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Published-Ahead-of-Print February 22, 2008, DOI:10.2164/jandrol.107.004218

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Reversibility of the Effects of Subchronic Exposure to Cancer Chemotherapeutics, Bleomycin, Etoposide and Cisplatin (BEP), on Spermatogenesis, Fertility and Progeny Outcome in the Male Ratin the Male Rat

Ludovic Marcon , Barbara F. Hales , and Bernard Robaire *

* To whom correspondence should be addressed. E-mail: bernard.robaire{at}mcgill.ca.

Testicular cancer is the most common cancer among young men of reproductive age. A regimen of bleomycin, etoposide and cis-platin (BEP) 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; bleomycin on days two, nine, and 16) or vehicle. Reproductive and progeny outcome parameters were assessed at the end of BEP treatment and up to nine weeks post-treatment, at three week intervals. BEP treatment reduced testicular weights and impaired spermatogenesis, characterized by abnormal testis histology and germ cell depletion. Germ cell apoptosis increased ≥3-fold in BEP-treated rats compared to controls at the end of treatment; nine weeks post-treatment, germ cell apoptosis in BEP-treated rats did not differ from controls. BEP-exposed males were fertile; a decrease in litter size and increase in pre- and post-implantation losses were observed. Pre-implantation loss remained elevated in litters sired by BEP-treated males up to nine weeks post-treatment; however, neither post-implantation loss nor litter sizes differed from controls. Thus, both germ cell apoptosis and the post-implantation loss induced by BEP treatment were reversible. The persistence of the elevation in pre-implantation loss nine weeks after BEP treatment suggests that spermatogonia are affected.


Key words: Fertility • Infertility • Spermatogenesis • Testis • cancer therapeutics • progeny outcome






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