Air Pollution Triggers Metabolomic Signature of Mitochondrial Dysfunction in Mice and Humans: Implications for Cardiovascular Disease Development.

Abstract

Background: Previous animal studies found that subchronic exposure to diesel exhaust induces hyperlipidemia, accompanied by upregulation of 12-LOX (lipoxygenase) and 15-LOX pathways and hepatic mitochondrial dysfunction. However, the human relevance of these findings has not been established.

Methods: We studied ApoE^-/- mice exposed to diesel exhaust or filtered air for 2 weeks, and 26 healthy adults who traveled from Los Angeles (particulate matter with an aerodynamic diameter <2.5 µm: 14.4 µg/m³) to Beijing (particulate matter with an aerodynamic diameter <2.5 µM: 67.6 µg/m³) for 10 weeks. Both mice and humans were previously found to have increased 12- and 15-LOX metabolite levels but normal HDL (high-density lipoprotein) and total cholesterol levels in the blood after air pollution exposure. In this study, we profiled blood metabolomics and lipidomics across multiple platforms in mice and humans, and conducted integrated data analyses to identify common metabolic pathways that were affected by air pollution, mechanistically related to oxidative stress and hyperlipidemia.

Results: Enrichment analysis of overlapping metabolites detected in both mice and humans indicates that air pollution induced metabolic alterations in (1) dicarboxylic acids, (2) acylcarnitines, (3) tryptophan, (4) pyrimidine, and (5) lysine pathways. Although the metabolomic signatures of tryptophan, pyrimidine, and lysine metabolites differed between mice and humans, we observed consistent increases in long-chain dicarboxylic acids and medium-to-long-chain acylcarnitines, likely due to mitochondrial dysfunction as evidenced by impaired mitochondrial respiration in a Seahorse assay on livers from the same mice. In the human study, the changes in dicarboxylic acids and acylcarnitines were significantly associated with increased lipid peroxidation products from 12- and 15-LOX pathways and exposure biomarkers for polycyclic aromatic hydrocarbons.

Conclusions: We provide real-world human evidence supporting that mitochondrial dysfunction and impaired fatty acid oxidation are plausible mechanisms mediating the adverse early metabolic effects of air pollution.