Chemical Pollutant Exposure in Neurodevelopmental Disorders: Integrating Toxicogenomic and Transcriptomic Evidence to Elucidate Shared Biological Mechanisms and Developmental Signatures

Rapid industrialization has introduced a range of chemicals into the environment, posing significant risks to fetal and child brain development. Using the Comparative Toxicogenomics Database (CTD), we constructed chemical exposome frameworks for seven neurodevelopmental disorders (NDDs) and identified chemical pollutants of epidemiological concern, including air pollutants (n = 8), toxic elements (n = 14), pesticides and related compounds (n = 18), synthetic organic chemicals (n = 16), and solvents (n = 5). Gene set enrichment analysis validated and revealed significant toxicogenomic associations between these chemical pollutants and NDDs, including autism spectrum disorder (ASD) (12 pollutants, proportional reporting ratio (PRR) 3.56-7.21) and intellectual disability (ID) (9 pollutants, PRR 3.13-5.59). Functional annotation of pollutant-specific gene sets highlighted shared biological processes, such as metabolic processes (e.g., xenobiotic metabolic process, xenobiotic catabolic process, and cytochrome P450 pathway) for ASD and cognitive processes (e.g., cognition, social behavior, and synapse assembly) for ID (Bonferroni-corrected <i>p</i>-values < 0.05). Time trajectory analysis of developmental transcriptomic data from the BrainSpan database for ASD (275 genes) and ID (93 genes) revealed three distinct expression patterns of chemical-pollutant-associated genes-higher prenatal, postnatal, and perinatal expression-indicating common and divergent underlying mechanisms across critical windows of chemical pollutant exposure.