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.
Department of Cardiothoracic Surgery, Children's Hospital of Chongqing Medical University, Chongqing, China.
Sci Total Environ. 2024 Oct 20;948:174738. doi: 10.1016/j.scitotenv.2024.174738. Epub 2024 Jul 14.
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.
2,2',4,4'-四溴二苯醚 (PBDE-47) 作为多溴二苯醚 (PBDEs) 中最常见的同系物，已被发现大量积累在环境中，并导致精子发生功能障碍。然而，其具体的潜在因素和机制尚未阐明。在此，雄性 Sprague-Dawley (SD) 大鼠通过灌胃暴露于玉米油、10mg/kg 体重 (BW) PBDE-47 或 20mg/kg bw PBDE-47 30 天。PBDE-47 暴露导致血睾屏障 (BTB) 完整性破坏和精子发生异常。鉴于支持细胞是主要的毒性靶标，为了探讨潜在的涉及机制，我们对支持细胞进行了 RNA 测序 (RNA-seq)，结果显示差异表达基因富集在铁死亡和溶酶体途径中。随后，我们证明 PBDE-47 暴露后睾丸和支持细胞中的铁死亡明显增加，而铁死亡抑制剂 ferrostatin-1 处理后支持细胞的连接功能得到恢复。由于谷胱甘肽过氧化物酶 4 (GPX4) 在 PBDE-47 暴露的睾丸和支持细胞中显著减少，并且考虑到 RNA-seq 结果，我们检查了伴侣介导的自噬 (CMA) 的活性，并验证了 PBDE-47 暴露后 LAMP2a 和 HSC70 的表达明显上调。值得注意的是，Lamp2a 敲低不仅通过抑制 GPX4 降解抑制铁死亡，而且还恢复了由 PBDE-47 引起的受损连接功能。这些综合研究结果强烈表明，PBDE-47 通过 CMA 介导的 GPX4 降解诱导支持细胞铁死亡，导致 BTB 相关蛋白表达减少，最终导致 BTB 完整性破坏和精子发生功能障碍。
