Development and Application of Biomarkers of Exposure - Biomedical

暴露生物标志物的开发和应用 - 生物医学

• 批准号: 7067249
• 负责人: Stephen M Rappaport
• 金额: $ 30.65万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7067249
• 关键词: age difference; air pollution; benzene; biomarker; blood chemistry; carbopolycyclic compound; clinical research; environmental exposure; environmental toxicology; gas chromatography mass spectrometry; gender difference; genetic susceptibility; human tissue; lifestyle; liquid chromatography mass spectrometry; occupational hazard; toxin metabolism; urinalysis

This project will build upon our previous innovations in developing biomarkers of exposure to benzene and polycyclic aromatic hydrocarbons (PAHs) and in applying these biomarkers in exposed populations. The biomarkers will include urinary analytes (unmetabolized parent compounds and stable metabolites) and blood-protein adducts of the reactive metabolites. Human cancers and other toxic effects of benzene and PAHs arise from metabolism of the parent compounds to toxic intermediates, including epoxides, diolepoxides, and quinones. Human metabolism can vary among individuals due to a host of factors. The following two hypotheses will be considered in this project: Hypothesis 1: biomarkers of exposure can be used to elucidate the human metabolism of benzene and PAHs. Hypothesis 2: biomarkers of exposure can be used to quantify interindividual variability of metabolism of benzene and PAHs, due to differences in gender, age, and physiological, lifestyle, and genetic factors. To test these hypotheses, we will pursue three specific aims. First, we will gather appropriate samples of urine and blood with which to evaluate exposure-biomarker relationships. Populations will include both high/moderate exposures (coke ovens, asphalt and rubber workers, persons using smoky coal for cooking and residential heating) and low/background exposures (workers exposed to diesel exhausts and jet fuel, smokers and nonsmokers in the general public). Second, we will develop or adapt ultra-trace mass spectrometric (GC-MS and LC-MS/MS) methods to measure the urinary and blood analytes. These methods will build upon existing GC-MS assays of protein adducts from our laboratory and will be expanded to include state-of-the-art LC-MS/MS methods for the urinary metabolites. Third, we will employ statistical models to characterize the exposure-biomarker relationships, paying particular attention to evidence of concavity, due to saturation of metabolism, and to the low-dose linear slope. Adding available covariates for gender, age, physiological and lifestyle factors, and genetic factors, we will explore the sources of interindividual variability in the exposure-specific levels of biomarkers. Blood samples from a study of childhood leukemias will also be analyzed for protein adducts of benzene and PAHs in collaboration with the U.C. Berkeley SBRP. This will allow Berkeley investigators to achieve additional specific aims in their program.

该项目将建立在我们之前的创新基础上，开发暴露于苯和多环芳烃(PAHs)的生物标记物，并在暴露人群中应用这些生物标记物。生物标志物将包括尿液分析物(未代谢的母体化合物和稳定的代谢物)和反应性代谢物的血液蛋白加合物。人类癌症和苯和多环芳烃的其他毒性效应源于母体化合物向有毒中间体的代谢，包括环氧化物、二环氧化物和苯二酚。由于多种因素，人的新陈代谢会因个体而异。本项目将考虑以下两个假设：假设1：暴露的生物标志物可以用来阐明人类对苯和多环芳烃的代谢。假设2：由于性别、年龄、生理、生活方式和遗传因素的差异，暴露的生物标记物可以用来量化苯和多环芳烃代谢的个体间变异性。为了检验这些假设，我们将追求三个具体目标。首先，我们将收集适当的样本 尿液和血液，用来评估暴露-生物标记物的关系。人群将包括高/中度暴露(焦炉、沥青和橡胶工人、使用烟煤做饭和住宅取暖的人)和低/本底暴露(接触柴油废气和喷气燃料的工人、普通公众中的吸烟者和不吸烟者)。其次，我们将开发或采用超微量质谱仪(GC-MS和LC-MS/MS)来测量尿液和血液中的分析物。这些方法将建立在我们实验室现有的蛋白质加合物的GC-MS分析基础上，并将扩展到包括最先进的尿代谢物的LC-MS/MS方法。第三，我们将采用统计方法 描述暴露-生物标志物关系的模型，特别注意新陈代谢饱和引起的凹陷的证据，以及低剂量的线性斜率。添加性别、年龄、生理和生活方式因素以及遗传因素的可用协变量，我们将探索暴露特定水平的生物标记物的个体间变异性的来源。还将与加州大学伯克利分校的SBRP合作，对儿童白血病研究的血液样本进行苯和多环芳烃的蛋白质加合物分析。这将使伯克利分校的调查人员能够在他们的项目中实现更多的具体目标。