Journal Article

Analysis of the Reversible Impact of the Chemodrug Busulfan on Mouse Testes

Thirouard, Laura, Garcia, Manon, Beaudoin, Claude, Caira, Françoise, Saru, Jean-Paul, Volle, David H., De Haze, Angélique, Holota, Hélène, Monrose, Mélusine

2021

Overview

Spermatogenesis is a process within the testis that leads to the production of spermatozoa. It is based on a population of spermatogonial stem cells, which have the capacity to self-renew and to differentiate throughout life to ensure the functions of reproduction are maintained. Male fertility disorders are responsible for half of the cases of infertility in couples worldwide. It is well known that cancer treatments are associated with reversible or irreversible fertility disorders. Busulfan (Bu) is an alkylating agent that significantly inhibits spermatogenesis. The present study relied on a combination of in vivo and in vitro approaches as well as RNAseq analysis to characterize the effects of Bu, in which mouse testes were used as a model. An in silico analysis revealed that many of the Bu-modulated genes are potentially regulated by the SIN3 Transcription Regulator Family Member A (SIN3A) and E2F Transcription Factor (E2F) families of transcription factors. The results demonstrate that the deregulated genes function in processes related to the cell cycle, DNA repair, and cell death mechanisms, including the Tumor Protein 53 (TP53) pathway. This reinforces the role of the TP53 signaling pathway as a major player in Bu effects. In addition, Bu altered the patterns of mRNA accumulation for various genes in undifferentiated spermatogonia. This work provides significant insight into the kinetics and impacts of busulfan, which could pave the way for developing strategies to minimize the impact of chemodrugs and, thus, could lead to germ cell lineage regeneration following anticancer treatments.

• Publisher: MDPI AG,MDPI
• Subject: Biochemistry, Molecular Biology / Busulfan / Cancer / Cancer therapies / Cell cycle / Cell death / Cell lineage / Chemotherapy / depletion / Development Biology / DNA repair / Drug dosages / E2F protein / Ecology, environment / Endocrinology and metabolism / Experiments / Fertility / Gametogenesis / Health / Human health and pathology / Infertility / Life Sciences / Males / Molecular Networks / p53 Protein / regeneration and fertility / Reproductive Biology / Sexual reproduction / Signal transduction / Spermatogenesis / Spermatogonia / spermatogonial stem cell / Stem cell transplantation / Stem cells / Testes / Transcription factors