Air pollution and the risk of schizophrenia: current evidence, mechanisms, and future directions

Schizophrenia (SCZ) is a complex, polygenic neurodevelopmental disorder influenced by interactions between genetic vulnerability and environmental exposures. While research has historically prioritized genetic factors, air pollution has emerged as a potentially modifiable environmental factor associated with the onset, progression, and relapse of the disorder. This review synthesizes current clinical, epidemiological, and preclinical evidence to clarify the relationship between various air pollutants and SCZ. Epidemiological data, including large-scale cohort studies such as the UK Biobank, demonstrate dose-dependent associations between long-term exposure to particulate matter (PM₂.₅, PM₁₀) and gaseous pollutants (NO₂, SO₂, CO) and increased SCZ risk. Notably, individuals with high polygenic risk scores (PRS) may exhibit heightened vulnerability, with hazard ratios reaching up to 7.38 when combined with high pollution exposure. Mechanistically, air pollutants may influence SCZ-related biology through direct neurotoxicity via olfactory translocation, neuroinflammatory signaling, oxidative stress, disruption of neuroplasticity (including brain-derived neurotrophic factor (BDNF) suppression), and dysregulation of the gut-brain axis. However, most mechanistic evidence is preclinical, and the translational gap to human disease remains substantial. Despite these insights, challenges remain regarding causal inference, biomarker validation, and geographical representation in research. Moving forward, large-scale longitudinal cohorts and the integration of exposomics with genomics are essential to refine risk stratification. At present, the evidence supports cautious consideration of air pollution as an environmental factor associated with schizophrenia, rather than as a proven causal determinant.