| 论文摘要： |
Bis(2-ethylhexyl)-2,3,4,S-tetrabromophthalate (TBPH) is a ubiquitous environmental contaminant, but its toxicity is not fully understood. Accordingly, we investigated the effects of TBPH and its metabolite, mono-(2-ethyhexyl)-tetrabromophthalate (TBMEHP), on lipid metabolism using a zebrafish model. The molecular docking study revealed that TBPH and TBMEHP bind to zebrafish peroxisome proliferator-activated receptor gamma (PPAR gamma), with binding energies similar to rosiglitazone, a PPAR gamma agonist. Zebrafish embryos 0.75 hpf were exposed to TBPH (0.2-2000 nM) or TBMEHP (0.2-2000 nM) until 72 hpf, and their effects on PPAR gamma-mediated lipid metabolism were evaluated. Significant regional DNA demethylation of the PPAR gamma promoter was observed in the larvae at 72 hpf. Demethylation of the PPAR gamma promoter accompanied by upregulation of tet1 and tet2 transcription caused upregulation of PPAR gamma transcription and certain downstream genes involved in lipid lipolysis, transport, and metabolism. The triglyceride and total cholesterol concentrations in the larvae were significantly reduced following exposure to TBPH or TBMEHP. Furthermore, significant increases in the whole ATP content and locomotor activity in the 120 hpf larvae were observed. The overall results suggest that both TBPH and TBMEHP affect methylation of the PPAR gamma promoter, subsequently influencing larvae lipid metabolism via the PPAR gamma signaling pathway and disrupting energy homeostasis. |
