Exposure to multiple ambient air pollutants changes white matter microstructure during early adolescence with sex-specific differences

Outdoor ambient air pollution is increasingly recognized for its neurotoxic effects. Criteria pollutants like PM_2.5 and NO₂ (from combustion) and O₃ (from photooxidation) cause immune responses in the lungs, leading to systemic inflammation. Inflammatory components can enter the brain, potentially affecting the blood-brain barrier. Children are particularly vulnerable due to higher respiratory rates, rapid neural development, and time spent outdoors. However, the long-term effects of air pollution on adolescent brain development and sex-specific differences are unclear. The brain undergoes significant white matter maturation during adolescence, crucial for neural network organization and cognitive functions. Given air pollution's neuroinflammatory effects, white matter microstructure development may be vulnerable. Previous ecological and cross-sectional studies have shown links between air pollutant exposure and altered white matter structure in youth, but these studies have limitations regarding study design and potential sex-specific relationships. Restriction spectrum imaging (RSI), a new technique, allows for a more detailed analysis of white matter microstructure by quantifying intracellular isotropic (RNI) and directional (RND) diffusion. This study uses longitudinal data from the Adolescent Brain Cognitive Development (ABCD) Study to investigate the effects of one year of annual exposure to PM_2.5, NO₂, and O₃ at ages 9–10 years on white matter microstructure development over two years, considering sex-specific effects. The study addresses the potential long-term neurodevelopmental effects of air pollution exposures below current US standards.

Several studies support the harmful effects of air pollution on the developing brain. Calderón-Garcidueñas et al. found increased white matter pathology in young people from Mexico City exposed to high pollution levels. Research using the Generation R cohort in the Netherlands linked prenatal and childhood exposure to PM_2.5, NO₂, and NOx to lower fractional anisotropy and higher mean diffusivity, suggesting reduced white matter integrity. Peterson et al. showed that higher prenatal PM_2.5 exposure was associated with a higher average diffusion coefficient, suggesting less myelin. These studies suggest a link between ambient air pollution and white matter microstructure, but discrepancies exist due to variations in study samples, exposure timing, age, and MRI techniques. Sex differences in air pollution's health effects have been observed, but their impact on white matter development remains unclear. Prior diffusion MRI studies have either not examined sex differences or lacked longitudinal designs, limiting their ability to assess the impact on neurodevelopmental trajectories. The use of RSI in this study aims to provide more detailed and biophysically interpretable metrics of white matter health compared to conventional diffusion tensor imaging.

This longitudinal study utilized data from the Adolescent Brain Cognitive Development (ABCD) Study. The study included 8182 participants (45% with two DWI scans) aged 9–10 years at baseline, followed for two years. Annual average concentrations of PM_2.5, NO₂, and O₃ were assigned to each child's residential address based on a 1-km² resolution spatiotemporal model. Diffusion-weighted imaging (DWI) was acquired using a harmonized protocol across 21 sites, employing a multi-shell acquisition and multiband EPI with slice acceleration. Images were corrected for distortion, bias field, and motion. White matter tracts were identified using AtlasTrack. Restriction spectrum imaging (RSI) was performed to quantify RNI and RND. Covariates included demographic, socioeconomic factors, handedness, scanner manufacturer, frame displacement, tract volume, and meteorological season. Sex-stratified linear mixed-effects models were used, adjusting for covariates. The models tested the effects of pollutants on RNI/RND at age 9 and their interaction with age over time. Sensitivity analyses included formal testing for sex differences, exclusion of subjects who moved residences, and inclusion of all three age-by-pollutant interactions.

Higher PM_2.5 exposure was associated with higher RND at age 9 in both sexes, but not with changes over time. Higher NO₂ exposure was linked to higher RNI at age 9 in both sexes, and it attenuated RNI increase over time in females. Higher O₃ exposure was associated with differences in RND and RNI at age 9, and with changes in RND and RNI over time in both sexes. Sex-specific patterns were observed: PM_2.5 and NO₂ affected more tracts in females at age 9; O₃ effects were more prevalent in males longitudinally, while NO₂ effects were more prevalent in females longitudinally. Sensitivity analyses generally supported the findings from the sex-stratified models, with female youth driving the longitudinal relationship between NO₂ and RNI, and male youth driving the longitudinal relationship between O₃ and RNI. Pollutant concentrations in the study were below current EPA standards but exceeded latest WHO guidelines.

This study provides the first longitudinal, nationwide evidence in the US linking annual air pollution exposure at ages 9–10 years to altered white matter microstructure development, with sex-specific differences. Even at relatively low levels (below EPA standards but above WHO guidelines), exposure disrupted white matter at age 9 and/or during the 9–13-year period. The effects varied by pollutant and sex, influencing both RNI (glial cells) and RND (axons). Affected tracts connect regions important for complex behaviors. The findings suggest that low-level pollution during adolescence may have long-term consequences. The results add to existing neuroimaging studies linking air pollution to brain structure and function in children and adolescents. While some previous studies showed null results, the longitudinal nature of this study highlights the importance of considering the timing of exposure and assessment. The observed changes in white matter connectivity may increase the risk for future cognitive, behavioral, or emotional problems, particularly considering sex differences in mental health disorders. Systemic inflammation, potentially caused by the pollutants’ effects on the lungs, is suggested as a mechanism. While further study is needed to fully understand the mechanisms involved, the different pathways for each pollutant might explain the observed sex-specific differences. This study suggests a need for reconsidering air quality standards to protect children's brain health.

This longitudinal study demonstrates a link between exposure to criteria air pollutants and altered white matter microstructure development in early adolescence, with sex-specific patterns. The effects are observable even at concentrations below current EPA standards, highlighting the potential long-term consequences of low-level pollution. Future research should investigate cumulative effects, other developmental windows of vulnerability, and the mediating roles of inflammatory biomarkers. The findings have implications for revising air pollution regulatory standards to protect developing youth.

The study is limited by the availability of air pollution data from only one year (ages 9–10) and cannot determine the cumulative effects of long-term exposure. It does not capture factors such as time spent outdoors or indoor air pollution exposure. The ABCD Study sample is not fully representative of all American adolescents, limiting the generalizability of the findings. Further research examining various chemical compositions and doses is needed, along with investigation into immune and inflammatory mechanisms using blood or saliva-based biomarkers.