Untargeted serum metabolomics and air pollution in Parkinson's disease.

Mechanisms linking air pollution to Parkinson's disease (PD) remain unclear despite consistent toxicological and epidemiological evidence. In this exploratory study, we investigated metabolic disturbances associated with air pollution in PD using untargeted metabolomics. Serum samples were collected from 616 PD patients and 271 controls in central California, a region with high air pollution. Exposures to particulate matter (PM2.5), carbon monoxide, and nitrogen dioxide were estimated for the 1-, 3-, and 5-year periods prior to serum collection using three modeling approaches: chemical transport, dispersion, and land use regression. We performed a metabolome-wide association study using liquid chromatography-high-resolution mass spectrometry (2716 HILIC and 2046 C18 features), followed by pathway enrichment analysis. We identified 101 annotated metabolites and 23 metabolic pathways associated with air pollution exposure, particularly PM2.5 and traffic-related pollutants. Control profiles aligned with prior studies, and PD patients showed similar disruptions. Air pollution was associated with inflammation-related lipid metabolism (reduced arachidonate; elevated leukotriene), membrane phospholipid remodeling (reduced choline phosphate and LysoPC), amino acid metabolism (reduced aspartate and serine), and dopamine biosynthesis (reduced tyrosine) in PD patients. These findings suggest that air pollution may contribute to PD through inflammation, oxidative stress, and mitochondrial dysfunction.