Abstract

2,4,6-Tribromophenol (TBP) is a widespread emerging environmental pollutant that tends to accumulate in the brain. Growing evidence implicates disrupted brain lipid homeostasis in contaminant-induced neurotoxicity. To explore this potential link, we investigated the neurotoxic and lipid-disrupting effects of TBP using zebrafish larvae. Multi-level neurotoxicity assessment in whole larvae showed that TBP exposure induced concentration-dependent decreases in locomotor activity and a trend toward anxiety-like behaviors. Moreover, TBP significantly altered neuronal differentiation. At the neurochemical level, neurotransmitter homeostasis was disrupted, specifically marked by decreases in the levels of acetylcholine, serotonin, and epinephrine. Concomitantly, TBP induced a systemic lipid dysregulation, characterized by elevated total cholesterol and reduced triglyceride levels. Region-specific alterations were evident: abnormal neutral lipid accumulation occurred in the yolk sac, while lipid levels in the head region exhibited significant reductions. The transcripts of lipid metabolism genes in whole larvae were widely suppressed. To explore the correlation between lipid dysregulation and neurotoxicity, a rescue experiment was conducted using the liver X receptor (LXR) agonist GW3965. LXR activation restored the gene expression of systemic lipid transport and normalized head lipid levels. Notably, this restoration of lipid homeostasis partially alleviated the TBP-induced neurotransmitter deficits. Collectively, these results suggest that TBP exposure may impair neurodevelopment and function, and support lipid metabolic disruption as a potential mechanistic link underlying the consequent neurotoxicity. Our findings provide a preliminary mechanistic basis for evaluating the neurotoxic potential of other emerging environmental contaminants with metabolism-disrupting properties.