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

Show simple item record 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. 2021-01-12T12:44:01Z 2021-01-12T12:44:01Z 2020-12-04
dc.identifier.citation 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 .
dc.identifier.other PURE: 158920131
dc.identifier.other PURE UUID: 55951da0-e222-4396-9c20-aae633f10ae9
dc.identifier.other WOS: 000595575400001
dc.description.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. en
dc.format.extent 16
dc.language.iso eng
dc.relation.ispartof BMC Medicine
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject Human
dc.subject Testis
dc.subject Cisplatin
dc.subject Germ cell
dc.subject Fertility
dc.subject Prepubertal
dc.subject Foetal
dc.subject Xenograft
dc.subject SURVIVORS
dc.subject EXPOSURE
dc.subject ADOLESCENT
dc.subject CELLS
dc.subject 3123 Gynaecology and paediatrics
dc.title Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer en
dc.type Article
dc.contributor.organization Children's Hospital
dc.contributor.organization Clinicum
dc.contributor.organization HUS Children and Adolescents
dc.contributor.organization University of Helsinki
dc.contributor.organization Helsinki University Hospital Area
dc.description.reviewstatus Peer reviewed
dc.relation.issn 1741-7015
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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