PAEs宫内联合暴露致子代生殖毒性的代谢组学判断

项目名称： PAEs宫内联合暴露致子代生殖毒性的代谢组学判断

项目编号： No.81202208

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 预防医学、地方病学、职业病学、放射医学

项目作者： 陈波

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 邻苯二甲酸酯类物质（PAEs）具有生殖毒性，胎儿宫内暴露是观察其生殖危害的最敏感时期，联合暴露是机体接触化学物的最现实场景，而早期特征性代谢谱的改变则是反映机体损伤的敏感效应。本研究拟通过SD孕鼠的染毒实验和男性新生儿的胎粪暴露评估，构建不同的暴露场景，利用特征性代谢谱图的分析判定生殖损伤效应，描述剂量-反应关系曲线，鉴定特征性的代谢产物用以筛选有用的效应生物标志物，分析代谢通路和分子机制，为评价PAEs宫内暴露的健康风险提供新思路；研究同时利用代谢组学技术分析邻苯二甲酸二丁酯（DBP）和邻苯二甲酸2-乙基-己基酯（DEHP）在独立和联合暴露下出现生殖毒性的差别，评价毒作用模式以何种机制（剂量相加、效应相加、协同或拮抗）为主，为化学物联合暴露的机制研究提供新方法；研究也将根据新生儿胎粪中PAEs的一级和二级代谢物的浓度水平，估算其累积生殖风险，为今后化学物累积暴露的健康风险评估提供新探索。

中文关键词： 邻苯二甲酸酯类物质；累积暴露；子代；生殖毒性；代谢组学

英文摘要： Phthalate esters are ubiquitous environmental contaminants with suspected reproductive toxicity. The most sensitive scenario of the toxicity of phthalates lies in the prenatal exposure in utero. People are usually exposed to the mixtures, rather than the individual phthalate. And the early specific changes in metabolic profiles are sensitive end points for effect evaluation. However, there are lack of the literature discussing the metabolomic research of combined exposure to phthalates in utero. In this study, we will build different exposure scenarios by conducting animal experiments of SD rats and neonatal exposure assessment of meconium, assess the reproductive effects by metabolomic analyses of the metabolic phenotypes related to phthalate exposure. Such an description of dose-response curve will benefit the identification of new biomarkers, the clarification of metabolic pathways and molecular mechanism. Metabolomic approaches will also be used to discriminate the mode of action (dose-additive, effect-additive, synergistic or antagonistic effect) after the combined exposure to dibutyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) in both SD rats and human male neonates. Finally, the study will also estimate the cumulative exposure to DBP and DEHP by using their metabolites in neonatal meconium. The c

英文关键词： Phthalic acid esters；Cumulative Exposure；Offspring；Reproductive Toxicity；Metabonomics