MiR-93 alleviates DEHP plasticizer-induced neurotoxicity by negatively regulating TNFAIP1 and inhibiting ubiquitin-mediated degradation of CK2β.

Feng Qiu, Simei He, Zilong Zhang, Siyu Dai, Jin Wang, Ning Liu, Zhiwei Li, Xiang Hu, Shuanglin Xiang, Chenxi Wei

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 2023 Aug

filter terms:

Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer that is widely used in various products, such as plastic packaging in food industries. As an environmental endocrine disruptor, it induces adverse effects on brain development and function. However, the molecular mechanisms by which DEHP induces learning and memory impairment remain poorly understood. Herein, we found that DEHP impaired learning and memory in pubertal C57BL/6 mice, decreased the number of neurons, downregulated miR-93 and the β subunit of case in kinase 2 (CK2β), upregulated tumor necrosis factor-induced protein 1 (TNFAIP1), and inhibited Akt/CREB pathway in mouse hippocampi. Co-immunoprecipitation and western blotting assays revealed that TNFAIP1 interacted with CK2β and promoted its degradation by ubiquitination. Bioinformatics analysis showed a miR-93 binding site in the 3'-untranslated region of Tnfaip1. A dual-luciferase reporter assay revealed that miR-93 targeted TNFAIP1 and negatively regulated its expression. MiR-93 overexpression prevented DEHP-induced neurotoxicity by downregulating TNFAIP1 and then activating CK2/Akt/CREB pathway. These data indicate that DEHP upregulates TNFAIP1 expression by downregulating miR-93, thus promoting ubiquitin-mediated degradation of CK2β, subsequently inhibiting Akt/CREB pathway, and finally inducing learning and memory impairment. Therefore, miR-93 can relieve DEHP-induced neurotoxicity and may be used as a potential molecular target for prevention and treatment of related neurological disorders. Copyright © 2023 Elsevier Ltd. All rights reserved.

Citation

Feng Qiu, Simei He, Zilong Zhang, Siyu Dai, Jin Wang, Ning Liu, Zhiwei Li, Xiang Hu, Shuanglin Xiang, Chenxi Wei. MiR-93 alleviates DEHP plasticizer-induced neurotoxicity by negatively regulating TNFAIP1 and inhibiting ubiquitin-mediated degradation of CK2β. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2023 Aug;178:113888