Aryl Phosphate Esters Within a Major PentaBDE Replacement Product Induce Cardiotoxicity in Developing Zebrafish Embryos: Potential Role of the Aryl Hydrocarbon Receptor
Aryl Phosphate Esters Within a Major PentaBDE Replacement Product Induce Cardiotoxicity in Developing Zebrafish Embryos: Potential Role of the Aryl Hydrocarbon Receptor
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DOI：
10.1093/toxsci/kft020
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发表时间：
2013-05-01
影响因子：
3.8
通讯作者：
Volz, David C.
中科院分区：
文献类型：
--
作者：
McGee, Sean P.;Konstantinov, Alex;Volz, David C.
Firemaster 550(FM550)是一种溴化和芳基磷酸酯(APE)组分的添加剂阻燃剂配方，作为主要用于聚氨酯泡沫塑料的商用多溴联苯醚混合物(称为五溴二苯醚)的主要替代产品推出。然而，人们对以FM550为基础的成分在脊椎动物早期发育过程中的潜在影响知之甚少。因此，我们首先以斑马鱼为动物模型，筛选出FM550各组分的发育毒性。基于这些初步的筛选分析，我们发现，暴露在高达10µM的溴化成分中对胚胎的存活或发育没有显著影响，而暴露于磷酸三苯(TPP)或单取代异丙基三芳基磷酸(Mono-ITP)--两种类人猿，几乎占FM550的50%--会对胚胎发育期间的心脏循环和功能产生靶向影响。由于这些心脏异常类似于芳香烃受体(AHR)激动剂诱导的表型，我们随后将发育中的胚胎暴露于TPP或Mono-ITP中，同时存在或不存在AHR拮抗剂(CH223191)或AHR2特异性吗啉。基于这些研究，我们发现CH223191可以阻止暴露于单一ITP后的心脏畸形，但不能阻止TPP，而AHR2基因敲除未能阻止这两种成分的心脏毒性作用。最后，使用基于细胞的人AHR报告实验，我们发现单一的ITP(而不是TPP)在与有效的参考AHR激动剂(β-萘黄酮)相似的标称浓度下导致人AHR驱动的荧光素酶活性显著增加。总体而言，我们的发现表明，FM550的两个主要类人猿成分在脊椎动物早期发育过程中会导致严重的心脏异常。
Firemaster 550 (FM550) is an additive flame retardant formulation of brominated and aryl phosphate ester (APE) components introduced as a major replacement product for the commercial polybrominated diphenyl ether mixture (known as PentaBDE) used primarily in polyurethane foam. However, little is known about the potential effects of FM550-based ingredients during early vertebrate development. Therefore, we first screened the developmental toxicity of each FM550 component using zebrafish as an animal model. Based on these initial screening assays, we found that exposure to the brominated components as high as 10 mu M resulted in no significant effects on embryonic survival or development, whereas exposure to triphenyl phosphate (TPP) or mono-substituted isopropylated triaryl phosphate (mono-ITP)-two APEs comprising almost 50% of FM550-resulted in targeted effects on cardiac looping and function during embryogenesis. As these cardiac abnormalities resembled aryl hydrocarbon receptor (AHR) agonist induced phenotypes, we then exposed developing embryos to TPP or mono-ITP in the presence or absence of an AHR antagonist (CH223191) or AHR2-specific morpholino. Based on these studies, we found that CH223191 blocked heart malformations following exposure to mono-ITP but not TPP, whereas AHR2 knockdown failed to block the cardiotoxic effects of both components. Finally, using a cell-based human AHR reporter assay, we found that mono-ITP (but not TPP) exposure resulted in a significant increase in human AHR-driven luciferase activity at similar nominal concentrations as a potent reference AHR agonist (beta-naphthoflavone). Overall, our findings suggest that two major APE components of FM550 induce severe cardiac abnormalities during early vertebrate development.