Unveiling Molecular Mechanisms and Salient Targets in Phthalates‐Induced Neurodevelopmental Disorders Through Comprehensive Network Toxicology and Molecular Docking Strategy

ABSTRACT Phthalates are well‐known emerging contaminants in the environment and food packaging, posing serious risks to human health as endocrine disruptors with significant neurotoxic potential. Epidemiological and experimental evidence have linked early‐life phthalate exposure to neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the precise molecular mechanisms responsible for these associations remain poorly understood. This study aimed to comprehensively investigate the putative toxic targets and molecular pathways underlying phthalate‐induced ADHD and ASD through integrated network toxicology and molecular docking approaches. Targets related to phthalates, ADHD, and ASD were extracted from various databases, yielding 21 potential targets associated with ADHD and ASD, which are common to the studied phthalates. Network analysis highlighted BDNF and ESR1 as the top two core targets. Functional enrichment analyses demonstrated that the core targets are involved in multiple pathways. Furthermore, the GEO database was queried to identify differentially expressed genes (DEGs) and gene modules through Weighted Gene Co‐expression Network Analysis (WGCNA) using the R package. Moreover, molecular docking demonstrated high binding affinity between phthalates and core targets, with di(2‐ethylhexyl) phthalate with BDNF and diisononyl phthalate with ESR1, emphasizing the potential role of phthalate exposure in neurodevelopmental disorders. The stability of these complexes was demonstrated through molecular dynamics simulations, which confirmed their binding interactions remained constant throughout the simulation. Our findings contribute to a deeper understanding of the intricate molecular mechanisms of phthalate‐induced neurotoxicity, offering a valuable foundation for the development of future therapeutic strategies to mitigate their adverse effects on neurodevelopment.