MiR-93 alleviates DEHP plasticizer-induced neurotoxicity by negatively regulating TNFAIP1 and inhibiting ubiquitin-mediated degradation of CK213
MiR-93 alleviates DEHP plasticizer-induced neurotoxicity by negatively regulating TNFAIP1 and inhibiting ubiquitin-mediated degradation of CK213
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DOI：
10.1016/j.fct.2023.113888
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发表时间：
2023-06-20
影响因子：
4.3
通讯作者：
Wei，Chenxi
中科院分区：
文献类型：
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作者：
Qiu，Feng;He，Simei;Wei，Chenxi
邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种增塑剂，广泛用于各种产品，如食品工业中的塑料包装。作为一种环境内分泌干扰物，它对大脑发育和功能产生不利影响。然而，DEHP诱导学习和记忆障碍的分子机制仍然知之甚少。在此，我们发现DEHP损害青春期C57 BL/6小鼠的学习和记忆，减少神经元数量，下调miR-93和酪蛋白激酶2（CK 2 β）的β亚基，上调肿瘤坏死因子诱导蛋白1（TNFAIP 1），并抑制小鼠大脑中Akt/CREB通路。免疫共沉淀和蛋白质印迹分析表明TNFAIP 1与CK 2 β相互作用并通过泛素化促进其降解。生物信息学分析显示Tnfaip 1的3′-非翻译区存在miR-93结合位点。双荧光素酶报告基因检测显示，miR-93靶向TNFAIP 1并负调控其表达。miR-93过表达通过下调TNFAIP 1进而激活CK 2/Akt/CREB通路来防止DEHP诱导的神经毒性。这些数据表明，DEHP通过下调miR-93上调TNFAIP 1表达，从而促进泛素介导的CK 2 β降解，随后抑制Akt/CREB通路，最终诱导学习记忆障碍。因此，miR-93可以减轻DEHP诱导的神经毒性，并可能作为预防和治疗相关神经系统疾病的潜在分子靶点。
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 casein 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 ofTnfaip1. 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.