Sakr Samar, Ibrahim Nahla M, Ibrahim Basma A, Z El Desoky Ansam M, Abd Elbaki Bassant T, Eldesoqui Mamdouh, Mohammed Zeinab A
Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Egypt.
Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, Egypt.
Reprod Toxicol. 2025 Oct;137:109042. doi: 10.1016/j.reprotox.2025.109042. Epub 2025 Aug 30.
Azathioprine (AZA) is a widely employed immunosuppressive and chemotherapeutic medication that may exhibit detrimental effects on testes. Fluvastatin is a lipid-lowering agent with promising reproductive properties. This work aimed to assess the testicular toxicity of AZA and the probable protective role of fluvastatin. Forty adult male albino rats were assigned to four equal groups: Control, Fluvastatin (6 mg/kg), AZA (15 mg/kg), and AZA and fluvastatin. After 4 weeks, sera were obtained for testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) investigations. Semen samples were collected to test sperm parameters. Testes were harvested for biochemical investigations, gene transcription, and histological and immunohistochemical examinations. In the AZA group, results exposed a considerable decline in sperm parameters, sex hormones, and testicular weight. Oxidative stress was evident by the diminished catalase (CAT) and superoxide dismutase (SOD) activity, and malondialdehyde (MDA) levels elevation. Inflammation was reflected by increased NOD-Like Receptor family Pyrin domain-containing 3 inflammasome (NLRP3), Interleukin-6 (IL-6), and Interleukin-1 Beta (IL-1β), besides decreased Interleukin-10 (IL-10). Gene transcription indicated that AZA disrupts the mammalian target of the rapamycin (mTOR) cascade and the autophagic and apoptotic-related genes in testes, thus impairing the blood-testis barrier (BTB) and spermatogenesis. Testes displayed disorganized germinal epithelium and deformed seminiferous tubules. A positive p53 immunoreaction and a lost vimentin spoke-like pattern were also demonstrated. Fluvastatin exhibited antioxidant and anti-inflammatory defense, regulated the mTOR pathway, restored the lost autophagy/apoptosis balance, and improved the architectural and immunohistochemical alterations. Therefore, fluvastatin can be considered a candidate for future usage to combat AZA-induced testicular toxicity.
硫唑嘌呤（AZA）是一种广泛使用的免疫抑制剂和化疗药物，可能对睾丸产生有害影响。氟伐他汀是一种具有良好生殖特性的降脂药物。这项工作旨在评估AZA的睾丸毒性以及氟伐他汀可能的保护作用。将40只成年雄性白化大鼠分为四组，每组数量相等：对照组、氟伐他汀组（6毫克/千克）、AZA组（15毫克/千克）以及AZA与氟伐他汀联合组。4周后，采集血清进行睾酮、黄体生成素（LH）和卵泡刺激素（FSH）检测。收集精液样本以检测精子参数。摘取睾丸进行生化检测、基因转录以及组织学和免疫组织化学检查。在AZA组中，结果显示精子参数、性激素和睾丸重量显著下降。过氧化氢酶（CAT）和超氧化物歧化酶（SOD）活性降低以及丙二醛（MDA）水平升高表明存在氧化应激。除白细胞介素-10（IL-10）减少外，含NOD样受体家族吡咯结构域3炎性小体（NLRP3）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）增加反映出炎症。基因转录表明AZA破坏睾丸中的雷帕霉素哺乳动物靶标（mTOR）级联以及自噬和凋亡相关基因，从而损害血睾屏障（BTB）和精子发生。睾丸显示生精上皮紊乱和生精小管变形。还证实了p53免疫反应阳性和波形蛋白轮辐样模式消失。氟伐他汀表现出抗氧化和抗炎防御作用，调节mTOR途径，恢复失去的自噬/凋亡平衡，并改善结构和免疫组织化学改变。因此，氟伐他汀可被视为未来对抗AZA诱导的睾丸毒性的候选药物。
