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

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Harvard

Tharmalingam, MD, Matilionyte, G, Wallace, WHB, Stukenborg, J-B, Jahnukainen, K, Oliver, E, Goriely, A, Lane, S, Guo, J, Cairns, B, Jorgensen, A, Allen, CM, Lopes, F, Anderson, RA, Spears, N & Mitchell, RT 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, pp. 374. https://doi.org/10.1186/s12916-020-01844-y

APA

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, 18(1), 374. https://doi.org/10.1186/s12916-020-01844-y

CBE

Tharmalingam MD, Matilionyte G, Wallace WHB, Stukenborg J-B, Jahnukainen K, Oliver E, Goriely A, Lane S, Guo J, Cairns B, Jorgensen A, Allen CM, Lopes F, Anderson RA, Spears N, Mitchell RT. 2020. Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer. BMC Medicine. 18(1):374. https://doi.org/10.1186/s12916-020-01844-y

MLA

Vancouver

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. / Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer. In: BMC Medicine. 2020 ; Vol. 18, No. 1. pp. 374.

Bibtex

@article{118a147f1f2342f7a375fe78e37dc1e4,
title = "Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer",
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.",
author = "Tharmalingam, {Melissa D} and Gabriele Matilionyte and Wallace, {William H B} and Jan-Bernd Stukenborg and Kirsi Jahnukainen and Elizabeth Oliver and Anne Goriely and Sheila Lane and Jingtao Guo and Bradley Cairns and Anne Jorgensen and Allen, {Caroline M} and Federica Lopes and Anderson, {Richard A} and Norah Spears and Mitchell, {Rod T}",
year = "2020",
month = dec,
day = "4",
doi = "10.1186/s12916-020-01844-y",
language = "English",
volume = "18",
pages = "374",
journal = "BMC Medicine",
issn = "1741-7015",
publisher = "BioMed Central Ltd",
number = "1",

}

RIS

TY - JOUR

T1 - Cisplatin and carboplatin result in similar gonadotoxicity in immature human testis with implications for fertility preservation in childhood cancer

AU - Tharmalingam, Melissa D

AU - Matilionyte, Gabriele

AU - Wallace, William H B

AU - Stukenborg, Jan-Bernd

AU - Jahnukainen, Kirsi

AU - Oliver, Elizabeth

AU - Goriely, Anne

AU - Lane, Sheila

AU - Guo, Jingtao

AU - Cairns, Bradley

AU - Jorgensen, Anne

AU - Allen, Caroline M

AU - Lopes, Federica

AU - Anderson, Richard A

AU - Spears, Norah

AU - Mitchell, Rod T

PY - 2020/12/4

Y1 - 2020/12/4

N2 - 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.

AB - 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.

U2 - 10.1186/s12916-020-01844-y

DO - 10.1186/s12916-020-01844-y

M3 - Journal article

C2 - 33272271

VL - 18

SP - 374

JO - BMC Medicine

JF - BMC Medicine

SN - 1741-7015

IS - 1

ER -

ID: 61412646