DEHP/乙醇基于PPARα/γ信号通路致肝脏损伤的联合毒性效应研究

项目名称： DEHP/乙醇基于PPARα/γ信号通路致肝脏损伤的联合毒性效应研究

项目编号： No.81673173

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 贾旭东

作者单位： 国家食品安全风险评估中心

项目金额： 25万元

中文摘要： 邻苯二甲酸二(2-乙基己)酯（DEHP）具有潜在的肝脏毒性效应，由于DEHP和乙醇的毒性作用靶器官均为肝脏，且具有相似的基于过氧化物酶体增殖物激活受体（PPARs）细胞信号通路的毒性作用方式，因此同时暴露时可能会发生联合毒性作用。目前关于二者联合暴露毒性研究极其缺乏，单纯根据DEHP毒性研究结果进行食品安全风险评估可能会低估该类物质对人群健康的总体影响。本实验室初步研究已经提示二者联合暴露可能增加单一暴露条件下的肝脏损伤及PPAR反应活性。因此，我们提出研究假说“DEHP和乙醇联合暴露能够通过PPARα/γ信号通路对肝脏产生协同毒性效应”。本项目拟通过动物试验、肝细胞体外试验研究验证DEHP和乙醇对肝脏的联合毒性作用，并通过基因敲除动物模型、RNAi和PPARα/γ超表达细胞模型阐明PPARα/γ毒性通路在肝脏毒性损伤中的作用机制，从而为增塑剂与乙醇联合暴露的食品安全风险评估提供依据。

中文关键词： 邻苯二甲酸二(2-乙基己)酯；乙醇；联合毒性；过氧化物酶体增殖物激活受体

英文摘要： As one of the most common type of plasticizer in food contaminants, di(2-ethylhexyl)phthalate (DEHP) is of potential liver toxicity and has imposed serious threat on food safety and human health. Ethanol and DEHP both toxicologically targeted liver and share similar mode of actions based on peroxisome proliferators-activated receptors (PPARs) signaling pathway. Hence the joint exposure to the two chemicals may generate combined toxicity in liver. Currently, toxicological studies regarding their co-exposure are very rare, and the food safety risk assessment according to the toxicity of DEHP alone would probably underestimate the overall health effect in actual cases. Our preliminary study showed that the combined exposure of DEHP and ethanol could enhance the hepatotoxicity as well as PPAR response in comparison with those under single exposure. Therefore, we hypothesized that DEHP and ethanol synergize the toxicological effects on liver through PPARα/γ signal pathway under co-exposure. This project is to validate the combined toxicity of DEHP and ethanol by chronic oral toxicity test in animals and in vitro test in human primary hepatocytes. In addition, the knockout animal (PPARα/γ- null) models, RNAi and PPARα/γ-overexpression cell models will be used to investigate the underlying mechanisms by which DEHP and ethanol jointly induce hepatic lesions via PPARα/γ toxicity pathway. The results are expected to provide scientific basis for the food safety risk assessment of joint exposure of plasticizer and alcohol in the human diet.

英文关键词： DEHP;Ethanol;Combined toxicity;PPARs