Zhao Yonggang, Peng Mo, Liu Honglei, Zhang Xiaoyu, Fu Dan
Environment Monitoring Center of Jiangsu Province, Nanjing 210019, China.
Nanjing Shenghong Environmental Technology Co., Ltd., Nanjing 210017, China.
Toxics. 2025 Apr 8;13(4):285. doi: 10.3390/toxics13040285.
Tris(2-chloroethyl) phosphate (TCEP) is a representative chlorinated organophosphate flame retardant (OPFR) that demonstrates greater persistence than other non-halogenated alkyl or aryl OPFRs. Although TCEP has been shown to accumulate significantly in the environment and contribute to testicular toxicity and spermatogenic dysfunction, the precise underlying factors and mechanisms of action remain unclear. Herein, male ICR mice were gavaged with corn oil, 50 mg/kg body weight (bw) TCEP, or 100 mg/kg bw TCEP from postnatal day (PND) 22 to PND 35. TCEP exposure resulted in the disruption of blood-testis barrier (BTB) integrity and in abnormal testicular development. Considering that Sertoli cells constitute the primary target of toxicants and that TCEP induces oxidative stress in the testis and other organs, we focused on ferroptosis in Sertoli cells. Our findings revealed a significant increase in ferroptosis in the testes and Sertoli cells following TCEP exposure, and we observed functional restoration of Sertoli cell junctions upon treatment with the ferroptosis inhibitor ferrostatin-1. Furthermore, ferritin heavy chain 1 (FTH1) was markedly reduced in TCEP-exposed testes and Sertoli cells. Since nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy is essential for the degradation of FTH1, we assessed ferritinophagic activity and found significant upregulation of NCOA4, ATG5, ATG7, and LC3B II/I in TCEP-exposed testes and Sertoli cells. These results strongly suggest that TCEP triggers Sertoli cell ferroptosis by activating ferritinophagy that leads to reduced expression of BTB-associated proteins, ultimately causing BTB disruption and testicular developmental toxicity.
磷酸三（2-氯乙基）酯（TCEP）是一种典型的氯化有机磷酸酯阻燃剂（OPFR），与其他非卤代烷基或芳基OPFR相比，具有更强的持久性。尽管已证明TCEP在环境中会大量积累，并导致睾丸毒性和生精功能障碍，但其确切的潜在因素和作用机制仍不清楚。在此，从出生后第22天（PND）至第35天，给雄性ICR小鼠灌胃玉米油、50mg/kg体重（bw）的TCEP或100mg/kg bw的TCEP。TCEP暴露导致血睾屏障（BTB）完整性破坏和睾丸发育异常。鉴于支持细胞是毒物的主要靶细胞，且TCEP可在睾丸和其他器官中诱导氧化应激，我们将研究重点放在支持细胞的铁死亡上。我们的研究结果显示，TCEP暴露后睾丸和支持细胞中的铁死亡显著增加，并且在用铁死亡抑制剂铁抑素-1处理后，我们观察到支持细胞连接功能得到恢复。此外，在TCEP暴露的睾丸和支持细胞中，铁蛋白重链1（FTH1）明显减少。由于核受体辅激活因子4（NCOA4）介导的铁蛋白自噬对于FTH1的降解至关重要，我们评估了铁蛋白自噬活性，发现TCEP暴露的睾丸和支持细胞中NCOA4、ATG5、ATG7和LC3B II/I显著上调。这些结果强烈表明，TCEP通过激活铁蛋白自噬触发支持细胞铁死亡，导致BTB相关蛋白表达降低，最终引起BTB破坏和睾丸发育毒性。
