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The challenges of male fertility after cancer treatments, "Beyond the Abstract," by Bernard Robaire and Géraldine Delbès

BERKELEY, CA (UroToday.com) - The incidence of cancer affecting men at the reproductive age is increasing worldwide. Thanks to early diagnosis and the improved treatment success with combination chemotherapies, the survival rates of many cancers that affect these young men have improved tremendously in recent years. Survivorship, with an emphasis on the quality of life of this expanding volume of cancer patients is thus an increasingly important healthcare issue.[1] Interestingly, almost 80% of childless cancer survivors desire to have children and believe that their experience of surviving cancer makes them better parents.[2]

Our recent prospective study on young cancer patients demonstrates that, even before receiving chemotherapy, a significant proportion of patients have poor semen quality .[3] Moreover, cytotoxic chemotherapy negatively affects spermatogenesis, quantitatively and qualitatively.[4, 5] Finally, in these cancer survivors, we have observed that despite the recovery of spermatogenesis as demonstrated by an increase in sperm density and motility in semen two-years post-chemotherapy, there is an increased incidence of aneuploidy in sperm,[6] abnormal chromatin structure [5, 7] and epigenetic defects.[8] Such persistent damage may contribute to increased risks of male-mediated adverse reproductive outcomes in cancer survivors. Defining the underlying mechanism of sperm functional damage after chemotherapy should yield clinically relevant information that will help clinicians to improve the quality of counseling to these young cancer patients on the risks of impaired reproductive health after cancer.

With this goal, we have shown, using the rat model, that the chemotherapeutic cocktail used to treat testicular cancer (BEP: bleomycin, etoposide and cisplatin) induces a dose and time-dependant appearance of defects in spermatogenesis,[9] abnormalities in sperm chromatin[10] and epigenetic defects,[11] ultimately leading to an increased postnatal mortality in pups sired by males treated with BEP.[9] DNA damage in mature spermatozoa was observed only after 9 weeks of treatment, suggesting that BEP treatment induces damage in spermatogonial DNA that cannot be repaired and is subsequently detected in mature spermatozoa.[10] Using transcriptome profiling, we investigated the signaling pathways activated in germ cells after BEP exposure. We found that, in spite of increased DNA damage, there was a lack of activation of DNA repair pathways in round spermatid,[12] but a selective induction of the glutathione-S transferase (GST) gene family.[13] We hypothesized that the GST family plays a key role in male germ cell survival after BEP exposure despite the amount of DNA damage. The demonstration of a specific pathway involved in male germ cell survival is very limited technically as there is a lack of relevant cell lines for germ cells to study the role of specific pathways in vitro. Germ cells at different stages of spermatogenesis maturation can be isolated using BSA gradient and maintained as primary culture, but their survival in vitro without supporting cells is limited. With these limitations in mind, our study suggesting male germ cell survival pathways is promising and could lead to the discovery of biomarkers of male germ cell insults as well as new therapeutic perspectives to minimize the gonadotoxic effect of chemotherapy.

References:

  1. Chan PT. Fertility after cancer in men. Can Urol Assoc J. June 2009; 3(3): 223–224.
  2. Schover LR. Psychosocial aspects of infertility and decisions about reproduction in Young cancer survivors: a review. Med Pediatr Oncol 1999; 33: 53-59.
  3. O'Flaherty C, Vaisheva F, Hales BF, Chan P, Robaire B. Characterization of sperm chromatin quality in testicular cancer and Hodgkin's lymphoma patients prior to chemotherapy. Hum Reprod 2008; 23: 1044-1052.
  4. Chan P. T. K., Rosberger Z., Achille M., Hales B. and Robaire B. Multi-Center Prospective analysis of the acute andrological profile changes in young men undergoing combination chemotherapy for neoplasia. Abstract at the 31st American Society of Andrology Annual Meeting 2006.
  5. O'Flaherty C, Hales BF, Chan P, Robaire B. Impact of chemotherapeutics and advanced testicular cancer or Hodgkin lymphoma on sperm deoxyribonucleic acid integrity. Fertil Steril. Sep 2010;94(4):1374-9
  6. Tempest HG, Ko E, Chan P, Robaire B, Rademaker A, Martin RH. Sperm aneuploidy frequencies analyzed before and after chemotherapy in testicular cancer andHodgkin's lymphoma patients. Hum Reprod 2008; 23: 251-258.
  7. O'Flaherty CM, Chan PT, Hales BF, Robaire B. Sperm chromatin structure components are differentially repaired in cancer survivors. J Androl. 2012 Jul-Aug;33(4):629-36
  8. Chan D., Delbès G., O’Flaherty C., Chan P., Robaire B. and Trasler J.M.. Effects of cancer and chemotherapy treatments on the human sperm epigenome. CFAS 57th Annual Meeting, Toronto (Canada) Sept 2011.
  9. Bieber AM, Marcon L, Hales BF, Robaire B. Effects of chemotherapeutic agents for testicular cancer on the male rat reproductive system, spermatozoa, and fertility. J Androl. 2006 Mar-Apr;27(2):189-200
  10. Delbes G, Hales BF, Robaire B. Effects of the chemotherapy cocktail used to treat testicular cancer on sperm chromatin integrity. J Androl. 2007 Mar-Apr;28(2):241-9
  11. Chan D, Delbès G, Landry M, Robaire B, Trasler JM. Epigenetic alterations in sperm DNA associated with testicular cancer treatment. Toxicol Sci. 2012 Feb;125(2):532-43
  12. Delbès G, Chan D, Pakarinen P, Trasler JM, Hales BF, Robaire B. Impact of the chemotherapy cocktail used to treat testicular cancer on the gene expression profile of germ cells from male Brown-Norway rats. Biol Reprod. 2009 Feb;80(2):320-7
  13. Delbès G, Chan D, Hales BF, Trasler JM, Robaire B. Selective induction of glutathione S-transferases in round spermatids from the Brown-Norway rat by the chemotherapeutic regimen for testicular cancer. Reprod Toxicol. 2013 Apr;36:24-32

Written by:
Bernard Robairea and Géraldine Delbèsb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

aDepartments of Pharmacology and Therapeutics and of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada.
bINRS, Institut Armand Frappier, Laval, Quebec, Canada

Selective induction of glutathione S-transferases in round spermatids from the Brown-Norway rat by the chemotherapeutic regimen for testicular cancer - Abstract

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