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

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.

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。

大量研究发现脑发育的关键时期-出生前后接触环境不利因素如环境雌激素双酚A（BPA）和应激等可破坏青春期情绪行为的性别性，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。本项目主要以围生期暴露BPA 子代鼠作为脑发育期接触环境不利因素诱发焦虑/抑郁症性别差异性发病的动物模型，以与抑郁和焦虑行为有关的关键脑区—杏仁核以及下丘脑-垂体-肾上腺（HPA）轴作为研究靶点，采用分子生物学、电生理学以及药理学等手段，进行了为期三年的关于的深入研究，发现(1)HPA轴活性的性别二态性的消除是BPA诱发焦虑/抑郁症性别差异性发病直接机制；(2) 杏仁核-GABA神经元的性分化发育被扰乱是BPA的性别相关性焦虑/抑郁症的根本机制；(3) 表观遗传改变是BPA和PRS诱发焦虑/抑郁症性别差异性发病具有长时程效应的关键环节。根据研究结果，本项目提出脑发育期接触环境不利因素→干预脑发育表观遗传→影响中枢神经内分泌功能诱发抑郁症性别差异性发病的思路。其研究成果为脑发育期环境不利因素暴露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。各项工作始终按照既定计划有序进行，执行结果撰写SCI文章6篇。其中4篇已发表，2篇投稿中。