Integrated plasma proteomics and metabolomes reveal potential biomolecules linking PM_2.5 to depression

The biomolecular pathways linking fine particulate matter (PM_2.5) and its constituents to depression remain elusive. With 24,940 depression-free participants in the UK Biobank, exposure to PM_2.5 and its 5 constituents (ammonium, nitrate, sulfate, elemental carbon, and organic carbon) was estimated. We integrated Olink-based proteomics and NMR-based metabolomics using Cox proportional hazards models, mediation analyses, functional enrichment analyses, and drug predictive analyses. We identified 982 depression cases during a mean follow-up of thirteen years. PM_2.5 and its constituents was associated with increased depression risk, with HRs up to 1.20 per SD increment in ammonium. We identified 140 proteins and 3 metabolites as statistically-significant mediators, with mediation proportions up to 8.00% and 3.42%. These mediators were enriched in lipid and unsaturated fatty acid metabolism, immune regulation, and inflammation responses. Drug predictive analyses showed potential drug repurposing. Shifts in biomolecules partially explained PM_2.5-depression associations, highlighting inflammation and lipid dysregulation as potential pathways.