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

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.

Air pollution contributes to 7 million deaths per year worldwide; the vast majority of those deaths are attributed to cardiovascular disease (CVD). The objective of this proposal is to examine the initial steps that lie on the causal pathway(s) linking exposure to air pollution and disease risk using multivariate metabolic phenotyping technologies (metabolomics) that have emerged as a powerful new method to capture biomarker information on a range of toxicological and disease processes.

Our proposal takes advantage of existing data and samples from human chamber studies with three exposure scenarios (diesel, biodiesel, wood smoke), a 'real world' study of urban and peri-urban residents in Beijing with extensive personal exposure monitoring during winter and summer (AIRLESS and Oxford Street II with its extensive monitoring of air pollutants and already available metabolic data.

We will use the metabolome-wide association study paradigm to investigate the metabolic fingerprint associated with (a) short- and long-term exposures to air pollutants and whether these are these replicated across different exposure scenarios. We will then apply chemometric, statistical and analytical chemistry approaches to structurally detect the significant metabolic features, followed by bioinformatics, statistical methods and analysis to identify the underlying metabolic pathways involved in different exposures and exposure scenarios, as well as exposure-specific pathways. The resulting data are expected to provide novel insights into the mechanisms underlying the adverse health effects of air pollution and provide a firm foundation for future work which addresses the possible links between these perturbations and early disease events.

This work will have academic, economic and societal impact, effectively enhancing the knowledge economy across disciplines (toxicology, biochemistry [metabolomics], epidemiology, biostatistics, and bioinformatics). Our applied scientific research will be widely disseminated and applicable internationally and as such, its generation will enhance the status of UK science.

The project has considerable potential to deliver strategic impact at the public health level in that the knowledge gained has potential to improve our understanding of a fundamental environmental influence (i.e the air we breathe) on health. The results of this research could help identify the most toxic forms of pollution (i.e. diesel, woodsmoke, brake wear PM) and may guide environmental strategies to improve air quality and potentially lead to improved public health. Together these should result in reductions in health-care costs and lead to significant health gains and a better quality of life.

In addition, this work has potential to contribute to policy development. Advances into understanding the mode of action and toxic properties of particulates and gaseous pollutants will empower the design and help implement effective air pollution abatement and control policies and measures, including policy, technical and behavioural change, thereby reducing the high burden of air pollution related morbidity and mortality. With the advancement of evidence-based policy, UK led research of this nature can become a test-bed for cities around the world, therefore generating international interest and leadership.