Abstract 4142331: Metabolomic Signature of Mitochondrial Dysfunction After Subacute Air Pollution Exposure: An Animal-to-Human Translational Study

Introduction: Exposure to air pollution is among the leading risk factors for cardiovascular diseases. This animal-to-human translational study aims to identify metabolomic signatures connecting subacute air pollution exposure with early mechanisms mediating chronic cardiovascular disease development. Methods: We studied ApoE -/- mice exposed to diesel exhaust (DE) or filtered air (FA) for 2 weeks and 26 healthy adults who traveled from Los Angeles (average PM 2.5 levels = 14.4 µg/m 3 ) to Beijing (average PM 2.5 levels = 67.6 µg/m 3 ) for 10 weeks. We previously reported increased systemic lipid peroxidation, inhibited paraoxonase 1 activity, without changes in HDL or total cholesterol levels in both animals and humans after air pollution exposure. In this study, we profiled plasma metabolomics using multiple analytical platforms and identified 547 metabolites in animals, and 1357 metabolites in humans with confirmed structure or putative chemical ID. We conducted enrichment analysis using ChemRICH algorithm and characterized molecular signature of common metabolic pathways affected by air pollution in both animals and humans. Results: Enrichment analysis of 154 overlap metabolites in animal and human plasma indicated that air pollution caused common metabolic alterations of (1) dicarboxylate acids, (2) acyl-carnitines, (3) tryptophan, (4) pyrimidine, and (5) lysine. Although the metabolomic signatures of tryptophan, pyrimidine, and lysine differ between animals and humans following air pollution exposure, we observed consistent increases in long-chain dicarboxylate acids and medium- to long-chain acyl-carnitines – likely due to mitochondrial dysfunction as evidenced by impaired mitochondrial respiration by a Seahorse assay on livers from the same animals. Conclusion: Subacute exposure to air pollution induced common metabolomic signatures of dicarboxylate acids and acyl-carnitines, suggestive of mitochondrial dysfunction.