Male reproductive toxicity is a well-known adverse effect of cisplatin (CIS), an important antineoplastic agent used to control several types of cancers. Tadalafil (TDF), is a long-acting phosphodiesterase-5 (PDE5) inhibitor commonly used as treatment for erectile dysfunction. The aim of this work was to study the possible protective effect of TDF against CIS-induced testicular toxicity in rats and the possible involvement of Nrf2/HO-1 pathway, which demonstrates antioxidant and inflammatory activities utilizing zinc protoporphyrin-IX (ZnPP) as HO-1 inhibitor. Results revealed that TDF attenuated the CIS-induced disturbances in sperm count and activities, normalized the serum testosterone level, improved the CIS-induced changes in epididymal and testicular weights and restored the normal structure of testicular tissues. In addition, TDF upregulated the gene expression levels of Nrf2 and HO-1 and the activity of HO-1 whereas, it reduced the CIS-induced changes in testicular oxidative stress markers and the levels of inflammatory mediators (TNF-α and iNOS). Furthermore, TDF antagonized the CIS-induced increase in testicular gene expression of apoptotic markers caspase-3 and Bax, and the decrease in Bcl-2. However, ZnPP co-administration significantly attenuated all TDF-mediated improvements in CIS-induced testicular toxicity, biochemical changes, and apoptosis. In conclusion, TDF exerts a protective effect against CIS-induced reproductive toxicity in males, through different mechanisms, besides its inhibitory action to PDE5, possibly mediated by the upregulation of Nrf2/HO-1, along with its antioxidant, anti-inflammatory, and anti-apoptotic effects. Hence, the use of TDF represents a promising therapeutic approach to protect the male reproductive system from the harmful toxic effects of CIS.

男性生殖毒性是众所周知的顺铂 (CIS) 的副作用，顺铂是一种重要的抗肿瘤药物，用于控制多种类型的癌症。他达拉非 (TDF) 是一种长效磷酸二酯酶 5 (PDE5) 抑制剂，常用于治疗勃起功能障碍。这项工作的目的是研究 TDF 对 CIS 诱导的大鼠睾丸毒性的可能保护作用以及 Nrf2/HO-1 通路的可能参与，该通路证明了利用锌原卟啉-IX (ZnPP) 作为 H2O 的抗氧化和炎症活性-1 抑制剂。结果表明，TDF 可减轻 CIS 引起的精子数量和活动障碍，使血清睾酮水平正常化，改善 CIS 引起的附睾和睾丸重量变化，恢复睾丸组织的正常结构。此外，TDF 上调了 Nrf2 和 HO-1 的基因表达水平以及 HO-1 的活性，而它降低了 CIS 诱导的睾丸氧化应激标志物和炎症介质（TNF-α 和 iNOS）水平的变化。此外，TDF 拮抗 CIS 诱导的凋亡标志物 caspase-3 和 Bax 的睾丸基因表达增加，以及 Bcl-2 的减少。然而，ZnPP 共同给药显着减弱了 TDF 介导的 CIS 诱导的睾丸毒性、生化变化和细胞凋亡的所有改善。总之，TDF 除了对 PDE5 的抑制作用外，还通过不同的机制对 CIS 诱导的雄性生殖毒性发挥保护作用，这可能是由 Nrf2/HO-1 的上调及其抗氧化、抗炎和抗凋亡作用。因此，