TNFAIP1在增塑剂DEHP诱发学习记忆障碍中的作用与机制研究

DEHP暴露与学习记忆障碍密切相关。我们前期发现氧化应激使TNFAIP1上调介导了DEHP诱发的神经毒性；DEHP下调ERβ，通过上调TNFAIP1抑制CK2β和Akt/CREB通路；TNFAIP1与CK2β存在相互作用，TNFAIP1促进其相互作用蛋白泛素化降解。同行发现拮抗ERβ促进TNFAIP1表达；CK2激活Akt。因此我们提出DEHP诱发学习记忆障碍的“四阶段机制”假说：DEHP诱导氧化应激和抑制ERβ，从而上调TNFAIP1表达，促进与其结合的CK2泛素化降解，进而抑制Akt/CREB通路，造成突触可塑性降低和神经元凋亡，最终诱发学习记忆障碍。本项目将在体内整体水平（C57BL/6小鼠）和体外器官水平（海马脑片三维培养模型）利用分子事件阻断技术探讨“四阶段机制”的正确性。这将有利于阐明环境内分泌干扰物诱发学习记忆障碍和相关神经疾病的分子机制，也为开发新的治疗靶点提供借鉴和参考。

Exposure to di-(2-ethylhexyl) phthalate (DEHP) plasticizer is closely related to learning and memory impairment. Our previous studies found that oxidative stress-induced upregulation of tumor necrosis factor α-induced protein 1 (TNFAIP1) mediated DEHP-induced neurotoxicity; DEHP downregulated estrogen receptor β (ERβ), and inhibited protein kinase CK2β and Akt/CREB pathway by upregulating TNFAIP1; TNFAIP1 interacted with CK2β, and TNFAIP1 promoted ubiquitin degradation of its interacting proteins. It is reported that antagonizing ERβ promoted expression of TNFAIP1; CK2 activated Akt. Based on these points, we proposed the four-stage mechanism hypothesis that DEHP firstly induced oxidative stress and inhibited ERβ, thereby upregulated TNFAIP1 expression and promoted its binding protein CK2 ubiquitin degradation. Then Akt/CREB pathway was inhibited, which resulted in synaptic plasticity reduction and neuronal apoptosis, ultimately induced learning and memory impairment. We will use molecular event blocking technology to explore the validity of the four-stage mechanism in vivo based on C57BL/6 mice and in vitro based on three-dimensional culture model of hippocampal slice. Our study will be helpful to further clarify the molecular mechanisms of environmental endocrine disruptors-induced learning and memory impairment and related neurological disorders. It will also provide a reference for developing new therapeutic targets of these diseases.