Mechanisms by which PM2.5-PAHs drive neurodevelopmental co-morbidities across the placental-blood-brain barrier: A network toxicology analysis

Polycyclic aromatic hydrocarbons (PAHs), major toxic components of ambient PM₂.₅, pose a significant threat to children's neurodevelopment due to their ability to cross the placental and immature blood-brain barriers. Epidemiological evidence links PAHs exposure to cognitive impairment (CI), attention-deficit/hyperactivity disorder (ADHD), mood disorder (MD), and autism spectrum disorder (ASD), yet the underlying molecular mechanisms remain poorly understood. Here, we employed an integrative framework combining multi-disease network toxicology, subcellular and neuroanatomical localization, miRNA regulatory network analysis, and molecular docking to systematically investigate PAHs-induced neurodevelopmental toxicity. Our results revealed two tiers of mechanisms: shared effects, in which PAHs disrupted MAPK and PI3K-Akt signaling pathways, impairing neuronal survival, differentiation, and synaptic plasticity across all four disorders; and disease-specific mechanisms, including AKT1/EGFR/SMAD3-mediated CI via medullary cognitive circuit dysfunction, JUN-driven ADHD through cerebellar network disruption, PRKCA/PRKCG and FOS-mediated MD via hippocampal and hypothalamic dysregulation, and HSP90AA1-linked ASD through white matter developmental impairment. Molecular docking confirmed stable interactions between PAHs and these core targets, while miRNA regulators further highlighted post-transcriptional networks. This study proposes a comprehensive "PAHs-target-pathway-disease" framework, suggests potential intervention targets and early biomarkers, and offers mechanistic insights that may support public health strategies aimed at mitigating PAH-related neurodevelopmental risks in children.