Chemotherapy induced damage to spermatogonial stem cells in prepubertal mouse in vitro impairs long-term spermatogenesis

Toxicology Reports

Satish K. Adiga¹  Rod T. Mitchell²  Prathima Tholeti³  Federica Lopes⁴  Richard A. Anderson⁴  Norah Spears⁵ 

[1] Corresponding author at: MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.;Department of Clinical Embryology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India;MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK;Biomedical Sciences, University of Edinburgh, Edinburgh, UK;Department of Clinical Embryology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India;

关键词: Chemotherapy;    In vitro;    Spermatogonial stem cells;    Testis;    Prepubertal mouse;   

DOI  :  

来源: DOAJ

【 摘 要 】

Chemotherapy can affect testis development of young boys with cancer, reducing the chances of fatherhood in adulthood. Studies using experimental models are needed to determine the damage caused by individual chemotherapy drugs in order to predict the risk of infertility and direct patients towards appropriate fertility preservation options. Here, we investigated the individual role of two drugs, cisplatin and doxorubicin, using an in vitro culture model of prepubertal (postnatal day 5) mouse testis that supports induction and maintenance of full spermatogenesis. Twenty-four hour exposure with either drug at clinically-relevant doses (0.25, 0.5 or 0.75 μg/mL for cisplatin, or 0.01, 0.03 or 0.05 μg/mL for doxorubicin), induced an acute significant loss of spermatogonial stem cells (SSCs; PLZF+), proliferating SSCs (PLZF+BrdU+), total germ cells (MVH+), and spermatocytes (SCP3+) one week after chemotherapy exposure. By the time of the first (Week 4) and second (Week 8) waves of spermatogenesis, there was no longer any effect on SSC or proliferating SSC numbers in drug-exposed testis compared to untreated tissue: however, the populations of total germ cells and spermatocytes were still lower in the higher-dose cisplatin treated groups, along with a reduced frequency of round and elongated spermatids in both cisplatin- and doxorubicin-treated testis fragments. Overall, this study details a direct impairment of germ cell development following acute chemotherapy-induced damage during the prepubertal phase, most likely due to an effect on SSCs, using an in vitro culture system that successfully recapitulates key events of mouse spermatogenesis.

【 授权许可】

Unknown