Metabolomics revealed novel associations between multiple ambient air pollutants exposure and substance use...

Substance use disorders (SUDs) constitute a significant global public health challenge. Although air pollution is a recognized risk factor for various mental and behavioral disorders, its prospective relationship with SUDs and the underlying mechanisms involved remain inadequately elucidated.

This prospective cohort study included 216,737 participants from the UK Biobank. An air pollution score (APS) was constructed based on NO₂, NO_x, PM_2.5, PM_2.5-10 and PM₁₀ concentrations. An APS-related metabolic signature was derived using elastic net regression from 168 plasma metabolites. Cox proportional hazards models evaluated associations between air pollution, the metabolic signature, and the incidence of SUDs, including alcohol use disorders (AUDs) and tobacco use disorders (TUDs). Mediation analysis quantified the mediation proportion of metabolites and the metabolic signature.

Long-term exposure to air pollution was significantly associated with increased risk of SUDs, AUDs, and TUDs. The APS-related metabolic signature comprising 151 metabolites was significantly associated with an increased risk of SUDs (HR_{per SD} = 1.127, 95% CI: 1.106-1.148) and TUDs (HR_{per SD} = 1.159, 95% CI: 1.135-1.183). Further analysis revealed that citrate was the primary mediator linking APS to SUDs and TUDs, whereas cholesterol and cholesteryl esters in medium very low-density lipoprotein (VLDL) constituted the principal mediators for AUDs. The overall metabolic signature mediated 5.4% and 6.8% of the relationship between APS and SUDs and TUDs, respectively.

Long-term ambient air pollution is associated with higher SUD risk, partially mediated by metabolomic changes.