Long-term air pollution exposure and the blood metabolome: The rotterdam study

Air pollution is a well-established risk factor for several adverse health outcomes, but the specific molecular mechanisms, particularly those involving metabolic processes, remain incompletely understood.

To evaluate associations between long-term air pollutant exposure and circulating plasma metabolites in two sub-cohorts of the population-based Rotterdam Study.

We analyzed data from 1455 participants of sub-cohort I (mean age 76.9 years, 58% female, 2002-2004) and 1061 participants from sub-cohort III (mean age 62.6 years, 56% female, 2012-2014). Mean annual exposure to fine particulate matter (PM_2.5), black carbon, nitrogen dioxide, and ozone (measured both annually and in warm seasons only) were estimated at residential addresses using land use regression models. Plasma metabolites were measured by Metabolon Inc., using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. Cross-sectional associations between each air pollutant and 940 metabolites were determined using linear regression models. Benjamini-Hochberg false discovery rate (FDR) was utilized to control for multiple testing. Enrichment analysis was performed on statistically significant associated metabolites to identify significant metabolic pathways (p-value <0.05).

In sub-cohort I, PM_2.5, black carbon, nitrogen dioxide, annual ozone and ozone in warm season were statistically significantly associated with, respectively, 63, 30, 20, 31, and 41 metabolites (FDR <0.05) mostly belonging to lipid and amino acid sub-classes, and unannotated metabolites. Sphinganine, X - 16576 and 2-pyrrolidinone displayed statistically significant associations across all five air pollutants. In sub-cohort III, black carbon, nitrogen dioxide and ozone in warm seasons were associated with a single unannotated metabolite (X - 24970), and annual ozone with two unannotated metabolites (X - 24970 and X - 24306). Enriched pathways identified in sub-cohort I included pyrimidine metabolism and steroid hormone biosynthesis.

Our study revealed associations of long-term air pollutant exposure with several metabolites and enrichment of two pathways, which are known to be involved in the adrenal and reproductive system and cell metabolism.