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  2. Environmental cadmium impairs blood-testis barrier via activating HRI-responsive mitochondrial stress in mice

Environmental cadmium impairs blood-testis barrier via activating HRI-responsive mitochondrial stress in mice

  • Sci Total Environ. 2022 Mar 1;810:152247. doi: 10.1016/j.scitotenv.2021.152247.
Guo-Xiang Zhou 1 Wei-Bo Liu 1 Li-Min Dai 1 Hua-Long Zhu 1 Yong-Wei Xiong 1 Dai-Xin Li 1 De-Xiang Xu 1 Hua Wang 2
Affiliations

Affiliations

  • 1 Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
  • 2 Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China. Electronic address: wanghuadev@126.com.
Abstract

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.

Keywords

Blood-testis barrier; Cadmium; HRI; Mitochondrial stress.

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