State Key Laboratory of Developmental Biology of Freshwater Fish, School of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China; The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, School of Life Sciences, Hunan Normal University, Changsha, 410081, Hunan, China.
School of Medicine, Hunan Normal University, Changsha, 410013, Hunan, China.
Chemosphere. 2020 Feb;241:125114. doi: 10.1016/j.chemosphere.2019.125114. Epub 2019 Oct 14.
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.
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，导致 DEHP 神经毒性的分子机制尚不清楚。肿瘤坏死因子诱导蛋白 1（TNFAIP1）最初在脐静脉内皮细胞中发现，后来发现其在阿尔茨海默病的进展中很重要。在此，我们通过涉及环磷腺苷反应元件结合蛋白（CREB）信号通路的方法，在小鼠神经母细胞瘤细胞系（N2a 细胞）中探讨了 TNFAIP1 在 DEHP 诱导的神经毒性中的作用机制。我们发现，DEHP 暴露会诱导细胞凋亡，并下调脑源性神经营养因子（BDNF）、突触蛋白 PSD95 和突触素-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、CaMKIV、PKA 催化亚基和 CREB 的水平。使用 TNFAIP1 小干扰 RNA（siRNA）表达载体下调 TNFAIP1 可防止 DEHP 抑制 CREB 通路，从而减少细胞凋亡并恢复 BDNF、PSD95 和突触素-1 的表达。我们的数据表明，下调 TNFAIP1 通过激活 CREB 通路来防止 DEHP 诱导的神经毒性。因此，TNFAIP1 是缓解 DEHP 诱导的神经毒性和相关神经紊乱的潜在靶点。
