Jesus A. Araujo

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 3 ) to Beijing (particulate matter with an aerodynamic diameter 3 ) 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.

Background: Exposure to air pollution is associated with worldwide morbidity and mortality. Diesel exhaust (DE) emissions are important contributors which induce vascular inflammation and metabolic disturbances by unknown mechanisms. We aimed to determine molecular pathways activated by DE in the liver that could be responsible for its cardiometabolic toxicity. Methods: Apolipoprotein E knockout (ApoE KO) mice were exposed to DE or filtered air (FA) for two weeks, or DE for two weeks followed by FA for 1 week. Expression microarrays and global metabolomics assessment were performed in the liver. An integrated transcriptomic and metabolomic analytical strategy was employed to dissect critical pathways and identify candidate genes that could dissect DE-induced pathogenesis. HepG2 cells were treated with an organic extract of DE particles (DEP) vs. vehicle control to test candidate genes. Results: DE exposure for 2 weeks dysregulated 658 liver genes overrepresented in whole cell metabolic pathways, especially including lipid and carbohydrate metabolism, and the respiratory electron transport pathway. DE exposure significantly dysregulated 118 metabolites, resulting in increased levels of triglycerides and fatty acids due to mitochondrial dysfunction as well as increased levels of glucose and oligosaccharides. Consistently, DEP treatment of HepG2 cells led to increased gluconeogenesis and glycogenolysis indicating the ability of the in-vitro approach to model effects induced by DE in vivo. As an example, while gene network analysis of DE livers identified phosphoenolpyruvate carboxykinase 1 (Pck1) as a key driver gene of DE response, DEP treatment of HepG2 cells resulted in increased mRNA expression of Pck1 and glucose production, the latter replicated in mouse primary hepatocytes. Importantly, Pck1 inhibitor mercaptopicolinic acid suppressed DE-induced glucose production in HepG2 cells indicating that DE-induced elevation of hepatic glucose was due in part to upregulation of Pck1 and increased gluconeogenesis. Conclusions: Short-term exposure to DE induced widespread alterations in metabolic pathways in the liver of ApoE KO mice, especially involving carbohydrate and lipid metabolism, together with mitochondrial dysfunction. Pck1 was identified as a key driver gene regulating increased glucose production by activation of the gluconeogenesis pathway.

Inflammatory bowel disease (IBD) is an immunologically complex disorder involving genetic, microbial, and environmental risk factors. Its global burden has continued to rise since industrialization, with epidemiological studies suggesting that ambient particulate matter (PM) in air pollution could be a contributing factor. Prior animal studies have shown that oral PM₁₀ exposure promotes intestinal inflammation in a genetic IBD model and that PM_2.5 inhalation exposure can increase intestinal levels of pro-inflammatory cytokines. PM₁₀ and PM_2.5 include ultrafine particles (UFP), which have an aerodynamic diameter of 3, 6 h/day, 3–5 days/week, starting 7–10 days before disease induction. No differences in weight change, clinical disease activity, or histology were observed between the PM and FA-exposed groups. In conclusion, UFP inhalation exposure did not exacerbate intestinal inflammation in acute, chemically-induced colitis models.