Transcriptomic, Oxidative Stress, and Inflammatory Responses to Air Pollutants

描述(由申请人提供)：短期暴露于美国环保局监管的大气颗粒物(PM)空气污染，直径为2.5微米(PM2.5)和10微米(PM10)，与心血管住院和死亡率的急剧增加有关。然而，其致病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助氧化剂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，这些因素有可能引发心肌梗死等不良事件。我们的总体目标是对颗粒物暴露的化学特征进行表征，并将这些暴露与潜在易感老年受试者队列中相互关联的健康结果联系起来。我们将对居住在洛杉矶盆地的120名受试者进行每周12次重复测量，以评估受试者内部暴露-反应关系。要测量的结果包括血液中氧化应激和炎症的系统性生物标记物、呼吸道炎症、内皮功能障碍、血压和全血基因表达(&gt；31,000个基因)，重点是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接触超细颗粒物(PM&lt；0.1um)、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有关。我们进一步假设，这些PM特征将与车辆交通来源有关，我们将发现与PM2.5和PM10质量的相关性较弱。这一假设是基于观察到的，即具有氧化潜力和高毒性的化学物质构成PM2.5的一小部分且高度可变，但在交通源附近地区的未受监管的超细PM质量中所占比例要大得多。我们将通过以下三个目标来验证我们的假设：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全身和呼吸道氧化应激和炎症生物标志物的关系。我们预计不同的污染物成分会影响呼吸道和全身炎症。3.研究空气污染暴露与外周血管内皮功能和血压的关系。这将是第一批评估重复基因表达反应与化学特征的环境空气污染之间关系的人类转录研究之一。我们提出的对PM氧化潜力和有毒化学成分对遗传、生物标志物和生理结果综合影响的评估为研究人群中的空气污染提供了一种新的方法。对颗粒物暴露的病理生理反应(以大小、毒性和来源为特征)的研究对现有方法提出了挑战和改进。结果将为旨在保护敏感人群的监管决策提供参考，因为PM2.5或PM10不能很好地代表PM的假定致病成分。

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.