Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada.
Biol Reprod. 2012 May 31;86(5):166, 1-10. doi: 10.1095/biolreprod.111.098616. Print 2012 May.
Testicular cancer, currently the most common cancer affecting men of reproductive age, is one of the most curable malignancies due to the progress made in the early diagnosis and effective treatment of this disease. The coadministration of bleomycin, etoposide, and cis-platinum (BEP) has brought the 5-yr survival rate of testis cancer patients to over 90%. However, this treatment results in reproductive chemotoxic effects. We assessed the effect of BEP treatment on sperm chromatin integrity and sperm head protein profiles of adult male Brown Norway rats following 9 wk of treatment with BEP and in animals treated for 9 wk and then subjected to a 9-wk recovery period. Both the susceptibility of DNA to denaturation and the number of strand breaks were significantly increased in mature sperm following 9 wk of treatment with BEP; proteomic analysis revealed that the expression of several proteins, including HSP90AA1 and HSP90B1, was markedly affected. Following a 9-wk recovery period, mature sperm did not show significant DNA damage, indicating that repair had potentially occurred. Interestingly, the protamination level of the sperm of these animals was significantly decreased, while histones HIST1H1D (H1.2), HIST1H4B (H4), HIST2H2AA3 (H2A1), and HIST1H2BA (H2B1A) were concomitantly up-regulated; this was not observed in the sperm immediately following 9 wk of treatment. Thus, there are persistent effects on proteins in sperm heads from the cauda epididymidis 9 wk posttreatment, in the absence of DNA strand breaks. We suggest that these effects on the sperm head proteome may contribute to long-lasting adverse effects in the progeny of BEP-exposed males.
睾丸癌是目前最常见的影响生殖年龄男性的癌症之一，由于在早期诊断和有效治疗这种疾病方面取得的进展，它是最可治愈的恶性肿瘤之一。博来霉素、依托泊苷和顺铂（BEP）的联合应用使睾丸癌患者的 5 年生存率超过 90%。然而，这种治疗会导致生殖细胞的化学毒性作用。我们评估了 BEP 治疗对成年雄性棕色挪威大鼠精子染色质完整性和精子头部蛋白谱的影响，这些大鼠在接受 9 周 BEP 治疗后以及在接受 9 周治疗然后进行 9 周恢复期的动物中。在接受 9 周 BEP 治疗后，成熟精子的 DNA 变性易感性和链断裂数量显著增加；蛋白质组学分析表明，包括 HSP90AA1 和 HSP90B1 在内的几种蛋白质的表达明显受到影响。在 9 周恢复期后，成熟精子没有表现出明显的 DNA 损伤，表明可能发生了修复。有趣的是，这些动物的精子鱼精蛋白水平显著降低，而组蛋白 HIST1H1D（H1.2）、HIST1H4B（H4）、HIST2H2AA3（H2A1）和 HIST1H2BA（H2B1A）同时上调；在接受 9 周治疗后立即观察到这种情况。因此，在没有 DNA 链断裂的情况下，在治疗后 9 周时，来自附睾尾部的精子头部的蛋白质仍然存在持久的影响。我们认为，这些对精子头部蛋白质组的影响可能导致 BEP 暴露雄性后代的长期不良影响。
