College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin, 150030, China.
Branch of Animal Husbandry and Veterinary of Heilongjiang Academy of Agricultural Sciences, Qiqihar, 161000, China.
Chem Biol Interact. 2023 Apr 1;374:110424. doi: 10.1016/j.cbi.2023.110424. Epub 2023 Feb 26.
Hexavalent chromium (Cr(VI)) is a ubiquitous environmental pollutant that can cause reproductive toxicity. However, the exact mechanism of Cr(VI)-induced testis toxicity remains largely elusive. This study aims to explore the possible molecular mechanism of Cr(VI)-provoked testicular toxicity. Male Wistar rats were intraperitoneally injected with 0, 2, 4, or 6 mg/kg body weight/day of potassium dichromate (KCrO), respectively, for 5 weeks. The results revealed that Cr(VI)-treated rat testis presented varying degrees of damage in a dose-dependent manner. Concretely, Cr(VI) administration suppressed Sirtuin 1/Peroxisome proliferator-activated receptor-γ coactivator-1α pathway and led to mitochondrial dynamics disorder, along with the elevation of mitochondrial division and the repression of mitochondrial fusion. Meanwhile, the downstream effector of Sirt1, nuclear factor-erythroid-2-related factor 2 (Nrf2), was downregulated, and correspondingly exacerbated oxidative stress. Mitochondrial dynamics disorder and Nrf2 inhibition collectively contribute to abnormal mitochondrial dynamics in testis, which further promotes apoptosis and autophagy, evidenced by dose-dependently increasing the protein levels and gene expressions of apoptosis-related (including Bcl-2-associated X protein, cytochrome c, and cleaved-caspase 3) and autophagy-related (Beclin-1, ATG4B, and ATG5). Collectively, our results demonstrate that Cr(VI) exposure induced testis apoptosis and autophagy by disrupting the balance of mitochondrial dynamics and the oxidation-reduction process in rats.
六价铬（Cr(VI)）是一种普遍存在的环境污染物，可导致生殖毒性。然而，Cr(VI)引起睾丸毒性的确切机制在很大程度上仍难以捉摸。本研究旨在探讨 Cr(VI)诱发睾丸毒性的可能分子机制。雄性 Wistar 大鼠分别腹膜内注射 0、2、4 或 6 mg/kg 体重/天的重铬酸钾（KCrO），持续 5 周。结果表明，Cr(VI)处理的大鼠睾丸呈现出不同程度的损伤，且呈剂量依赖性。具体而言，Cr(VI)给药抑制了 Sirtuin 1/过氧化物酶体增殖物激活受体-γ共激活因子-1α 通路，并导致线粒体动力学紊乱，同时增加了线粒体分裂，抑制了线粒体融合。同时，Sirt1 的下游效应物核因子-红细胞 2 相关因子 2（Nrf2）下调，相应地加剧了氧化应激。线粒体动力学紊乱和 Nrf2 抑制共同导致睾丸中线粒体动力学异常，进一步促进凋亡和自噬，这一点从凋亡相关蛋白（包括 Bcl-2 相关 X 蛋白、细胞色素 c 和裂解型 caspase 3）和自噬相关蛋白（Beclin-1、ATG4B 和 ATG5）的蛋白水平和基因表达随剂量增加而增加可以得到证明。总之，我们的结果表明，Cr(VI)暴露通过破坏线粒体动力学平衡和氧化还原过程，诱导大鼠睾丸细胞凋亡和自噬。
