Tris (2-ethylhexyl) phosphate (TEHP) is a frequently used organophosphorus flame retardant with significant ecotoxicity and widespread human exposure. Recent research indicates that TEHP has reproductive toxicity. However, the precise cell mechanism is not enough understood. Here, by using testicular mesenchymal stromal TM3 cells as a model, we reveal that TEHP induces apoptosis. Then RNA sequencing analysis, immunofluorescence, and western blotting results show that THEP inhibits autophagy flux and enhances endoplasmic reticulum (ER) stress. Moreover, the activation of the ER stress is critical for TEHP-induced cell injury. Interestingly, TEHP-induced ER stress is contributed to autophagic flux inhibition. Furthermore, pharmacological inhibition of autophagy aggravates, and activation of autophagy attenuates TEHP-induced apoptosis. In summary, these findings indicate that TEHP triggers apoptosis in mouse TM3 cells through ER stress activation and autophagy flux inhibition, offering a new perspective on the mechanisms underlying TEHP-induced interstitial cytotoxicity in the mouse testis.

中文翻译：

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Tris(2-乙基己基)磷酸通过调节自噬和内质网应激诱导 TM3 Leydig 细胞的细胞毒性


磷酸三(2-乙基己基)酯 (TEHP) 是一种常用的有机磷阻燃剂，具有显着的生态毒性，人类广泛接触。最近的研究表明 TEHP 具有生殖毒性。然而，精确的细胞机制还没有得到足够的了解。在这里，通过使用睾丸间充质基质TM3细胞作为模型，我们揭示了TEHP诱导细胞凋亡。 RNA测序分析、免疫荧光和蛋白质印迹结果表明THEP抑制自噬流并增强内质网（ER）应激。此外，内质网应激的激活对于 TEHP 诱导的细胞损伤至关重要。有趣的是，TEHP 诱导的内质网应激会导致自噬流抑制。此外，自噬的药理学抑制会加剧，而自噬的激活会减弱 TEHP 诱导的细胞凋亡。总之，这些发现表明 TEHP 通过 ER 应激激活和自噬通量抑制触发小鼠 TM3 细胞凋亡，为 TEHP 诱导小鼠睾丸间质细胞毒性的机制提供了新的视角。