Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China; Key Laboratory for Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
Key Laboratory for Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
Toxicol Lett. 2023 Mar 15;377:38-50. doi: 10.1016/j.toxlet.2023.01.010. Epub 2023 Feb 2.
Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, and SSC homeostasis is essential for lifelong male fertility. Currently, environmental pollution remains one of the factors affecting human reproductive health. Chromium is a prevalent metal element, and excessive exposure to hexavalent chromium (Cr (VI)) can cause male reproductive disorders. Nevertheless, the toxic effects of Cr (VI) on SSCs and the underlying mechanisms remain incompletely understood. Here, we showed that Cr (VI) exposure triggered mitophagy in mouse SSCs/progenitors in a time-dependent manner. Concurrently, Cr (VI) treatment caused reactive oxygen species (ROS) accumulation and activated the HIF1α-mediated BNIP3 expression to trigger mitophagy. In addition, Cr (VI) exposure significantly decreased the level of mA modification. Further, we identified that YTHDF2 regulated the stability of Bnip3 and Hif1α mRNAs in an mA-dependent manner, which was involved in Cr (VI)-induced mitophagy. Collectively, our study not only expands the mechanisms for Cr (VI)-caused male reproductive toxicity, but also provides pharmacological targets for prevention and treatment of Cr (VI)-induced male fertility impairment.
精原干细胞（SSCs）是精子发生的基础，SSC 稳态对于男性终生生育能力至关重要。目前，环境污染仍然是影响人类生殖健康的因素之一。铬是一种常见的金属元素，六价铬（Cr（VI））的过度暴露会导致男性生殖障碍。然而，Cr（VI）对 SSCs 的毒性作用及其潜在机制仍不完全清楚。在这里，我们显示 Cr（VI）暴露以时间依赖性方式触发了小鼠 SSCs/祖细胞中的线粒体自噬。同时，Cr（VI）处理会导致活性氧（ROS）积累，并激活 HIF1α 介导的 BNIP3 表达以触发线粒体自噬。此外，Cr（VI）暴露会显著降低 mA 修饰水平。进一步，我们发现 YTHDF2 通过 mA 依赖性方式调节 Bnip3 和 Hif1α mRNA 的稳定性，这与 Cr（VI）诱导的线粒体自噬有关。总之，我们的研究不仅扩展了 Cr（VI）引起的男性生殖毒性的机制，而且为预防和治疗 Cr（VI）引起的男性生育力损害提供了药理学靶点。
