围生期接触环境雌激素双酚A诱发青少年时期焦虑/抑郁症性别差异性发病的分子机制研究

项目名称： 围生期接触环境雌激素双酚A诱发青少年时期焦虑/抑郁症性别差异性发病的分子机制研究

项目编号： No.81471385

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： 周蓉

作者单位： 南京医科大学

项目金额： 70万元

中文摘要： 前期研究发现围生期接触环境雌激素双酚A（BPA）可破坏青春期情绪行为的性别二态性，导致焦虑/抑郁症等情感障碍类疾病发病呈现女性显著高于男性的性别差异。在情绪相关行为调控中发挥关键作用的杏仁核-GABA神经元数量和功能在围生期性激素的调控下具有明显性别二态性（雌性﹥雄性）。预结果显示BPA子代雌鼠杏仁核GABA神经元数量减少，去抑制增强，出现类雄性焦虑以及抑郁样行为。提示BPA破坏杏仁核-GABA神经元性别二态性的正常构建是情绪行为性别差异改变的重要环节。本课题将探讨①BPA干扰杏仁核-GABA神经元性分化的靶受体；②分析各靶受体下游的信号通路及其相互间的调控和靶受体介导的表观遗传机制，明确BPA破坏杏仁核-GABA神经元性别二态性的分子机制。③阐明BPA干扰杏仁核-GABA神经元性分化发育与情绪行为的相关性。为BPA诱发的青少年情感障碍疾病进行个性化的预防、诊断和治疗提供新的理论依据。

中文关键词： 双酚A；焦虑/抑郁症；性别二态性；杏仁核-GABA神经元；雌激素受体

英文摘要： The behavioral evidence of our laboratory and others reveals that perinatal exposure of bisphenol A (BPA) alters sexually dimorphic affective behaviors leading to marked sex difference in the prevalence of adolescent anxiety/depression-like disorders (Prevalence: Female > Male). The establishment of sex difference in GABAergic interneurons within amygdala(Number and Function: Female > Male), which is one of the essential brain regions for the control of anxiety/depression-related behaviors depends on the regulation of sex hormones during the perinatal development. Our previous studies have indicated that the perinatal BPA exposure decreases the number and inhibition function of amygdala GABAergic neurons resulting in male-like anxiety behaviors. The hypothesis is therefore proposed that perinatal BPA exposure alleviates or reverses physiological sex difference in affective behaviors via disrupting sex differentiation of amygdala GABAergic neurons. The project will focus on ① determining the target receptors of BPA-effects on the sex differentiation of GABAergic neurons in amygdala. ② clarifying the molecular mechanisms of BPA-actions via analyzing the target receptors-mediated signal transduction pathways and their cross-talk. ③ elucidating the relation between BPA-disrupted sex difference in amygdala GABAergic neurons and affective behaviors via protecting the sex differentiation of GABAergic neurons against perinatal BPA exposure. The findings will provide the primary support for sex-specific precaution, diagnosis and treatment of child and adolescent affective disorders induced by perinatal BPA exposure.

英文关键词： bisphenol A;anxiety/depression disorder;sexual dimorphism;amygdala GABAergic neurons;estrogen receptors