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

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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 & Mitchell , R T 2020 , ' Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer ' , BMC Medicine , vol. 18 , no. 1 , 374 . https://doi.org/10.1186/s12916-020-01844-y

Title: Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer
Author: Tharmalingam, Melissa D.; Matilionyte, Gabriele; Wallace, William H. B.; Stukenborg, Jan-Bernd; Jahnukainen, Kirsi; Oliver, Elizabeth; Goriely, Anne; Lane, Sheila; Guo, Jingtao; Cairns, Bradley; Jorgensen, Anne; Allen, Caroline M.; Lopes, Federica; Anderson, Richard A.; Spears, Norah; Mitchell, Rod T.
Contributor: University of Helsinki, Children's Hospital
Date: 2020-12-04
Language: eng
Number of pages: 16
Belongs to series: BMC Medicine
ISSN: 1741-7015
URI: http://hdl.handle.net/10138/324425
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.
Subject: Human
Testis
Cisplatin
Germ cell
Fertility
Prepubertal
Foetal
Xenograft
HUMAN FETAL TESTIS
TESTICULAR TISSUE CRYOPRESERVATION
SURVIVORS
EXPOSURE
CHEMOTHERAPY
ADOLESCENT
IDENTIFICATION
TRANSPORTERS
CELLS
3123 Gynaecology and paediatrics
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