壬基酚暴露对抑郁行为和突触可塑性的影响及分子机制

The incidence of depression has increased dramatically in recent decades．Prior studies revealed that there was an association between environmental estrogen exposure and depressive disorders. Nonylphenol (NP) is a typical representative of environmental estrogen-like chemicals. Our previous studies had testified that NP exposure would induce synaptic morphological alterations in fetal rats, decrease in the learning and memory ability, and behavior disorders in F1 rats, however, whether exposure to NP would increase the risk of depression incidence has not been elucidated. . At first, our project intends to perform population survey to measure the concentrations of NP in serum and urine in depressed patients. The associations between NP concentration and the serum levels of monoamine neurotransmitters and hormones, and depression rating score was evaluated. We then use an animal model to explore the impact of NP exposure on depression-like behaviors and hippocampal synaptic plasticity in rats. Primary cultured hippocampus neurons were further exposed to NP to examine the adverse effects of NP on hippocampal synaptic markers, glutamate receptor proteins and ERK signaling pathway as well as estrogen receptors, for revealing whether chronic exposure to NP could lead to an increase in the risk of depression-like behaviors at the molecular level? We will first conduct a series of in vivo and in vitro toxicological experiments together with population-based epidemiological survey to investigate the relationship between NP exposure and the incidence of anxiety and depression and its molecular mechanism, for further preventing mental disorders induced by environmental estrogen-NP, and providing scientific basis of the drug target for the treatment of mental disorders.

抑郁症发病率急剧增高，研究显示，环境雌激素暴露是其危险因素之一。壬基酚(NP)是环境雌激素的典型代表，课题组研究发现孕期暴露NP可影响胎鼠突触形态,导致仔鼠学习记忆下降及行为异常，目前未见NP暴露与抑郁发病关系及其机制的报道。. 本项目拟通过人群调查，检测NP在抑郁症患者血清和尿液中的含量，分析其与患者血清及尿液单胺类神经递质、激素水平以及抑郁评分之间的相关性；通过动物实验，研究NP暴露对大鼠抑郁行为和海马神经元突触可塑性的影响及机制；开展原代海马神经元体外培养染毒，检测NP暴露对海马神经元突触标记分子、谷氨酸受体蛋白、ERK信号通路及雌激素受体等的影响，以此阐明慢性NP暴露是否可增加抑郁行为发生风险，并试图探讨相关的分子机制。本课题结合流行病学调查和体内、外实验，首次研究NP长期暴露与抑郁发病的关系及分子机制，为预防NP暴露所致的精神疾病和实施靶标药物治疗提供科学依据。

抑郁症发病率急剧增高，环境雌激素暴露是其危险因素。壬基酚(NP)是环境雌激素的典型代表，目前未见NP暴露与抑郁发病关系及其机制的报道。. 本项目通过人群调查率先发现：抑郁组人群SDS和SAS评分、血清中NP水平均高于健康组，多巴胺、肾上腺素、去甲肾上腺素和BDNF低于健康组，推测NP暴露与抑郁症发病可能有一定关联。通过动物实验和原代细胞培养进一步验证上述推测，结果发现：NP长期暴露可致大鼠抑郁样行为，伴血清神经递质5-HT、DA、NE释放降低、CORT释放增加，随着暴露时间延长，暴露浓度越高脑组织和细胞中蓄积NP越多，神经元突触可塑性改变（突触后致密物厚度降低，突触间隙和突触界面曲率增加）越明显，突触相关蛋白/基因（PSD-95和SynapsinΙ）表达降低；（3）同时发现，4mg/kg NP长期暴露可致大鼠焦虑样行为及神经营养因子相关蛋白/基因（BDNF、CREB、P-CREB、P-TrkB、TrkB）降低，暴露时间越长，损伤越严重。本课题结合流行病学调查和体内、外实验，首次研究NP长期暴露与抑郁发病的关系及分子机制，为预防NP暴露所致的精神疾病和实施靶标药物治疗提供科学依据。