Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang 471000, China.
Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
J Environ Sci (China). 2023 Mar;125:823-830. doi: 10.1016/j.jes.2022.02.046. Epub 2022 Mar 11.
Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a commonly used organophosphate-based flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophosphate pesticides, the neurotoxicity of TDCIPP has raised widespread concerns. TDCIPP can increase neuronal apoptosis and induce autophagy. However, its regulatory mechanism remains unclear. In this study, we found that the expression upregulation of the DNA Damage-Inducible Transcript 4 (DDIT4) protein, which might play essential roles in TDCIPP-induced neuronal autophagy and apoptosis, was observed in TDCIPP-treated differentiated rat PC12 cells. Furthermore, we determined the protective effect of the DDIT4 suppression on the autophagy and apoptosis induced by TDCIPP using Western blot (WB) and Flow cytometry (FACS) analysis. We observed that TDCIPP treatment increased the DDIT4, the autophagy marker Beclin-1, and the microtubule-associated protein light chain 3-II (LC3II) expressions and decreased the mTOR phosphorylation levels. Conversely, the suppression of DDIT4 expression increased the p-mTOR expression and decreased cell autophagy and apoptosis. Collectively, our results revealed the function of DDIT4 in cell death mechanisms triggered by TDCIPP through the mTOR signaling axis in differentiated PC12 cells. Thus, this study provided vital evidence necessary to explain the mechanism of TDCIPP-induced neurotoxicity in differentiated PC12 cells.
磷酸三（1,3-二氯-2-丙基）酯（TDCIPP）是一种常用的有机磷基阻燃剂，可在人体组织和器官中生物累积。由于其结构与神经毒性有机磷农药相似，TDCIPP 的神经毒性引起了广泛关注。TDCIPP 可增加神经元凋亡并诱导自噬。然而，其调节机制尚不清楚。在本研究中，我们发现，在 TDCIPP 处理的分化大鼠 PC12 细胞中，DNA 损伤诱导转录物 4（DDIT4）蛋白的表达上调，DDIT4 蛋白可能在 TDCIPP 诱导的神经元自噬和凋亡中发挥重要作用。此外，我们通过 Western blot（WB）和流式细胞术（FACS）分析确定了 DDIT4 抑制对 TDCIPP 诱导的自噬和凋亡的保护作用。我们观察到 TDCIPP 处理增加了 DDIT4、自噬标志物 Beclin-1 和微管相关蛋白轻链 3-II（LC3II）的表达，并降低了 mTOR 磷酸化水平。相反，DDIT4 表达的抑制增加了 p-mTOR 的表达，并减少了细胞自噬和凋亡。总之，我们的结果揭示了 DDIT4 在分化的 PC12 细胞中通过 mTOR 信号轴在 TDCIPP 触发的细胞死亡机制中的作用。因此，本研究为解释 TDCIPP 诱导分化的 PC12 细胞神经毒性的机制提供了必要的重要证据。
