Integration of network toxicology and bioinformatics reveals novel neurodevelopmental toxicity mechanisms of 2,2′,4,4′-tetrabromodiphenyl ether

Polybrominated diphenyl ethers, particularly 2,2′,4,4′-tetrabromodiphenyl ether (PBDE-47), are persistent environmental pollutants with suspected neurodevelopmental toxicity. This study systematically elucidated the mechanisms underlying PBDE-47-induced neurodevelopmental toxicity by integrating network toxicology and bioinformatic approaches. From 4070 potential targets, we identified 902 genes associated with neurodevelopmental disorders (ND), among which TP53, AKT1, and MAPK1 were identified as core regulatory factors via topological analysis. KEGG pathway enrichment analysis revealed significant enrichment in the HIF-1 signaling pathway and thyroid hormone signaling pathway. Molecular docking simulations confirmed that PBDE-47 stably binds to these key targets. Expression analysis validated the biological basis of PBDE-47 neurotoxicity. Single-cell RNA sequencing demonstrated the expression of target genes in neural cells. Immunohistochemistry further revealed the expression of AKT1 and MAPK1 in cortical neurons and glial cells. Ultimately, our study clarifies the multi-target and multi-pathway-mediated mechanisms of PBDE-47-induced neurodevelopmental toxicity, leading to an increased risk of ND. Although this computational approach provides mechanistic insights into environmentally induced ND, further experimental validation, epidemiological studies, and advanced spatial transcriptomic models are warranted to support these findings and facilitate the development of precise prevention strategies.