双酚A对雄激素调节神经行为和突触可塑性的影响及其机制研究

项目名称： 双酚A对雄激素调节神经行为和突触可塑性的影响及其机制研究

项目编号： No.81472935

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 徐晓虹

作者单位： 浙江师范大学

项目金额： 70万元

中文摘要： 环境内分泌干扰物双酚A对脑的影响引起广泛关注。双酚A影响脑和行为存在性别差异，雄性脑对双酚A更敏感。雄激素对雄性脑的调节与雌激素对雌性脑一样非常重要。但目前有关双酚A脑作用机制的研究主要聚焦在其雌激素活性上。本课题拟在前期研究基础上，以去势雄鼠模型研究双酚A对雄激素调节认知和情绪行为的影响；通过①检测去势雄鼠海马突触蛋白和突触形态可塑性，②用感染GFP病毒的海马神经元活细胞成像动态分析神经元树突生长，③双荧光标记分析海马神经元突触形成，④电生理技术检测海马脑片LTP，多层面分析无芳香化作用的5α-双氢睾酮对海马突触可塑性的影响以及双酚A的抗雄激素作用；最后，结合雌、雄激素受体拮抗剂、不透膜的BSA-双酚A、MAPK/ERK、MAPK/p38和CaMKII抑制剂，以及信号分子磷酸化检测等分析双酚A影响雄激素调节突触可塑性的信号通路，阐明双酚A影响雄性脑的分子机制，为双酚A毒性防治提供科学依据

中文关键词： 环境内分泌干扰物；双酚A；雄激素；学习记忆；突触可塑性

英文摘要： The effects of bisphenol A (BPA), an environmental endocrine disruptor, on the brain have attracted a growing attention. The previous researches have found that BPA sex-specifically affects the brain and behaviors of animal, and the male brain is more sensitive to BPA than that of females. Whereas earlier studies focused on the estrogenic properties of BPA. Recent studies revealed that BPA antagonizes androgen receptor (AR)-mediated transcriptional activities. Because androgens are just as critical in the cognitive functions and synaptogenesis in males as estrogens are in females, the potential exists that BPA also interferes with the physiology and morphology of the adult male brain. Thus, using castrated male rats, the following experiments were performed to investigate whether BPA interfered in androgen on the regulation of behaviours, including memory, anxiety, and depression, and synaptic plascity in hippocampus of adult male rats, brain areas with crucial influence on cognitive functions. The effects of BPA and androgen on structure modification of synapses will be examined using electron microscope. The protein expression and phosphorylation of synaptic proteins, NMDA and AMPA receptors, and signaling moleculars will be analyzed by Western bloting. Time-lapse imaging of living neurons and quantification will be used to examine the influence of BPA and androgen on growth of dendritic spin in the cultured hippocampus neurons expressing enhanced GFP. And changes of synaptogenesis were examed by double fluorescent labeling the cultured hippocampus neurons. In addition, the effect of BPA and androgen on efficiency of synaptic transmission will be measured by electrophysiological analyses of LTP of hippocampal slice. Furthermore, the signaling pathways through which BPA interferes in androgen on the regulation of behaviors and synaptic plasticity will be investigated using estrogen and androgen receptor antagonists, impermeable membrane BSA-BPA, inhibitors of MAPK/ERK, MAPK/p38, and CaMKII,respectively. The results of the present study will provide a scientific basis for prevention and control of adverse effects of BPA on brain.

英文关键词： environmental endocrine disruptor;bisphenol A;androgen;learning and memory;synaptic plasticity