1,3,6,8-Tetrabromocarbazole induces neurodegenerative damage in mice: Mechanistic insights from combined transcriptomic and metabolomic profiling

1,3,6,8-Tetrabromocarbazole (1368-BCZ), an emerging dioxin-like persistent organic pollutant, can enter the body through multiple routes including dietary intake, inhalation, and dermal contact. Growing concerns have been raised about its potential toxicity, particularly regarding its poorly characterized neurotoxic effects. This study aims to elucidate the neurotoxic effects of the emerging pollutant 1368-BCZ by establishing a subchronic exposure mouse model, and to investigate the underlying metabolic disruption mechanisms in the hippocampus that contribute to neurodegenerative damage, through an integrated approach combining neurobehavioral, histopathological, and multi-omics analyses. Neurobehavioral assessments revealed significant neurodegenerative damage in exposed mice, as evidenced by a decreased recognition index (∼10 %), prolonged escape latency (∼20 s), reduced time spent in the target quadrant (5-10 s), and fewer platform crossings (1-2 times) in behavioral tests. Histopathological examination demonstrated distinct damage in the hippocampus, a brain region crucial for episodic memory formation and spatial navigation. Furthermore, 1368-BCZ exposure significantly upregulated neurodegenerative-related proteins in hippocampal tissues, including Aβ (∼3-fold) and phosphorylated Tau (p-Tau, ∼1.5-2.0 fold) relative to the control group. Untargeted metabolomic analyses revealed that 1368-BCZ exposure-induced significant metabolic disturbances in mouse hippocampus, including the downregulation of 602 metabolites and upregulation of 78 metabolites. Integrated transcriptomic and untargeted metabolomic analyses revealed that 1368-BCZ exposure-induced the downregulation of Dpys, Mlycd, and Pank1 mediated the disruption and the cross-talk of the pantothenate and CoA biosynthesis pathway and the β-alanine metabolism pathway might be primarily contributed to neurodegenerative damage in mice. Collectively, our findings demonstrate that subchronic 1368-BCZ exposure induces significant neurotoxicity by disrupting hippocampal metabolic networks, ultimately leading to neurodegenerative damage in mice. This study not only characterizes the neurotoxic effects of 1368-BCZ but also establishes a link between its subchronic exposure and neurodegeneration in vivo, thereby firstly providing mechanistic insights into the neurotoxicity of this emerging persistent pollutant and underscoring its potential environmental health risks.