Utilizing Network Toxicology and Molecular Dynamics Simulations to Efficiently Evaluate the Neurotoxicity and Underlying Mechanisms of the Endocrine-Disrupting Chemical Triclosan

This study aims to elucidate the neurodevelopmental toxicity and molecular mechanisms of endocrine-disrupting chemicals (EDCs) in neurodevelopmental disorders (NDDs) through a network toxicology approach, using triclosan exposure as a case example. Potential targets of triclosan were identified via comparative analysis of toxicogenomics databases such as the Comparative Toxicogenomics Database (CTD), Similarity Ensemble Approach (SEA), SwissTargetPrediction, and TargetNet. NDD-related targets were retrieved from GeneCards, Disease Gene Network (DisGeNET), and Online Mendelian Inheritance in Man (OMIM), resulting in 633 overlapping genes associated with disease pathology and triclosan effectors. Protein-protein interaction networks were constructed using STRING and Cytoscape, applying median-based algorithms to identify six core genes: <i>AKT1</i>, <i>TP53</i>, <i>EGFR</i>, <i>FN1</i>, <i>SRC</i>, and <i>ESR1</i>. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses via Metascape revealed that triclosan-induced NDDs are primarily associated with endocrine signaling disruption and activation of the PI3K-Akt pathway. Molecular docking with CB-Dock2 demonstrated strong binding affinities between triclosan and the core targets, while YASARA molecular dynamics simulations confirmed stable interactions, notably with EGFR, exhibiting high binding stability. Collectively, these findings delineate the potential molecular mechanisms underlying triclosan-induced NDDs and underscore the utility of network toxicology, molecular docking, and molecular dynamics simulations in assessing neurotoxicity and related molecular pathways. This research provides novel insights for future investigations, enhances understanding of the potential impact of neurodevelopmental disorders on health, and lays a scientific foundation for the development of preventive and therapeutic strategies.