Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
Sci Total Environ. 2022 Mar 1;810:152247. doi: 10.1016/j.scitotenv.2021.152247. Epub 2021 Dec 9.
Cadmium (Cd) is a well-known testicular toxicant. Blood-testis barrier (BTB), a vital part of testes, which has been reported to be damaged upon Cd exposure. However, the detailed mechanism about Cd-mediated disruption of BTB remains unclear. This study aims to investigate the role of Heme-Regulated Inhibitor (HRI)-responsive mitochondrial stress in Cd-mediated disruption of BTB. Male mice are intraperitoneally injected (i.p.) with melatonin (Mel, a cellular stress antagonist, 5.0 mg/kg) before Cd treatment (i.p., 2.0 mg/kg) for 8 h, and then treated with Cd for 0-48 h. Mouse Sertoli cells are pretreated with Mel (10 μM) for 1 h, and then treated with Cd (10 μM) for 0-24 h. We find that Cd damages the BTB and reduces the Occludin protein, a crucial BTB-related protein via activating p38/matrix metalloproteinase-2 (p38/MMP2) pathway and Integrated Stress Response (ISR). Further experiments reveal that the Heme-Regulated Inhibitor (HRI)-responsive mitochondrial stress is triggered in Cd-treated Sertoli cells. Most importantly, Cd-activated p38 signaling and ISR are regulated by HRI-responsive mitochondrial stress in Sertoli cells. Unexpectedly, we find that melatonin rescues the Cd-mediated disruption of BTB through blocking HRI-responsive mitochondrial stress in testes. Overall, these data indicate that environmental cadmium exposure impairs the BTB through activating HRI-responsive mitochondrial stress in Sertoli cells.
镉（Cd）是一种众所周知的睾丸毒性物质。血睾屏障（BTB）是睾丸的重要组成部分，据报道，Cd 暴露会破坏血睾屏障。然而，Cd 介导的 BTB 破坏的详细机制尚不清楚。本研究旨在探讨血红素调节抑制剂（HRI）反应性线粒体应激在 Cd 介导的 BTB 破坏中的作用。雄性小鼠在 Cd 处理（腹腔内注射，2.0mg/kg）前腹腔内注射褪黑素（Mel，一种细胞应激拮抗剂，5.0mg/kg）8 小时，然后用 Cd 处理 0-48 小时。将小鼠支持细胞用 Mel（10μM）预处理 1 小时，然后用 Cd（10μM）处理 0-24 小时。我们发现 Cd 破坏 BTB，并通过激活 p38/基质金属蛋白酶-2（p38/MMP2）途径和整合应激反应（ISR）降低 Occludin 蛋白，Occludin 蛋白是一种重要的 BTB 相关蛋白。进一步的实验表明，Cd 处理的支持细胞中触发了 HRI 反应性线粒体应激。最重要的是，Cd 激活的 p38 信号和 ISR 受支持细胞中 HRI 反应性线粒体应激的调节。出乎意料的是，我们发现褪黑素通过阻断睾丸中 HRI 反应性线粒体应激来挽救 Cd 介导的 BTB 破坏。总的来说，这些数据表明，环境镉暴露通过激活支持细胞中的 HRI 反应性线粒体应激来破坏 BTB。
