Metabolomic signatures of the short-term exposure to air pollution and temperature
Graphical abstract
Introduction
Short-term exposures to air pollution and temperature have been reported be associated with inflammation and oxidative stress (Walker et al., 2016; Halonen et al., 2010a); biological processes that are linked to many adverse health effects such as pulmonary (Vieira et al., 2019), cardiovascular (Ljungman et al., 2018), and neurological diseases (Bejot et al., 2018), and mortality (Liu et al., 2019; Armstrong et al., 2019; Dauchet et al., 2018; Halonen et al., 2010b; Zuurbier et al., 2011). The plasma metabolome represents a collection of biologically active chemicals derived from endogenous processes and exogenous exposures (Rappaport et al., 2014). A metabolic signature in the blood associated with ambient air pollution exposure is plausible because some ambient air pollutants (ultrafine particles and gaseous air pollution) have been reported to enter the bloodstream directly from the lungs (Nemmar et al., 2002). In addition, larger particles unable to cross the lung epithelium as well as ambient temperature can induce inflammation in the lungs and trigger a systemic response observed in the peripheral blood (Halonen et al., 2010a; HOGG and VAN EEDEN, 2009). Although metabolomic profiling of plasma represents a powerful tool to increase mechanistic understanding, to date analytical and scientific uncertainties in metabolomics have limited its application for the measurement the response of exposure to air pollution.
Recently, several studies have examined the association between short-term exposure to air pollution and changes in the plasma metabolome and have reported perturbed pathways implicated in inflammation and oxidative stress (Ward-Caviness et al., 2016; Li et al., 2017; Vlaanderen et al., 2017; van Veldhoven et al., 2019; Surowiec et al., 2016; Liang et al., 2018, 2019; Walker et al., 2019; Ladva et al., 2018). However, replication of these findings is still lacking and the existing literature on the short-term exposure to air-pollution on the metabolome is limited. To date, no human studies have examined the untargeted metabolomic signature of ambient temperature despite the strong association of ambient temperature with mortality and morbidity, and only a few studies have controlled for ambient temperature in models examining the association with air pollution. In addition, existing studies have tended to analyses each metabolite individually, which fails to capture the correlation patterns of metabolites that exist within co-regulated metabolic pathways and which could be important for elucidating mechanisms.
Therefore, in this study we aimed to determine changes in the plasma metabolome related to short-term exposure to outdoor air pollution and temperature, while using novel statistical methods e.g., independent component analysis (ICA) for highly dimension data. We performed mass-spectrometry based plasma untargeted metabolomic profiling of a large and well-characterized cohort of men (the Normative Aging Study). We hypothesized that short-term exposure to air pollution and temperature are associated with changes in the plasma metabolome consistent with perturbation of metabolic pathways that are related to the adverse health effects of air pollution and temperature exposure. We further tested if the metabolic signatures would be modified by metabolic conditions such as obesity and diabetes.
Section snippets
Participants and study design
The Normative Aging Study (NAS) established in 1963 is a longitudinal study of aging among men based in Boston, Massachusetts. Men (N = 2280), 21–80 years old between 1963 and 1970 and free of known chronic diseases were enrolled in NAS and have been followed since (Payton et al., 1998). Participants periodically self-reported information about their medical history, dietary intake, and other health-related history throughout the follow-up. Men had physical examinations and laboratory tests
Results
Overall, 456 men provided 648 blood samples between 2000 and 2016 were included in the analysis; 1158 distinct metabolites were quantified and passed our in-house QC pipeline in these samples. We had access to all metabolites as quantified by Metabolon in these samples. Approximately 64% of the participants provided one blood sample, 31% provided two samples, and 6% provided three samples. The highest percentage of the measured metabolites were lipids (39%), followed by metabolites of
Discussion
This is the first study, to date, to report the untargeted metabolomic signature of temperature exposure and the largest study to report untargeted metabolomic signature of air pollution. The observed results for ambient temperature exposure could help explain the previously reported excess mortality with both high and low short-term temperature exposure (Guo et al., 2016) and increased hospital admissions with high short-term temperature exposure (Zanobetti and Schwartz, 2005, 2006;
Conclusions
Metabolomics is a powerful tool for exploring the short-term effects of xenobiotic agents. In this study, we identified several significant metabolites and metabolic pathways associated with short-term exposure to air pollution and temperature; using a global and untargeted approach that both confirmed previous findings and revealed new ones. Those metabolic pathways were involved in inflammation and oxidative stress, immunity, and nucleic acid damage and repair. Cautions need to be taken while
Sources of funding
This work was supported by U.S. EPA grant RD-835872. This metabolomics profiling was supported by PR161204 W81XWH-17-1-0533 from the Congressionally Directed Medical Research Programs (CDMRP), USAMRDC. The VA Normative Aging Study is a research component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) at VA Boston Healthcare System and is supported by the Cooperative Studies Program/Epidemiology Research and Information Centers, Office of Research and
Author contributions
Conceptualization (FN, RK, JL-S, JS), Data curation (FN, RK, PV, JS), Formal analysis (FN, JS), Funding acquisition (RK, PK, PV, JS), Investigation (FN, RK, JL-S, JS), Methodology (FN, RK, JS), Project administration (FN, JS), Resources (FN, RK, PV, JS), Software (FN, RK, JS), Supervision (JS), Validation (FN, JS), Visualization (FN, RK), Writing - original draft (FN), Writing - review & editing (FN, RK, PK, PV, JL-S, JS).
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments:
We acknowledge all members of the Normative Aging Study (NAS) team. A special thanks to all study participants.
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