环境污染是当前危害人类健康的重大问题之一，儿童为高危暴露人群且受到的危害更大。邻苯二甲酸二丁酯（DBP）是目前最常见的环境污染物之一，大量研究显示孕期暴露DBP会导致儿童认知障碍，但其机制仍未明确。本课题组前期研究发现围生期暴露DBP可导致子代未成熟脑海马区的芳香化酶表达增高、雌激素β受体表达下降及BDNF释放减少。本课题拟在前期工作基础上，针对围生期暴露DBP延缓子代海马神经发育的分子机制进行深入研究，结合体外和体内实验，围绕（1）DBP如何调控雌激素β受体-BDNF信号通道在海马神经元发育过程的多靶向调节作用；（2）发育早期海马区神经递质GABA是否介入DBP作用；（3）发现可能直接参与DBP神经毒的靶点细胞这几个方面，进一步深入研究围生期暴露DBP对子代鼠认知行为/记忆能力影响，确认DBP诱发大脑神经毒的作用位点、分子机制，为有效规避DBP的神经毒性提供重要的实验基础。

There is increasing concern about adverse effect of chemical pollutants on human health, especially their potential toxicity on children’s development. Dibutyl phthalate (DBP) is one of the mostly used chemicals in plastics factory and has shown an estrogen-like activity that may alter normal brain development. Although many data on neurotoxicity effects of DBP have been elucidated, however, the mechanisms underlying DBP-induced brain impairment remain unclear. Our previous studies showed that perinatal exposure of DBP significantly up-regulated the expression of aromatase, down-regulated the expression of estrogen receptor beta (ERβ) and BDNF, postponed hippocampal neuronal development, and induced hippocampal neurotoxicity in neonatal and immatural offspring rats, suggest that environmental expo-sure to DBP during gestation may contribute to poor neurodevelopmental outcomes. To further understand the mechanisms of DBP’s adverse effects on neonatal brain development, we will focus on: (1) How does perinatal DBP exposure modulate the hippocampal ERβ –BDNF signal pathway; (2) Whether the functions of hippocampal GABA signal involve the adverse effect of DBP; (3) What type of hippocampal GABAergic neuron primary participates the adverse effect of DBP during neurodevelopment. In addition, our studies also will demonstrate the correlative index of perinatal DBP exposure and immatural brain dysfunction that may provide the information of preventing DBP influence during gestation. In this study, we will use tissue culture techniques, molecular biology tools, electrophysiology techniques and behavior studies to verify our specific aims.

环境污染是当前危害人类健康的重大问题之一，儿童为高危暴露人群且受到的危害更大。邻苯二甲酸二丁酯（DBP）是目前最常见的环境污染物之一，大量研究显示孕期暴露DBP会导致儿童认知障碍，但其机制仍未明确。本课题组研究发现围生期中、高剂量（200mg/kg/d及500mg/kg/d） DBP暴露可导致孕鼠体重增长减少，活仔率降低，高剂量组更明显。围生期DBP暴露损害了幼年期子鼠的认知功能，而对成年子鼠的认知功能影响较小；低中剂量（50mg/kg/d及200mg/kg/d）组认知损害明显，雌雄无统计学差异性，尤其是200mg/kg/d中剂量组认知损害较50mg/kg/d低剂量组更明显。而高剂量组（500mg/kg/d）雌性子鼠认知损害明显，而雄性子鼠损害相对较轻，表明DBP暴露对子代大鼠的认知损害具有年龄、剂量及性别差异性。DBP围生期暴露后，海马区BDNF及NPY表达与对照组相比有降低趋势。结合我们既往研究发现DBP围生期暴露后海马区ERβ表达降低，提示DBP神经毒性的分子机制可能是影响了雌激素信号通路，并进一步影响了BDNF的表达。本研究中NPY表达的同步下调，推测DBP可能通过影响雌激素受体与NPY 共存的GABAergics 神经细胞而发挥其神经毒性，从而推测DBP神经毒性的靶点细胞可能为GABAergics 神经细胞。本研究可为有效规避DBP的神经毒性提供重要的实验基础。