Stage-specific effects of early-life tobacco exposure on mental health, inflammation, and brain structure-function coupling.

Early-life tobacco exposure is a significant risk factor for depression and anxiety. Understanding its immune and neural mechanisms-and how risks differ by age of smoking initiation-is essential for designing effective prevention and intervention strategies. Using data from 375,903 participants in the UK Biobank, we found that in utero tobacco exposure was associated with increased risk of depression and anxiety, elevated inflammatory markers, and reduced structure-function (SF) coupling in the thalamus and putamen. Childhood smoking initiation was associated with a significantly higher risk of depression, anxiety, and systemic inflammation compared to adulthood initiation, whereas adolescent initiation did not differ significantly from adulthood initiation. Both childhood and adolescent initiation were associated with reduced SF coupling in brain regions involved in reward processing and cognitive control, relative to never-smokers. Mediation analyses revealed that systemic inflammation and SF coupling jointly mediated the association between early-life tobacco exposure and psychiatric risk. CRP emerged as a key mediator linking early smoking initiation to SF coupling alterations. Moreover, interaction models revealed that in utero tobacco exposure exacerbated the pro-inflammatory effects of childhood smoking initiation. Together, these findings underscore that early-life tobacco exposure contributes to long-term mental health vulnerability via neuroimmune pathways, with childhood representing a particularly sensitive period-underscoring the need for developmental-stage prevention and mechanism-based interventions.