INSERM U1103, Université Clermont Auvergne, CNRS UMR-6293, GReD Institute, Team-Volle, F-63001 Clermont-Ferrand, France.
Cells. 2021 Sep 13;10(9):2403. doi: 10.3390/cells10092403.
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.
精子发生是睾丸内导致精子产生的过程。它基于精原干细胞群，这些细胞具有自我更新和分化的能力，以确保生殖功能得以维持。男性生育障碍是全球夫妇不孕的一半原因。众所周知，癌症治疗与可逆或不可逆的生育障碍有关。白消安（Bu）是一种烷化剂，可显著抑制精子发生。本研究结合体内和体外方法以及 RNAseq 分析，以小鼠睾丸为模型，对 Bu 的作用进行了特征描述。计算机分析显示，许多 Bu 调节的基因可能受到 SIN3 转录调节剂家族成员 A（SIN3A）和 E2F 转录因子（E2F）转录因子家族的调节。结果表明，失调基因在与细胞周期、DNA 修复和细胞死亡机制相关的过程中发挥作用，包括肿瘤蛋白 53（TP53）途径。这强化了 TP53 信号通路作为 Bu 作用的主要参与者的作用。此外，Bu 改变了未分化精原细胞中各种基因的 mRNA 积累模式。这项工作深入了解了白消安的动力学和影响，为开发策略以最小化化疗药物的影响铺平了道路，从而可以在癌症治疗后导致生殖细胞谱系再生。
