2. Academic Validation
  3. 2,2',4,4'-Tetrabromodiphenyl ether exposure disrupts blood-testis barrier integrity through CMA-mediated ferroptosis

2,2',4,4'-Tetrabromodiphenyl ether exposure disrupts blood-testis barrier integrity through CMA-mediated ferroptosis

  • Sci Total Environ. 2024 Jul 14:948:174738. doi: 10.1016/j.scitotenv.2024.174738.
Xu Huang 1,  Yan Fu 1,  Siyuan Wang 1,  Qitong Guo 1,  Yuhao Wu 2,  Xiangqin Zheng 1,  Junke Wang 3,  Shengde Wu 1,  Lianju Shen 4,  Guanghui Wei 5
Affiliations

Affiliations

  • 1 Department of Urology, Children's Hospital of Chongqing Medical University, China; Pediatric Research Institute, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, China.
  • 2 Department of Cardiothoracic Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Urology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 4 Pediatric Research Institute, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, China. Electronic address: 482061@hospital.cqmu.edu.cn.
  • 5 Department of Urology, Children's Hospital of Chongqing Medical University, China; Pediatric Research Institute, Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, China. Electronic address: u806806@cqmu.edu.cn.
PMID: 39009145 DOI: 10.1016/j.scitotenv.2024.174738
Abstract

2,2',4,4'-Tetrabromodiphenyl ether (PBDE-47), being the most prevalent congener of polybrominated diphenyl ethers (PBDEs), has been found to accumulate greatly in the environment and induce spermatogenesis dysfunction. However, the specific underlying factors and mechanisms have not been elucidated. Herein, male Sprague-Dawley (SD) rats were exposed to corn oil, 10 mg/kg body weight (bw) PBDE-47 or 20 mg/kg bw PBDE-47 by gavage for 30 days. PBDE-47 exposure led to blood-testis barrier (BTB) integrity disruption and aberrant spermatogenesis. Given that Sertoli cells are the main toxicant target, to explore the potential mechanism involved, we performed RNA Sequencing (RNA-seq) in Sertoli cells, and the differentially expressed genes were shown to be enriched in Ferroptosis and lysosomal pathways. We subsequently demonstrated that Ferroptosis was obviously increased in testes and Sertoli cells upon exposure to PBDE-47, and the junctional function of Sertoli cells was restored after treatment with the Ferroptosis inhibitor ferrostatin-1. Since Glutathione Peroxidase 4 (GPX4) was dramatically reduced in PBDE-47-exposed testes and Sertoli cells and considering the RNA-sequencing results, we examined the activity of chaperone-mediated Autophagy (CMA) and verified that the expression of LAMP2a and HSC70 was upregulated significantly after PBDE-47 exposure. Notably, Lamp2a knockdown not only inhibited Ferroptosis by suppressing GPX4 degradation but also restored the impaired junctional function induced by PBDE-47. These collective findings strongly indicate that PBDE-47 induces Sertoli cell Ferroptosis through CMA-mediated GPX4 degradation, resulting in decreased BTB-associated protein expression and eventually leading to BTB integrity disruption and spermatogenesis dysfunction.

Keywords

BTB; CMA; Ferroptosis; PBDE-47.

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