1. Knockdown of TNFAIP1 prevents di-(2-ethylhexyl) phthalate-induced neurotoxicity by activating CREB pathway
- Author
-
Feng Qiu, Chenxi Wei, Mengting Gong, Shuanglin Xiang, Yubo Zhou, Junzhi Yi, Yeke Deng, and Ning Liu
- Subjects
endocrine system ,Small interfering RNA ,Environmental Engineering ,Health, Toxicology and Mutagenesis ,0208 environmental biotechnology ,Phthalic Acids ,Down-Regulation ,Apoptosis ,02 engineering and technology ,010501 environmental sciences ,CREB ,01 natural sciences ,Cell Line ,Mice ,Neuroblastoma ,Downregulation and upregulation ,Neurotrophic factors ,Plasticizers ,Diethylhexyl Phthalate ,medicine ,Environmental Chemistry ,Animals ,Cyclic AMP Response Element-Binding Protein ,CAMK ,0105 earth and related environmental sciences ,Adaptor Proteins, Signal Transducing ,Gene knockdown ,biology ,Chemistry ,Public Health, Environmental and Occupational Health ,Neurotoxicity ,Endothelial Cells ,General Medicine ,General Chemistry ,medicine.disease ,Pollution ,020801 environmental engineering ,Cell biology ,Gene Expression Regulation ,biology.protein ,Neurotoxicity Syndromes ,Signal transduction - Abstract
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.
- Published
- 2019