Reversibility of the effects of subchronic exposure to the cancer chemotherapeutics bleomycin, etoposide, and cisplatin on spermatogenesis, fertility, and progeny outcome in the male rat

Testicular cancer is the most common cancer among young men of reproductive age. A regimen of bleomycin, etoposide, and cisplatin (BEP regimen) is the standard chemotherapy for testicular cancer. BEP has adverse effects on spermatogenic function that pose a long-term reproductive health risk to cancer survivors and their progeny. Using a rat model, we investigated the persistence of the effects of BEP on male reproductive function, fertility, and progeny outcome. Adult male Sprague-Dawley rats received a BEP regimen mimicking human clinical exposure (three 21-day cycles of etoposide and cisplatin on days 1-5 and bleomycin on days 2, 9, and 16, or vehicle). Reproductive and progeny outcome parameters were assessed at the end of BEP treatment and up to 9 weeks post-treatment, at 3-week intervals. BEP treatment reduced testicular weights and impaired spermatogenesis, characterized by abnormal testis histology and germ cell depletion. Germ cell apoptosis increased at least 3-fold in BEP-treated rats compared with controls at the end of treatment; 9 weeks posttreatment, germ cell apoptosis in BEP-treated rats did not differ from controls. BEP-exposed males were fertile; a decrease in litter size and an increase in preimplantation and postimplantation losses were observed. Preimplantation loss remained elevated in litters sired by BEP-treated males up to 9 weeks posttreatment; however, neither postimplantation loss nor litter sizes differed from controls. Thus, both germ cell apoptosis and the postimplantation loss induced by BEP treatment were reversible. The persistence of the elevation in preimplantation loss 9 weeks after BEP treatment suggests that spermatogonia are affected.