The Role of Metabolic Perturbations in Mediating the Effects of Ambient Air Pollution on Lung Cancer in the Cancer Prevention Studies Restricted; Files Only

Chow, Sabrina (Spring 2023)

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Background. Exposure to ambient air pollution is an established risk factor for lung cancer. Despite this, the identification of underlying biological mechanisms of air pollution carcinogenicity remains uncertain. To address these knowledge gaps, we applied high-resolution metabolomics to detect metabolic signatures of exogeneous air pollution exposures and endogenous processes involved in lung carcinogenesis in a well-established U.S. cancer cohort. Methods. A total of 1,360 participants (680 matched lung cancer and control pairs) within the established Cancer Prevention Study cohorts completed comprehensive questionnaires during enrollment and follow-up to assess changes in personal and lifestyle factors and medical conditions. Participant’s plasma metabolome from non-fasting blood samples was profiled with ultrahigh-performance liquid chromatography-tandem mass spectrometry. Assessment of exposure to six ambient air pollutants, including carbon monoxide (CO), nitrogen dioxide (NO2), particulate matter (PM10), fine particulate matter (PM2.5), sulfur dioxide (SO2), and ozone (O3), was conducted using spatiotemporally-resolved models based on residential address at blood draw. We conducted a metabolome-wide association study using multivariate linear regression models to assess associations of air pollution and lung cancer with a meet-in-the-middle approach. Metabolites significant at the FDR < 0.2 level in the air pollution model were analyzed in the lung cancer model. High-dimensional mediation analysis was used as a secondary analysis to compare results from the meet-in-the-middle analysis. Results. Among 1,232 metabolic features extracted, seven were significantly associated with air pollution exposure and lung cancer incidence at the FDR < 0.2 level in the meet-in-the-middle analysis. Six features were significant via high-dimensional mediation analysis. All confirmed metabolites are enriched within peptide, lipid, and amino acid pathways. The metabolites gamma-glutamylglutamine and gamma-glutamylmethionine were each significantly associated with CO, NO2, and PM10 exposure and lung cancer incidence in both analyses. Conclusion. This is the largest prospective metabolomics study examining biological perturbations associated with air pollution exposure and lung cancer outcomes. The findings provide an indication of association between air pollution and lung cancer mediated via peptide metabolism. Findings from this study support future studies to further clarify the specific role of these identified metabolites and pathways as mediators of air pollution carcinogenicity.

Table of Contents



Study Population and Design

Air Pollution Assessment

Metabolomic Profiling

Data Analysis





Tables and Figures

Table 1 Demographic Characteristics for Participants in CPS-II Nutrition and CPS-3 Cohorts

Table 2 Metabolic features significantly associated with air pollutant exposure models

Table 3 Metabolites significantly associated with air pollutant exposure and lung cancer incidence using meet-in-the-middle (MITM) and high dimensional mediation analysis (HDMA) analytical approaches

Figure 1 Volcano plots of associations between changes in metabolite intensities and air pollutants.

Figure 2 Mechanistic figure depicting the metabolic pathways that lead to biological changes in the association between air pollution and lung cancer.

Supplemental Materials

Supplement 1 Air pollution assessments based on residential address at blood draw (n = 1,360)

Supplement 2 Pathway breakdown for combined significant metabolites in meet-in-the-middle (MITM) and high dimensional mediation analysis (HDMA)

Supplement 3 Summary of exclusion criteria for study participants included in final analysis.

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