Knockdown of TNFAIP1 prevents di-(2-ethylhexyl) phthalate-induced neurotoxicity by activating CREB pathway
Knockdown of TNFAIP1 prevents di-(2-ethylhexyl) phthalate-induced neurotoxicity by activating CREB pathway
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TNFAIP1 的敲低通过激活 CREB 通路预防邻苯二甲酸二（2-乙基己基）酯诱导的神经毒性
DOI：
10.1016/j.chemosphere.2019.125114
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发表时间：
2020-02-01
期刊：
影响因子：
8.8
通讯作者：
Xiang, Shuanglin
中科院分区：
文献类型：
--
作者：
Qiu, Feng;Zhou, Yubo;Xiang, Shuanglin
邻苯二甲酸二(2-乙基己基)酯 (DEHP) 是一种广泛使用的增塑剂。它具有神经毒性，接触它会导致神经发育、行为和认知受损。然而，DEHP 引起的神经毒性的分子机制尚未明确。肿瘤坏死因子诱导蛋白1（TNFAIP1）首先在脐静脉内皮细胞中发现，并进一步发现在阿尔茨海默病的进展中具有重要作用。在此，我们探讨了小鼠神经母细胞瘤细胞系（N2a 细胞）中 TNFAIP1 在 DEHP 诱导的神经毒性中的机制，该神经毒性涉及环 AMP 反应元件结合蛋白（CREB）信号通路。我们发现，暴露于DEHP可诱导细胞凋亡，下调脑源性神经营养因子（BDNF）、突触蛋白PSD 95和synapsin-1的表达，同时上调TNFAIP1的表达，并降低CREB信号通路中磷酸化Akt、CaMK IV、PKA催化亚基和CREB的水平。使用 TNFAIP1 小干扰 RNA (siRNA) 表达载体敲低 TNFAIP1 可阻止 DEHP 抑制 CREB 通路，从而减少细胞凋亡并恢复 BDNF、PSD 95 和 synapsin-1 的表达。我们的数据表明，TNFAIP1 的下调可通过激活 CREB 通路来预防 DEHP 诱导的神经毒性。因此，TNFAIP1是缓解DEHP引起的神经毒性和相关神经系统疾病的潜在靶点。 (C) 2019 Elsevier Ltd. 保留所有权利。
Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer. It has neurotoxicity and exposure to it causes impairment of neurodevelopment, behavior and cognition. However, the molecular mechanisms responsible for the DEHP-induced neurotoxicity are not yet clearly defined. Tumor necrosis factor-induced protein 1 (TNFAIP1) was first discovered in umbilical vein endothelial cells and was further found to be important in the progress of Alzheimer's disease. Herein we explore the mechanism of TNFAIP1 in DEHP-induced neurotoxicity with the involvement of cyclic AMP response elements binding protein (CREB) signaling pathway in a mouse neuroblastoma cell line (N2a cells). We found that exposure to DEHP induced apoptosis and downregulated the expression of brain-derived neurotrophic factor (BDNF), synaptic proteins PSD 95 and synapsin-1 while upregulated the expression of TNFAIP1 and decreased the levels of phosphorylated Akt, CaMK IV, catalytic subunits of PKA and CREB in CREB signaling pathway. Knockdown of TNFAIP1 using TNFAIP1 small interfering RNA (siRNA) expression vector prevented DEHP from inhibiting CREB pathway, thus reduced apoptosis and restored expression of BDNF, PSD 95 and synapsin-1. Our data indicate that downregulation of TNFAIP1 prevents DEHP-induced neurotoxicity via activating CREB pathway. Therefore, TNFAIP1 is a potential target for relieving the DEHP-induced neurotoxicity and related neurological disorders. (C) 2019 Elsevier Ltd. All rights reserved.