Exposure to traffic-related pollutants, including diesel exhaust, is associated with increased risk of cardiopulmonary disease and mortality; however, the precise biochemical pathways underlying these effects are not known. To investigate biological response mechanisms underlying exposure to traffic related pollutants, we used an integrated molecular response approach that included high-resolution metabolomic profiling and peripheral blood gene expression to identify biological responses to diesel exhaust exposure. Plasma samples were collected from 73 non-smoking males employed in the US trucking industry between February 2009 and October 2010, and analyzed using untargeted high-resolution metabolomics to characterize metabolite associations with shift- and week-averaged levels of elemental carbon (EC), organic carbon (OC) and particulate matter with diameter ≤ 2.5 μm (PM_2.5). Metabolic associations with EC, OC and PM_2.5 were evaluated for biochemical processes known to be associated with disease risk. Annotated metabolites associated with exposure were then tested for relationships with the peripheral blood transcriptome using multivariate selection and network correlation. Week-averaged EC and OC levels, which were averaged across multiple shifts during the workweek, resulted in the greatest exposure-associated metabolic alterations compared to shift-averaged exposure levels. Metabolic changes associated with EC exposure suggest increased lipid peroxidation products, biomarkers of oxidative stress, thrombotic signaling lipids, and metabolites associated with endothelial dysfunction from altered nitric oxide metabolism, while OC exposures were associated with antioxidants, oxidative stress biomarkers and critical intermediates in nitric oxide production. Correlation with whole blood RNA gene expression provided additional evidence of changes in processes related to endothelial function, immune response, inflammation, and oxidative stress. We did not detect metabolic associations with PM_2.5. This study provides an integrated molecular assessment of human exposure to traffic-related air pollutants that includes diesel exhaust. Metabolite and transcriptomic changes associated with exposure to EC and OC are consistent with increased risk of cardiovascular diseases and the adverse health effects of traffic-related air pollution.

接触与交通相关的污染物（包括柴油机尾气）会增加心肺疾病和死亡的风险；然而，这些影响背后的精确生化途径尚不清楚。为了研究交通相关污染物暴露的生物反应机制，我们使用了一种综合分子反应方法，包括高分辨率代谢组学分析和外周血基因表达，以确定对柴油机尾气暴露的生物反应。血浆样本是从 2009 年 2 月至 2010 年 10 月期间在美国卡车运输行业工作的 73 名非吸烟男性采集的，并使用非目标高分辨率代谢组学进行分析，以表征代谢物与元素碳 (EC) 平均水平和周平均水平的关系，有机碳（OC）和直径≤2.5μm的颗粒物（PM _2.5 ）。针对已知与疾病风险相关的生化过程，评估了与 EC、OC 和 PM _{2.5 的}代谢关联。然后使用多变量选择和网络相关性测试与暴露相关的注释代谢物与外周血转录组的关系。周平均 EC 和 OC 水平是工作周内多个轮班的平均值，与班次平均暴露水平相比，导致与暴露相关的代谢变化最大。 与EC暴露相关的代谢变化表明脂质过氧化产物、氧化应激生物标志物、血栓信号脂质以及与一氧化氮代谢改变引起的内皮功能障碍相关的代谢物增加，而OC暴露与抗氧化剂、氧化应激生物标志物和一氧化氮的关键中间体相关生产。与全血 RNA 基因表达的相关性为与内皮功能、免疫反应、炎症和氧化应激相关的过程的变化提供了额外的证据。我们没有检测到与 PM _{2.5 的}代谢关联。这项研究对人类接触交通相关空气污染物（包括柴油机尾气）的情况进行了综合分子评估。与接触 EC 和 OC 相关的代谢和转录组变化与心血管疾病风险增加以及交通相关空气污染对健康的不利影响一致。