有机磷阻燃剂 TDCPP 在体内和体外通过线粒体自噬相关的铁死亡诱导神经毒性,Chemosphere

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有机磷阻燃剂 TDCPP 在体内和体外通过线粒体自噬相关的铁死亡诱导神经毒性
Chemosphere ( IF 8.1 ) Pub Date : 2022-09-07 , DOI: 10.1016/j.chemosphere.2022.136345
Bo Qian ₁ , Rong-Juan Jiang ₁ , Jia-Le Song ₁ , Chen-Qiang Wang ₁

Affiliation

三 (1,3-二氯-2-丙基) 磷酸 (TDCPP) 具有神经毒性，但其机制仍不清楚。最近的证据表明，铁死亡可能与 TDCPP 诱导的神经毒性有关。为了探索铁死亡在 TDCPP 诱导的神经毒性中的作用和潜在机制，我们检测了暴露于 TDCPP 后小鼠和 PC12 细胞中铁死亡的发生。体外结合RNA测序分析阐明了TDCPP诱导铁死亡的机制。体内_结果表明，口服TDCPP（100 mg/kg，30 d）可抑制小鼠的学习记忆能力，减少海马神经元，诱导丙二醛（MDA）积累，降低小鼠体内谷胱甘肽（GSH）和超氧化物歧化酶（SOD）水平。海马体。此外，TDCPP 暴露（100 mg/kg，30 天）改变了海马中铁死亡和自噬相关蛋白的丰度。体外的结果表明，TDCPP 暴露（0、5、20、50、100 和 200 μM）24 h 诱导 PC12 细胞剂量依赖性细胞死亡，并且通过与 ferrostatin-1 共同处理（1 μM，24 小时）。同样，TDCPP 暴露（0、50、100 和 200 μM）24 小时增加了 MDA 和 LPO 的水平，但降低了 PC12 细胞中减少的 GSH。此外，TDCPP 暴露（0、50、100 和 200 μM）24 小时改变了 PC12 细胞中的铁死亡和自噬相关蛋白的丰度。RNA 测序显示 TDCPP 暴露（100 μM，24 小时）诱导 SH-SY5Y 细胞中的线粒体自噬激活。同时，体外实验证实，TDCPP 暴露（0、50、100 和 200 μM）24 小时会增加线粒体自噬相关蛋白磷酸酶和张力蛋白同源物诱导激酶 1（PINK1）、帕金森蛋白 2 E3 泛素蛋白连接酶（PARKIN）、肌醇的丰度PC12 细胞中的 1,4,5-三磷酸受体 1 (IP3R1) 和电压依赖性阴离子通道 1 (VDAC1)。此外，TDCPP 处理（100 μM，24 h）增加了 PARKIN 的线粒体募集，降低了线粒体膜电位（MMP）水平，并增加了 Fe ²⁺线粒体中的水平。此外，在 TDCPP 暴露（0、50、100 和 200 μM）24 小时后，在 PC12 细胞中观察到 ATP 水平降低和活性氧（ROS）水平升高。综上所述，铁死亡与 TDCPP 诱导的神经毒性有关，其机制可能与 PINK1/PARKIN 介导的线粒体损伤引发的线粒体自噬有关。

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Organophosphorus flame retardant TDCPP induces neurotoxicity via mitophagy-related ferroptosis in vivo and in vitro

Tris (1,3-dichloro-2-propyl) phosphate (TDCPP) has neurotoxicity, but its mechanism remains unclear. Evidence recently showed that ferroptosis might be associated with TDCPP-induced neurotoxicity. To explore the role and underlying mechanism of ferroptosis in TDCPP-induced neurotoxicity, the occurrence of ferroptosis was examined in mice and PC12 cells upon TDCPP exposure. The mechanism of TDCPP-induced ferroptosis was clarified in vitro combined with the RNA sequencing assay. The in vivo results showed that orally TDCPP exposure (100 mg/kg, 30 d) inhibited the learning and memory ability of mice, reduced hippocampus neurons, induced malondialdehyde (MDA) accumulation, and decreased glutathione (GSH) and superoxide dismutase (SOD) levels in the hippocampus. Moreover, TDCPP exposure (100 mg/kg, 30 d) altered the ferroptosis and autophagy-related protein abundances in the hippocampus. The in vitro results showed that TDCPP exposure (0, 5, 20, 50, 100, and 200 μM) for 24 h induced dose-dependent cell death in PC12 cells, and the cell death was ameliorated by the co-treatment with ferrostatin-1 (1 μM, 24 h). Similarly, TDCPP exposure (0, 50, 100, and 200 μM) for 24 h increased the levels of MDA and LPO, but decreased the reduced GSH in PC12 cells. Furthermore, TDCPP exposure (0, 50, 100, and 200 μM) for 24 h altered the ferroptosis and autophagy-related protein abundances in PC12 cells. The RNA-sequencing revealed that TDCPP exposure (100 μM, 24 h) induced mitophagy activation in SH-SY5Y cells. Meanwhile, the in vitro experiments confirmed that TDCPP exposure (0, 50, 100, and 200 μM) for 24 h increased abundances of mitophagy-related protein phosphatase and tensin homolog induced kinase 1(PINK1), Parkinson protein 2 E3 ubiquitin-protein ligase (PARKIN), inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), and voltage-dependent anion channel 1 (VDAC1) in PC12 cells. Moreover, TDCPP treatment (100 μM, 24 h) increased the mitochondrial recruitment of PARKIN, decreased the mitochondrial membrane potential (MMP) level, and increased the Fe²⁺ level in mitochondria. In addition, decreased ATP levels and increased reactive oxygen species (ROS) levels were observed in PC12 cells upon TDCPP exposure (0, 50, 100, and 200 μM) for 24 h. In summary, ferroptosis was associated with TDCPP-induced neurotoxicity, and the mechanism might be related to PINK1/PARKIN-mediated mitophagy initiated by mitochondrial damage.

更新日期：2022-09-11

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