Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer

Tharmalingam, M. D. et al. (2020) Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer. BMC Medicine, 18, 374. (doi: 10.1186/s12916-020-01844-y) (PMID:33272271) (PMCID:PMC7716476)

Abstract

Background: Clinical studies indicate chemotherapy agents used in childhood cancer treatment regimens may impact future fertility. However, effects of individual agents on prepubertal human testis, necessary to identify later risk, have not been determined. The study aimed to investigate the impact of cisplatin, commonly used in childhood cancer, on immature (foetal and prepubertal) human testicular tissues. Comparison was made with carboplatin, which is used as an alternative to cisplatin in order to reduce toxicity in healthy tissues. Methods: We developed an organotypic culture system combined with xenografting to determine the effect of clinically-relevant exposure to platinum-based chemotherapeutics on human testis. Human foetal and prepubertal testicular tissues were cultured and exposed to cisplatin, carboplatin or vehicle for 24 h, followed by 24–240 h in culture or long-term xenografting. Survival, proliferation and apoptosis of prepubertal germ stem cell populations (gonocytes and spermatogonia), critical for sperm production in adulthood, were quantified. Results: Cisplatin exposure resulted in a significant reduction in the total number of germ cells (− 44%, p < 0.0001) in human foetal testis, which involved an initial loss of gonocytes followed by a significant reduction in spermatogonia. This coincided with a reduction (− 70%, p < 0.05) in germ cell proliferation. Cisplatin exposure resulted in similar effects on total germ cell number (including spermatogonial stem cells) in prepubertal human testicular tissues, demonstrating direct relevance to childhood cancer patients. Xenografting of cisplatin-exposed human foetal testicular tissue demonstrated that germ cell loss (− 42%, p < 0.01) persisted at 12 weeks. Comparison between exposures to human-relevant concentrations of cisplatin and carboplatin revealed a very similar degree of germ cell loss at 240 h post-exposure. Conclusions: This is the first demonstration of direct effects of chemotherapy exposure on germ cell populations in human foetal and prepubertal testis, demonstrating platinum-induced loss of all germ cell populations, and similar effects of cisplatin or carboplatin. Furthermore, these experimental approaches can be used to determine the effects of established and novel cancer therapies on the developing testis that will inform fertility counselling and development of strategies to preserve fertility in children with cancer.

• Item Type: Articles
• Additional Information: RTM was supported by a Wellcome Trust Intermediate Clinical Fellowship (Grant No. 098522) and a UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/S017151/1). JBS was supported by the Swedish Childhood Cancer Foundation (TJ2020-0026) and the Birgitta and Carl-Axel Rydbeck’s Research Grant for Pediatric Research (2020-00348). A.G. is supported by Wellcome (Investigator Award 21947) and by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). Experimental work was supported by UKRI (MR/S017151/1), Wellcome (Grant No. 098522) and Children with Cancer UK (15-198). This work was undertaken in the MRC Centre for Reproductive Health funded by the Grant MR/N022556/1.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Allen, Dr Caroline
• Authors: Tharmalingam, M. D., Matilionyte, G., Wallace, W. H. B., Stukenborg, J.-B., Jahnukainen, K., Oliver, E., Goriely, A., Lane, S., Guo, J., Cairns, B., Jorgensen, A., Allen, C. M., Lopes, F., Anderson, R. A., Spears, N., and Mitchell, R. T.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: BMC Medicine
• Publisher: BioMed Central
• ISSN: 1741-7015
• ISSN (Online): 1741-7015
• Copyright Holders: Copyright © 2020 The Author(s)
• First Published: First published in BMC Medicine 18:374
• Publisher Policy: Reproduced under a Creative Commons license