续14天。CYP暴露显著损害了雌性大鼠的生育能力，扰乱了发情周期，改变了卵巢和子宫系数。它还降低了抗氧化酶活性，同时提高了丙二醛水平。补充KAE通过恢复生育能力、使抗氧化酶活性正常化、降低丙二醛水平以及改善卵巢和子宫系数，有效逆转了这些变化。组织病理学分析显示，KAE处理组的子宫和卵巢完整性得以保留。此外，KAE调节了关键凋亡和氧化应激标志物（包括Bcl2、Bax、caspase-3、caspase-9和Nrf2）的mRNA表达。此外，基因本体研究表明，这些基因由于在线粒体和蛋白酶相关功能中强烈富集，参与了凋亡信号传导、免疫稳态和神经元调节。分子对接分析表明，与枸橼酸氯米芬相比，KAE表现出显著抑制Nrf2-KEAP1结合，对接分数良好表明了这一点。得出的结论是，KAE作为一种安全的天然替代品，具有对抗CYP诱导的氧化应激、细胞凋亡和生殖毒性的治疗潜力。
