Department of Clinical Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran.
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
BMC Pharmacol Toxicol. 2022 Jul 14;23(1):50. doi: 10.1186/s40360-022-00587-1.
Administration of antineoplastic drugs may cause azoospermia driving to subfertility. Production of animal azoospermia models is essential for evaluating new treatment methods before therapeutic interventions in human setup. This study aimed to investigate the toxic effects of Busulfan (an anticancer drug) on some vital organs and describe the best method and appropriate dose of Busulfan to induce an animal azoospermia model.
Rats were randomly assigned into four groups, treatment groups received 10 mg/kg, 40 mg/kg Busulfan intraperitoneally (IP), 5 mg/kg Busulfan intratesticular (IT), and control group. Blood, bone marrow, liver, renal, and testes samples were collected for histological (H&E staining), biochemical (serum levels of ALT, AST, ALP, creatinine, and urea), and hematological analyses.
Results revealed severe anemia and leukopenia in rats that received Busulfan via IP. By contrast, injection of 5 mg/kg Busulfan via IT did not cause anemia except with a mild decrease in RBC count. Non-significant differences in the M/E ratio were observed in all groups. The administration of 40 mg/kg of Busulfan led to evacuation and destruction in the spermatogenesis process with thin-walled seminiferous epithelium in most tubules, but in rats treated with 10 mg/kg of Busulfan, the normal spermatogenesis process was notified. IT injection of Busulfan contributed to the complete degradation of spermatogenesis in which all spermatogenic cells degenerated. In the renal tissue, hyperemia, extensive tubular necrosis degeneration, and hyaline casts were found after IP injection of Busulfan. In hepatic tissue, focal hemorrhagic, chronic cholangitis, and hepatocyte degeneration, and swelling were noticed. Biochemical analysis revealed apparent Busulfan toxicity of both hepatic and renal tissues in IP Busulfan-treated rats.
In summary, we found that the intratesticular injection of low doses of Busulfan (5 mg/kg) is a relatively non-invasive and safe method for producing the rat azoospermia model causing the least toxicity on vital organs.
抗肿瘤药物的给药可能导致不育症。在对人类进行治疗干预之前，评估新的治疗方法需要建立动物无精症模型。本研究旨在探讨白消安（一种抗癌药物）对某些重要器官的毒性作用，并描述诱导动物无精症模型的最佳方法和合适剂量。
将大鼠随机分为四组，实验组分别接受 10mg/kg、40mg/kg 白消安腹腔内（IP）注射、5mg/kg 白消安睾丸内（IT）注射和对照组。采集血液、骨髓、肝脏、肾脏和睾丸样本进行组织学（H&E 染色）、生化（血清 ALT、AST、ALP、肌酐和尿素水平）和血液学分析。
结果显示，接受 IP 注射白消安的大鼠出现严重贫血和白细胞减少。相比之下，IT 注射 5mg/kg 白消安不会导致贫血，只是红细胞计数略有下降。所有组的 M/E 比值均无显著差异。40mg/kg 白消安给药导致生精过程中精子排空和破坏，大多数小管的生精上皮变薄，但 10mg/kg 白消安处理的大鼠通知正常的生精过程。IT 注射白消安导致生精完全退化，所有精原细胞均退化。在肾组织中，IP 注射白消安后发现充血、广泛的肾小管坏死变性和透明管型。在肝组织中，发现局灶性出血、慢性胆管炎、肝细胞变性和肿胀。生化分析显示 IP 白消安处理的大鼠肝肾功能明显受损。
总之，我们发现睾丸内注射低剂量的白消安（5mg/kg）是一种相对非侵入性和安全的方法，可以产生对重要器官毒性最小的大鼠无精症模型。
