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）空气污染与心血管住院和死亡率的急性增加相关。然而，致病的化学成分和潜在的病理生理机制仍有待澄清。毒理学数据表明，化石燃料燃烧产生的促氧化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，这些因素有可能导致心肌梗死等不良事件。 我们的总体目标是对颗粒暴露进行化学表征，并将这些暴露与潜在易感老年受试者队列中相关的健康结果联系起来。我们将使用每周12次重复测量的方法，对居住在洛杉矶盆地的120名受试者中的每一位进行受试者内的风险-反应关系评估。待测量的结果包括血液中氧化应激和炎症的全身性生物标志物、气道炎症、内皮功能障碍、血压和全血基因表达（> 31，000个基因），重点关注与心血管疾病相关的生物途径中的基因。 我们的总体假设是，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PM暴露的总体氧化潜力相关。我们进一步假设，这些PM特性将与车辆交通源，我们会发现与PM2.5和PM10质量较弱的关联。这一假设是基于这样的观察，即具有氧化潜力和高毒性的化学物质在PM2.5中占很小且高度可变的比例，但在交通源附近的区域中，不受管制的超细PM质量占更大比例。 我们将测试我们的假设与以下三个目标：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全身和气道生物标志物的关系。我们预计不同的污染物成分将影响气道与全身炎症。3.检查空气污染暴露与外周内皮功能和血压的关系。 这将是第一个人类转录组学研究，以评估重复基因表达反应和化学特征的环境空气污染之间的关系。我们提出的评估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，为人群中的空气污染研究提供了一种新的方法。对颗粒物暴露（以尺寸、毒性和来源为特征）的病理生理反应的研究挑战并推进了现有的方法。结果将为旨在保护敏感人群的监管决策提供信息，因为PM的推定致病成分并不能很好地由PM2.5或PM10代表。