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  2. Mitochondrial ROS-associated integrated stress response is involved in arsenic-induced blood-testis barrier disruption and protective effect of melatonin

Mitochondrial ROS-associated integrated stress response is involved in arsenic-induced blood-testis barrier disruption and protective effect of melatonin

  • Environ Int. 2025 Mar:197:109346. doi: 10.1016/j.envint.2025.109346.
Feng-Wen Niu 1 Ming-Dong Liu 1 Kai Yao 1 Rui Yang 1 Lan Gao 2 Jin-Xia Zhai 3 Chuan Wang 1 Shi-Hao Zhang 1 De-Xiang Xu 4 Zhi-Hui Zhang 5
Affiliations

Affiliations

  • 1 Department of Urology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 2 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China.
  • 3 Department of Occupational and Environmental Health, School of Public Health, Anhui Medical University, Hefei, China.
  • 4 Department of Toxicology, School of Public Health, Anhui Medical University, Hefei, China. Electronic address: xudex@126.com.
  • 5 Department of Urology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: zhangzhihuidev@126.com.
Abstract

Arsenic (As) is an environmental metalloid. Previous studies have demonstrated that As exposure resulted in decline of sperm quality. This study aimed to investigate the impact of exposure to As on blood-testis barrier (BTB) in a mouse model. Four-week-old male mice were exposed to NaAsO2 (1 or 15 mg/L) for 6 weeks. Our results found that NaAsO2 exposure disrupted the BTB and reduced sperm counts in adult mice. NaAsO2 activated the integrated stress response (ISR) and downregulated barrier junction protein in mouse testes and Sertoli cells. Ribosome profiling Sequencing (Ribo-seq) and Ribosome-nascent chain complex-bound mRNA qPCR (RNC-qPCR) showed that translational efficiency of N-Cadherin and ZO-1, two key barrier junction proteins, was reduced in NaAsO2-treated Sertoli cells. Mechanistically, NaAsO2 exposure reduced SIRT3 protein via proteasomal degradation, thereby resulting in mitochondrial dysfunction and excess mitochondrial ROS (mtROS) generation in Sertoli cells. Melatonin alleviated NaAsO2-induced mitochondrial dysfunction and mtROS upregulation via reducing SOD2 acetylation in Sertoli cells. Moreover, melatonin antagonized NaAsO2-induced ISR, barrier junction proteins downregulation and barrier function impairment in Sertoli cells. Accordingly, melatonin attenuated NaAsO2-evoked BTB disruption and sperm count reduction in adult mice. These results suggest that mitochondrial dysfunction-associated translational inhibition of barrier junction proteins is involved in As-mediated BTB disruption and sperm quality decline.

Keywords

Arsenic; Blood-testis barrier; Integrated stress response; Mitochondrial dysfunction; Translational inhibition.

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