Doxorubicin and vincristine affect undifferentiated rat spermatogonia.

Abstract : Anticancer drugs, such as alkylating agents, can affect male fertility by targeting the DNA of proliferative spermatogonial stem cells (SSC). Therefore, to reduce such side effects, other chemotherapeutics are used. However, less is known about their potential genotoxicity on SSC. Moreover, DNA repair mechanisms in SSC are poorly understood. To model treatments deprived of alkylating agents that are commonly used in cancer treatment, we tested the impact of exposure to doxorubicin and vincristine, alone or in combination (MIX), on a rat spermatogonial cell line with SSC characteristics (GC-6spg). Vincristine alone induced a cell cycle arrest and cell death without genotoxic impact. On the other hand, doxorubicin and the MIX induced a dose-dependent cell death. More importantly, doxorubicin and the MIX induced DNA breaks, measured by the COMET assay, at a non-cytotoxic dose. To elucidate which DNA repair pathway is activated in spermatogonia after exposure to doxorubicin, we screened the expression of 75 genes implicated in DNA repair. Interestingly, all were expressed constitutively in GC-6spg, suggesting great potential to respond to genotoxic stress. Doxorubicin treatments affected the expression of 16 genes (>1.5 fold change; P < 0.05) involved in cell cycle, base/nucleotide excision repair, homologous recombination and non-homologous end joining (NHEJ). The significant increase in CDKN1A and XRCC1 suggest a cell cycle arrest and implies an alternative NHEJ pathway in response to doxorubicin-induced DNA breaks. Together, our results support the idea that undifferentiated spermatogonia have the ability to respond to DNA injury from chemotherapeutic compounds and escape DNA break accumulation.
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Article dans une revue
Reproduction, BioScientifica, 2017, 153 (6), pp.725-735. 〈10.1530/rep-17-0005〉
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Soumis le : jeudi 8 juin 2017 - 22:20:17
Dernière modification le : lundi 8 octobre 2018 - 17:44:05

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Hermance Beaud, Ans Van Pelt, Geraldine Delbes. Doxorubicin and vincristine affect undifferentiated rat spermatogonia.. Reproduction, BioScientifica, 2017, 153 (6), pp.725-735. 〈10.1530/rep-17-0005〉. 〈pasteur-01535430〉

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