Impact of 1,2-Bis (2,4,6-Tribromophenoxy) Ethane on Liver Metabolism and Intestinal Health in Zebrafish: Role of the Liver X Receptor

1,2-Bis (2,4,6-tribromophenoxy) ethane (BTBPE) has been increasingly detected in environmental and biota samples, primarily accumulating in the liver. However, the mechanism underlying BTBPE-induced metabolic dysregulation remains unclear. In this study, molecular docking and microscale thermophoresis assays indicated that BTBPE binds to zebrafish liver X receptor α (LXRα). Subsequently, zebrafish embryos were exposed to BTBPE, an LXR antagonist (GSK2033), or coexposed to BTBPE with an LXR agonist (GW3965) for 120 h postfertilization (hpf). The results showed that BTBPE induced reduction in body weight and lipid levels, likely via inhibition of the LXR signaling pathway. Exposure of adult female zebrafish to environmentally relevant concentrations of BTBPE (0.01-10 μg/L) for 28 days induced developmental toxicity, evidenced by decreases in body weight, growth rate, and fat accumulation. Metabolomic analysis revealed that BTBPE-induced alterations in liver metabolites were primarily associated with LXR-mediated lipid metabolic pathways such as glycerophospholipid metabolism and primary bile acid biosynthesis. Additionally, BTBPE impaired the physical barrier and induced inflammation, resulting in gut microbiota dysbiosis, which is potentially linked to LXR activation. These effects were validated through the alterations of multiple biomarkers at various levels. Overall, our results suggest that BTBPE disrupts lipid metabolism and gut function via the LXR-mediated pathway.