Fang Mingliang, Webster Thomas F, Ferguson P Lee, Stapleton Heather M
Nicholas School of the Environment, Duke University, Durham, North Carolina, USA.
Environ Health Perspect. 2015 Feb;123(2):166-72. doi: 10.1289/ehp.1408522. Epub 2014 Oct 14.
Accumulating evidence has shown that some environmental contaminants can alter adipogenesis and act as obesogens. Many of these contaminants act via the activation of the peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor.
Our goal was to determine the PPARγ ligand binding potency of several major flame retardants, including polybrominated diphenyl ethers (PBDEs), halogenated phenols and bisphenols, and their metabolites. Ligand binding activity of indoor dust and its bioactivated extracts were also investigated.
We used a commercially available fluorescence polarization ligand binding assay to investigate the binding potency of flame retardants and dust extracts to human PPARγ ligand-binding domain. Rosiglitazone was used as a positive control.
Most of the tested compounds exhibited dose-dependent binding to PPARγ. Mono(2-ethylhexyl) tetrabromophthalate, halogenated bisphenols and phenols, and hydroxylated PBDEs were found to be potent PPARγ ligands. The most potent compound was 3-OH-BDE-47, with an IC50 (concentration required to reduce effect by 50%) of 0.24 μM. The extent of halogenation and the position of the hydroxyl group strongly affected binding. In the dust samples, 21 of the 24 samples tested showed significant binding potency at a concentration of 3 mg dust equivalent (DEQ)/mL. A 3-16% increase in PPARγ binding potency was observed following bioactivation of the dust using rat hepatic S9 fractions.
Our results suggest that several flame retardants are potential PPARγ ligands and that metabolism may lead to increased binding affinity. The PPARγ binding activity of house dust extracts at levels comparable to human exposure warrants further studies into agonistic or antagonistic activities and their potential health effects.
越来越多的证据表明，一些环境污染物可改变脂肪生成并充当致肥胖物。这些污染物中的许多通过激活过氧化物酶体增殖物激活受体γ（PPARγ）核受体发挥作用。
我们的目标是确定几种主要阻燃剂，包括多溴二苯醚（PBDEs）、卤代酚和双酚及其代谢物的PPARγ配体结合能力。还研究了室内灰尘及其生物活化提取物的配体结合活性。
我们使用市售的荧光偏振配体结合测定法来研究阻燃剂和灰尘提取物与人PPARγ配体结合域的结合能力。罗格列酮用作阳性对照。
大多数测试化合物对PPARγ表现出剂量依赖性结合。发现单（2-乙基己基）四溴邻苯二甲酸酯、卤代双酚和酚以及羟基化PBDEs是有效的PPARγ配体。最有效的化合物是3-OH-BDE-47，其IC50（降低效应50%所需的浓度）为0.24μM。卤化程度和羟基位置强烈影响结合。在灰尘样品中，24个测试样品中的21个在浓度为3mg灰尘当量（DEQ）/mL时显示出显著的结合能力。使用大鼠肝脏S9组分对灰尘进行生物活化后，观察到PPARγ结合能力增加了3-16%。
我们的结果表明，几种阻燃剂是潜在的PPARγ配体，代谢可能导致结合亲和力增加。房屋灰尘提取物在与人类暴露相当的水平下的PPARγ结合活性值得进一步研究其激动或拮抗活性及其潜在的健康影响。
