Integration of network toxicology and transcriptomics reveals the novel neurotoxic mechanisms of 2, 2', 4, 4'-tetrabromodiphenyl ether

The brominated flame retardant 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47) is known as a developmental neurotoxicant, yet the underlying mechanisms remain unclear. This study aims to explore its neurotoxic mechanisms by integrating network toxicology with transcriptomics based on human neural precursor cells (hNPCs) and neuron-like PC12 cells. Network toxicology revealed that PBDE-47 crosses the blood-brain barrier more effectively than heavier PBDE congeners, and is associated with disruptions in 159 biological pathways, including cytosolic DNA-sensing pathway, ferroptosis, cellular senescence, and chemokine signaling pathway. Additionally, transcriptomic analyses of hNPCs and PC12 cells exposed to PBDE-47 uncovered substantial gene expression changes, with 855 and 702 genes up- and down-regulated in hNPCs, and 2844 and 2711 genes in PC12 cells, respectively. These differentially expressed genes were primarily implicated in crucial processes like neuroactive ligand-receptor interaction, nucleocytoplasmic transport, ferroptosis, p53 signaling, and cell cycle regulation. Integration of the results identified novel mechanisms of PBDE-47 neurotoxicity, such as neuroinflammation and cellular senescence, alongside established mechanisms like ferroptosis, apoptosis and cell cycle arrest. Overall, these findings provide critical insights into the mechanisms of PBDE-47 neurotoxicity, highlighting the integration of network toxicology and transcriptomics as a novel study approach to explore the modes of action of toxicants.