Mechanisms of developmental neurotoxicity of Dechlorane Plus, a recently identified persistent organic pollutant: An...

Dechlorane Plus (DP), a polychlorinated flame retardant, has recently been recognized as a persistent organic pollutant. In this study, the molecular mechanisms and targets associated with DP-induced developmental neurotoxicity (DNT) in humans were investigated through network toxicology, multi-level bioinformatics approaches, and molecular docking. Through comprehensive database analysis, 32 potential targets associated with DP-induced DNT were identified. Gene Ontology terms enrichment analysis revealed significant enrichment in pathways related to the nervous system processes, GABA-A receptor complex, and various binding and channel activities. KEGG pathway enrichment analysis indicated that DP-induced DNT is mediated through complex interactions involving neuroactive ligand-receptor interaction pathways. Further analysis using GeneMANIA, STRING, Cytoscape tools, and MCODE identified 11 hub targets, including GABRA1, GABRB1, GABRB3, and GABRG2 as key targets. Molecular docking revealed that DP binds to the GABRB3-GABRA1-GABRG2 protein complex to a degree comparable to the control bicuculline, a potent and selective antagonist of the GABA-A receptor. These findings suggest that DP may have antagonistic effects on the GABA-A receptor, potentially increasing neuronal excitability. This study offers valuable insights into the molecular mechanisms underlying DP-induced DNT and provides data for in vitro or in vivo studies.