Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Biol Reprod. 2024 Jul 12;111(1):197-211. doi: 10.1093/biolre/ioae042.
Heat stress induces testicular oxidative stress, impairs spermatogenesis, and increases the risk of male infertility. Recent studies have highlighted the antioxidative properties of the Sestrins family in reducing cellular oxidative damage. However, the role of Sestrins (Sestrin1, 2, and 3) in the testicular response to heat stress remains unclear. Here, we found that Sestrin2 and 3 were highly expressed in the testis relative to Sestrin1. Then, the Sestrin2-/- and Sestrin3-/- mice were generated by CRISPR/Cas9 to investigate the role of them on spermatogenesis after heat stress. Our data showed that Sestrin2-/- and Sestrin3-/- mice testes exhibited more severe damage manifested by exacerbated loss of germ cells and higher levels of oxidative stress as compared to wild-type counterparts after heat stress. Notably, Sestrin2-/- and Sestrin3-/- mice underwent a remarkable increase in heat-induced spermatocyte apoptosis than that of controls. Furthermore, the transcriptome landscape of spermatocytes and chromosome spreading showed that loss of Sestrin2 and Sestrin3 exacerbated meiotic failure by compromising DNA double-strand breaks repair after heat stress. Taken together, our work demonstrated a critical protective function of Sestrin2 and Sestrin3 in mitigating the impairments of spermatogenesis against heat stress.
热应激会导致睾丸氧化应激，损害精子发生，并增加男性不育的风险。最近的研究强调了 Sestrins 家族在减少细胞氧化损伤方面的抗氧化特性。然而，Sestrins（Sestrin1、2 和 3）在睾丸对热应激的反应中的作用尚不清楚。在这里，我们发现 Sestrin2 和 3 在睾丸中的表达相对于 Sestrin1 更高。然后，通过 CRISPR/Cas9 生成了 Sestrin2-/-和 Sestrin3-/-小鼠，以研究它们在热应激后对精子发生的作用。我们的数据表明，与野生型相比，Sestrin2-/-和 Sestrin3-/-小鼠睾丸在热应激后表现出更严重的损伤，表现为生殖细胞丢失加剧和氧化应激水平升高。值得注意的是，Sestrin2-/-和 Sestrin3-/-小鼠的热诱导精母细胞凋亡显著增加。此外，精母细胞的转录组图谱和染色体铺展表明，Sestrin2 和 Sestrin3 的缺失通过在热应激后损害 DNA 双链断裂修复，加剧了减数分裂失败。总之，我们的工作表明 Sestrin2 和 Sestrin3 在减轻热应激对精子发生的损伤方面具有关键的保护作用。
