Transcriptomic, Oxidative Stress, and Inflammatory Responses to Air Pollutants

对空气污染物的转录组、氧化应激和炎症反应

• 批准号: 8415850
• 负责人: RALPH J DELFINO
• 金额: $ 59.37万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415850
• 关键词: Acute; Address; Adverse event; Aerosols; Affect; Air Pollutants; Air Pollution; Area; Arteries; Biochemical Markers; Biological; Biological Assay; Biological Markers; Blood; Blood Cells; Blood Platelets; Blood Pressure; Blood Vessels; Caliber; Cardiovascular Diseases; Cardiovascular system; Characteristics; Chemicals; Data; Deposition; Elderly; Epidemiologic Studies; Exhalation; Exposure to; Fossil Fuels; Functional disorder; Gases; Gene Expression; Gene Expression Profile; Genes; Genetic Markers; Health; Hospitalization; Human; Individual; Inflammation; Inflammatory Response; Interleukin-6; Investigation; Knowledge; Lead; Life; Link; Los Angeles; Lung; Measurement; Measures; Mediating; Methods; Modeling; Myocardial Infarction; NF-kappa B; Nitric Oxide; Organic Chemicals; Outcome; Oxidants; Oxidative Stress; Oxidative Stress Induction; Ozone; Particle Size; Particulate Matter; Pathway interactions; Peripheral; Physiological; Plasma; Play; Poison; Population; Public Health; RNA; Reactive Oxygen Species; Research; Role; Sampling; Selectins; Signal Transduction; Source; TNF gene; Testing; Thrombosis; Toxic effect; Ultrafine; Vasodilation; Whole Blood; airway inflammation; base; biological adaptation to stress; cohort; cytokine; genome-wide; high risk; interest; mortality; novel; novel strategies; oxidation; oxidized low density lipoprotein; particle; particle exposure; peripheral blood; pollutant; public health relevance; reactive hyperemia; receptor; response; tonometry; trafficking; transcriptomics; ultrafine particle; von Willebrand Factor

DESCRIPTION (provided by applicant): Short-term exposures to US EPA-regulated atmospheric particulate matter (PM) air pollution with diameters <2.5 um (PM2.5) and <10 um (PM10), have been associated with acute increases in cardiovascular hospitalization and mortality. However, the causative chemical components and underlying pathophysiological mechanisms remain to be clarified. Toxicological data suggest pro-oxidant PM chemical species from fossil fuel combustion are causative factors in oxidative stress, inflammation, thrombosis, and vascular dysfunction, which have the potential to precipitate adverse events such as myocardial infarction. Our overall objective is to chemically characterize particle exposures and relate these exposures to interrelated health outcomes in a cohort of potentially susceptible elderly subjects. We will evaluate within-subject exposure-response relations using 12 weekly repeated measures in each of 120 subjects living in the Los Angeles Basin. Outcomes to be measured include systemic biomarkers of oxidative stress and inflammation in the blood, airway inflammation, endothelial dysfunction, blood pressure, and whole blood gene expression (>31,000 genes), focusing on genes in biological pathways relevant to cardiovascular disease. Our overarching hypothesis is that subject health outcomes will be associated with exposure to ultrafine PM (PM< 0.1 um), to organic aerosols from fossil fuel combustion, and to the overall oxidative potential of PM exposures. We further hypothesize that these PM characteristics will be linked to vehicular traffic sources, and that we will find weaker associations with PM2.5 and PM10 mass. This hypothesis is based on observations that chemicals with oxidative potential and high toxicity make up a small and highly variable fraction of PM2.5, but comprise a much greater proportion of unregulated ultrafine PM mass in areas near traffic sources. We will test our hypotheses with the following three aims: 1. Assess relations between air pollution exposures and genome-wide gene expression in peripheral blood. 2. Evaluate relations of air pollution exposures to systemic and airway biomarkers of oxidative stress and inflammation. We anticipate that different pollutant components will affect airway vs. systemic inflammation. 3. Examine relations of air pollution exposures to peripheral endothelial function and blood pressure. This will be among the first human transcriptomic studies to evaluate relations between repeated gene expression responses and chemically-characterized ambient air pollution. Our proposed assessment of the estimated effects of PM oxidative potential and toxic chemical components on combined genetic, biomarker, and physiologic outcomes offers a novel approach to air pollution research in populations. The investigation of pathophysiological responses to particle exposures (characterized by size, toxicity and source) challenges and advances existing approaches. Results will inform regulatory decisions aimed at protecting sensitive populations because putative causative constituents of PM are not well-represented by PM2.5 or PM10.

描述（由申请人提供）：短期暴露于美国epa规定的直径<2.5 um （PM2.5）和<10 um （PM10）的大气颗粒物（PM）空气污染中，与心血管住院和死亡率的急性增加有关。然而，致病的化学成分和潜在的病理生理机制仍有待阐明。毒理学数据表明，化石燃料燃烧产生的促氧化性PM化学物质是氧化应激、炎症、血栓形成和血管功能障碍的致病因素，有可能引发心肌梗死等不良事件。我们的总体目标是在一组可能易感的老年受试者中，对颗粒暴露进行化学表征，并将这些暴露与相关的健康结果联系起来。我们将对居住在洛杉矶盆地的120名受试者使用12周重复测量来评估受试者内部暴露-反应关系。测量的结果包括血液中氧化应激和炎症的全身生物标志物、气道炎症、内皮功能障碍、血压和全血基因表达（bbb31,000个基因），重点关注与心血管疾病相关的生物学途径中的基因。我们的首要假设是，受试者的健康结果将与暴露于超细PM （PM< 0.1 um）、化石燃料燃烧产生的有机气溶胶以及暴露于PM的整体氧化潜力有关。我们进一步假设，这些PM特征将与车辆交通源有关，并且我们将发现PM2.5和PM10质量的关联较弱。这一假设基于以下观察：具有氧化电位和高毒性的化学物质在PM2.5中所占比例很小且变化很大，但在交通源附近地区，不受管制的超细PM质量所占比例要大得多。我们将用以下三个目标来检验我们的假设：1。评估空气污染暴露与外周血全基因组基因表达之间的关系。2. 评估空气污染暴露与氧化应激和炎症的系统和气道生物标志物的关系。我们预计不同的污染物成分会影响气道和全身炎症。3. 检查空气污染暴露与外周内皮功能和血压的关系。这将是首批评估重复基因表达反应与化学特征环境空气污染之间关系的人类转录组学研究之一。我们提议评估PM氧化电位和有毒化学成分对遗传、生物标志物和生理结果的综合影响，为人群空气污染研究提供了一种新的方法。对颗粒暴露（以大小、毒性和来源为特征）的病理生理反应的研究挑战和推进了现有的方法。研究结果将为旨在保护敏感人群的监管决策提供信息，因为PM2.5或PM10并不能很好地代表PM的推定致病成分。