Untargeted serum metabolomics and air pollution in Parkinson’s disease

Mechanisms linking air pollution to Parkinson’s disease (PD) remain poorly understood despite consistent toxicological and epidemiological evidence. We investigated metabolic disturbances associated with air pollution in PD using untargeted metabolomics. Serum samples were collected from 616 PD patients and 271 controls residing in central California, a region with high air pollution. Exposures to particulate matter (PM _2.5 ), carbon monoxide, and nitrogen dioxide were estimated for the 1-, 3-, and 5-year periods prior to serum collection using residential addresses and three modeling approaches: chemical transport, dispersion, and land use regression. We conducted a metabolome-wide association study using untargeted serum metabolomics based on liquid chromatography-high-resolution mass spectrometry (detecting 2,716 HILIC and 2,046 C18 features). Pathway enrichment analysis identified biological pathways associated with air pollution exposure in PD patients and controls. We compared our findings with 22 previous air pollution metabolomics studies to assess external validity. We identified 26 annotated metabolites and 23 metabolic pathways associated with air pollution exposure, particularly PM _2.5 and traffic-related pollutants, in PD patients and controls. Metabolic profiles observed in controls aligned with prior studies, supporting external validity. Profiles in PD patients additionally indicated disease-specific disruptions. Air pollution was associated with inflammation-related lipid metabolism (e.g., increased leukotrienes; decreased eicosatrienoic acid and docosahexaenoic acids) and several amino acids (e.g., alanine, aspartate, and glutamate) in PD patients. We also found a reduction in tyrosine levels, possibly related to PD. Togethger, these findings suggest that air pollution may contribute to PD through inflammation, oxidative stress, and mitochondrial dysfunction.