双酚A对发育中脑内NMDA受体的影响及其机制研究

项目名称： 双酚A对发育中脑内NMDA受体的影响及其机制研究

项目编号： No.30872087

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 徐晓虹

作者单位： 浙江师范大学

项目金额： 31万元

中文摘要： 发育期暴露于低浓度环境内分泌干扰物双酚A（BPA）可改变动物的神经行为，但其影响脑发育的机制并不清楚。谷氨酸NMDA受体在脑和行为发育中起重要作用。本研究发现，围生期低剂量（0.04-50 mg/kg/d）BPA暴露下调仔鼠皮层和海马NMDA受体水平、改变其亚基组成，下调β38604;激素受体（ERβ65289;却上调雌激素合成关键酶P450arom，抑制树突发育，改变突触界面结构，并影响发育期和成年后的活动性、探究、焦虑、抑郁和学习记忆等行为及其性别分化。进一步研究发现，BPA（10-1000 nM）快速（0.5h）促进新生海马神经元树突丝密度和运动性，增加NMDA受体NR2A/B和ERKs磷酸化，这些作用可被ER拮抗剂或ERK激酶抑制剂抑制；BPA处理24h显著降低海马神经元NMDA-mEPSC振幅和NMDA介导mEPSC比例。以上结果提示，BPA可通过影响海马雌激素合成和ER表达干扰脑内雌激素对NMDA受体发育的调节作用，最终影响神经元树突发育和神经行为；膜ER介导的ERKs通路参与BPA对NMDA受体活性和树突发育的快速作用。本研究为阐明BPA影响脑发育的机制和这类环境污染物的毒性防治提供依据。

中文关键词： 双酚A；脑发育；NMDA受体；环境内分泌干扰物

英文摘要： Bisphenol-A (BPA), an environmental endocrine disrupter, has been shown to influence development of brain and behaviors; however, the mechanisms underlying the effect of BPA on brain development remains unknown. N-methyl-D-aspartate receptor (NMDAR), a subtype of glutamate receptor, is crucial for brain and behaviors development. The present study found that perinatal maternal exposure to low levels of BPA（0.04~50 mg/kg/d）down-regulated the expression of NMDA receptor and altered its subunits composition, down-regulated the expression of estrogen receptor (ER) βut up-regulated the expression of P450arom. BPA also inhibited the dendritic growth, influenced the synaptic interface structure, and thus permanently affected the behaviors, such as locomotor, exploratory, anxiety, depression, and learning-memory, and their sex differentiation of offspring in adulthood. Futhermore, exposed to BPA for 0.5-1 h rapidly enhanced the motility and the density of dendritic filopodia in the cultured hippocampal neurons, as well as the phosphorylations of NMDA receptor subunits NR2B and NR1, and ERKs in hippocampus of young rats, which were suppressed by an ER antagonist or an ERK-activating kinase inhibitor. In addition, exposure to BPA for 24 h significantly decreased the amplitude of NMDA miniature excitatory postsynaptic currents (mEPSC) and the current ratio of NMDA/AMPA minis. However, BPA attenuated the effects of 17βstradiol on the dendritic filopodia outgrowth and the expression of pNR2B when BPA was co-treated with 17βestradiol. These data show that BPA disturbs moduration effect of estrogen on NMDA receptor development by changing estrogen synthesis and estrogen receptor expression in brain; and a non-genomic effect via ER may mediate the influence of BPA on the phosphorylation of NMDAR subunits NR1 and NR2B through ERK signaling pathway. The results of the present study suggest that acute or chronic exposure to the low levels of BPA during developmental stage may have widespread effects on brain through affecting NMDA receptors.

英文关键词： bisphenol- - A; brain development; NMDA receptor; an environmental endocrine disrupter