Fluvastatin mitigates the testicular toxicity of Azathioprine via regulating mTOR pathway and restoring autophagy/apoptosis balance

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology Pub Date : 2025-08-30 DOI:10.1016/j.reprotox.2025.109042

Samar Sakr , Nahla M. Ibrahim , Basma A. Ibrahim , Ansam M. Z. El Desoky , Bassant T. Abd Elbaki , Mamdouh Eldesoqui , Zeinab A. Mohammed

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引用次数: 0

Abstract

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.

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氟伐他汀通过调节mTOR通路和恢复自噬/凋亡平衡来减轻硫唑嘌呤的睾丸毒性

硫唑嘌呤（AZA）是一种广泛使用的免疫抑制和化疗药物，可能对睾丸产生有害影响。氟伐他汀是一种具有良好生殖性能的降脂剂。本工作旨在评估AZA的睾丸毒性和氟伐他汀可能的保护作用。将40只成年雄性白化大鼠分为4组：对照组、氟伐他汀（6 mg/kg）、AZA（15 mg/kg）、AZA和氟伐他汀。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。采集精液样本检测精子参数。收集睾丸进行生化调查、基因转录、组织学和免疫组织化学检查。在AZA组中，结果显示精子参数、性激素和睾丸重量明显下降。过氧化氢酶（CAT）和超氧化物歧化酶（SOD）活性降低，丙二醛（MDA）水平升高，表明氧化应激明显。炎症反应表现为nod样受体家族含Pyrin结构域3炎性小体（NLRP3）、白细胞介素-6 （IL-6）、白细胞介素-1β (IL-1β)升高，白细胞介素-10 （IL-10）降低。基因转录表明，AZA破坏了哺乳动物雷帕霉素（rapamycin, mTOR）级联靶蛋白以及睾丸自噬和凋亡相关基因，从而损害了血睾丸屏障（blood-睾丸barrier， BTB）和精子发生。睾丸生发上皮组织紊乱，精小管畸形。阳性的p53免疫反应和丢失的vimentin辐条样模式也被证实。氟伐他汀具有抗氧化和抗炎防御作用，调节mTOR通路，恢复失去的自噬/凋亡平衡，改善结构和免疫组织化学改变。因此，氟伐他汀可以被认为是未来用于对抗aza诱导的睾丸毒性的候选药物。

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来源期刊

Reproductive toxicology 生物-毒理学

CiteScore

6.50

自引率

3.00%

发文量

131

审稿时长

45 days

期刊介绍： Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.