Bis(2-ethylhexyl)-2,3,4,5-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 γ (PPARγ), with binding energies similar to rosiglitazone, a PPARγ 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 PPARγ-mediated lipid metabolism were evaluated. Significant regional DNA demethylation of the PPARγ promoter was observed in the larvae at 72 hpf. Demethylation of the PPARγ promoter accompanied by upregulation of tet1 and tet2 transcription caused upregulation of PPARγ 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 PPARγ promoter, subsequently influencing larvae lipid metabolism via the PPARγ signaling pathway and disrupting energy homeostasis.

中文翻译：

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双（2-乙基己基）-2,3,4,5-四溴邻苯二甲酸酯通过DNA甲基化修饰影响斑马鱼幼虫的脂质代谢。

双（2-乙基己基）-2,3,4,5-四溴邻苯二甲酸酯（TBPH）是一种普遍存在的环境污染物，但其毒性尚不完全清楚。因此，我们使用斑马鱼模型调查了TBPH及其代谢产物单-（2-乙基己基）四溴邻苯二甲酸酯（TBMEHP）对脂质代谢的影响。分子对接研究表明，TBPH和TBMEHP与斑马鱼过氧化物酶体增殖物激活受体γ（PPARγ）结合，结合能与PPARγ激动剂罗格列酮相似。0.75 hpf的斑马鱼胚胎暴露于TBPH（0.2-2000 nM）或TBMEHP（0.2-2000 nM）直至72 hpf，并评估它们对PPARγ介导的脂质代谢的影响。在72 hpf的幼虫中观察到PPARγ启动子的重要区域DNA脱甲基。PPARγ启动子的去甲基化伴随tet1和tet2转录的上调引起PPARγ转录和某些参与脂质脂解，运输和代谢的下游基因的上调。暴露于TBPH或TBMEHP后，幼虫中的甘油三酸酯和总胆固醇浓度显着降低。此外，观察到120 hpf幼虫的总ATP含量和运动活性显着增加。总体结果表明，TBPH和TBMEHP都影响PPARγ启动子的甲基化，随后通过PPARγ信号通路影响幼虫脂质代谢并破坏能量稳态。暴露于TBPH或TBMEHP后，幼虫中的甘油三酸酯和总胆固醇浓度显着降低。此外，观察到120 hpf幼虫的总ATP含量和运动活性显着增加。总体结果表明，TBPH和TBMEHP均会影响PPARγ启动子的甲基化，随后通过PPARγ信号通路影响幼虫脂质代谢并破坏能量稳态。暴露于TBPH或TBMEHP后，幼虫中的甘油三酸酯和总胆固醇浓度显着降低。此外，观察到120 hpf幼虫的总ATP含量和运动活性显着增加。总体结果表明，TBPH和TBMEHP都影响PPARγ启动子的甲基化，随后通过PPARγ信号通路影响幼虫脂质代谢并破坏能量稳态。