Using metabolomics to investigate the metabolic signatures and associated pathways linked to short-term exposure to air pollutants

人类暴露在空气污染中每年导致全球约700万人死亡，由于心脏病在全球的高度流行，大多数死亡归因于心血管疾病(CVD)。暴露于恶劣空气质量和心血管疾病死亡率之间存在独立关联的流行病学证据令人信服。在疾病方面，心脏病、动脉硬化、心力衰竭、心律失常和中风都与空气污染有关。对于长期暴露在颗粒物(PM)中，相关的有害影响已被证明在低于当前年度国家标准的浓度下持续存在，而环境中PM(尤其是直径小于2.5微米的PM，PM2.5)的减少与动脉粥样硬化的缓慢进展有关。为了更好地了解此类研究中报告的空气污染与心血管疾病风险之间的关联是否为因果关系，需要对潜在的生化途径和伴随的机制进行更全面的表征。特别是，如果我们能够确定空气污染与心血管疾病之间联系的中间步骤(S)，这将指导适当的政策和行动，包括技术解决方案和行为改变，以减轻空气污染对健康的影响。在这项建议中，我们旨在使用新兴的“整体系统”方法来研究环境空气污染暴露与心血管疾病之间的机制途径。这些方法涉及代谢表型技术(代谢组学)，这些技术已成为获取一系列毒理学和疾病过程信息的强大工具。这类代谢图谱可捕捉人体新陈代谢的各种最终产物，并可探测来自不同来源的信号，包括遗传、饮食、其他生活方式、肠道微生物和环境影响，例如空气污染。具体地说，我们将使用本中心首创的代谢全组关联研究的概念来研究代谢指纹，这将使我们能够发现空气污染暴露的新的基于血液的标记(PM2.5和二氧化氮)。建立这样的生物标记是了解哪些生化途径受到空气污染影响的关键的第一步。这项研究的结果将使我们更好地了解颗粒物和气态污染物的作用模式和毒性特性。这些进展对于设计和实施更好的空气污染缓解和控制政策至关重要，从而减少与空气污染有关的疾病和死亡的沉重负担。

Human exposure to air pollution contributes to approximately 7 million deaths per year worldwide and owing to the high prevalence of heart disease across the globe, the majority of deaths are attributed to cardiovascular disease (CVD). The epidemiological evidence for independent associations between exposure to poor air quality and CVD mortality is compelling. With respect to illness, heart disease, furring of the arteries (atherosclerosis), heart failure, abnormal heart rhythms and stroke have all been associated with air pollution. For long-term exposure to particulate matter (PM), associated detrimental effects have been shown to persist at concentrations below current annual national standards, whilst reductions in ambient PM (particularly, PM less than 2.5 microns in diameter, PM2.5) have been associated with a slower progression of atherosclerosis.To better understand whether the associations between air pollution and risk of CVD reported in such studies are causal, requires a more comprehensive characterisation of the underlying biochemical pathways and accompanying mechanisms. In particular, if we can identify intermediate steps that lie on the casual pathway(s) linking air pollution to CVD, this could guide appropriate policy and action, including technical solutions and behavioural change, to mitigate the effects of air pollution on health.In this proposal, we aim to use emerging 'whole systems' approaches to study the mechanistic pathways linking ambient air pollution exposure to CVD. These approaches involve metabolic phenotyping technologies (metabolomics) that have emerged as a powerful tool to capture information on a range of toxicological and disease processes. Such metabolic profiling captures a wide range of end products of human metabolism and detects signals from a variety of sources including genetic, dietary, other lifestyle, gut microbial and environmental influences such as air pollutants.Specifically, we will use the concept of the metabolome-wide association study, pioneered by our Centre, to investigate the metabolic fingerprint, which will enable us to discover novel blood-based markers of air pollution exposure (PM2.5 and nitrogen dioxide). Establishing such bio-markers is a key initial step in understanding which biochemical pathways are influenced by air pollution. The results of this research should better our understanding of the mode of action and toxic properties of particulates and gaseous pollutants. Such advances are essential to design and implement better air pollution abatement and control policies, and hence reduce the high burden of air pollution related illness and mortality.