基于人胚胎干细胞模型评价DEHP的胚胎发育毒性及PPARs/TGF-β信号通路扰动在其毒性发生中的作用

邻苯二甲酸二乙基己基酯 (DEHP)是一种目前用量最大的增塑剂，广泛用于食品包装材料中，因其存在着迁移污染及被非法添加现象，已对食品安全构成明显危害,引起高度关注。动物实验证实DEHP具有广泛毒性效应，但缺乏确切的人群暴露流行病学数据，及动物实验数据外推人体的不确定性，对其风险评估与风险管理尚存在困难。本课题拟采用对人体具有高度预测性的人胚胎干细胞（hESC）实验模型，对DEHP的主要毒性终点发育毒性进行评价，阐明效应特征与剂量水平，为DEHP的危害评估与风险管理提供依据。同时，基于DEHP的重要作用靶点以及胚胎早期发育的重要调节信号途径，本课题将通过hESC的增殖与分化模拟胚胎早期发育,利用基因沉默技术系统研究DEHP对过氧化酶体增殖物激活受体（PPARs）与转化生长因子-β（TGF-β)之间信号通路的调控机制，初步阐明DEHP引起胚胎早期发育的主要毒性信号机制，为其危害防治提供理论依据

Di-(2-ethylhexyl)-phthalate(DEHP) is widely used in food packaging materials, as the largest amount plasticizer. DEHP poses significant hazards to food safety due to its migration pollutionin from packaging materials and being added illegally in some foods.In recent years, DEHP has drawn a lot of public concern. DEHP embryotoxicity has been confirmed in animal experiments. However, it is difficult to undertaken risk assessment and risk management for DEHP for several reasons, including uncertain extrapolation from animal experiment data to human bady, and lacking the accuary exposure and epidemiological data in people. The model of human embryonic stem cells (hESC) test can imitate the process of human embryonic development, and can highly predict DEHP embryonic toxicity in human body. In this project, the model of hESC test will be established to evaluate DEHP embryotoxicity. The peroxisome proliferator activated receptors(PPARs) are DEHP important targets, and transforming growth factor-β (TGF-β) is one of the most important regulating factor in early embryonic development. In order to explore the mechanism of DEHP embryotoxicity, the coaction and relation among DEHP, PPARs and TGF-β in differentiated hESCs will be investigated by using gene silencing technology in this study. The experimental data in this study will be provided as evidence for DEHP hazard assessment and risk management, and for the prevention of DEHP hazard.