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首页> 外文期刊>The Science of the Total Environment >Aryl hydrocarbon receptor activity of polyhalogenated carbazoles and the molecular mechanism
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Aryl hydrocarbon receptor activity of polyhalogenated carbazoles and the molecular mechanism

机译：多卤代咔唑的芳烃受体活性及其分子机理

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摘要

Polyhalogenated carbazoles (PHCZs) are a class of contaminants identified with persistence and bioaccumulation property from previous studies. However, the toxic effect and mechanism of PHCZs are not fully understood. In this study, eleven PHCZs, including four chlorocarbazoles, four bromocarbazoles and two bromo/chlorocarbazoles were screened for their potential aryl hydrocarbon receptor (AhR) activity by using a dioxin responsive element-driven luciferase reporter assay. We found that nine PHCZs significantly activated AhR in a concentration-dependent manner. Their potencies of AhR activation were 1000 to 100,000 folds less than that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent AhR ligand. The relative AhR activation potency of the nine PHCZs followed the order 2,3,6,7-tetrachloro-9H-carbazole 2,7-dibromo-9H-carbazole 1,3,6-tribromo-9H-carbazole 1,3,6,8-tetrachloro-9H-carbazole 1,3,6,8-tetrabromo-9H-carbazole 1-bromo-3,6-dichloro-9H-carbazole 3,6-dibromo-9H-carbazole 3-bromo-9H-carbazole 1,8-dibromo-3,6-dichloro-9H-carbazole, which was partly in line with the induction of AhR-mediated CYP1A1 expression. In silico analysis indicated that the nine PHCZs could be docked into the same pocket as TCDD due to their high structural similarity. However, the shrunk size of the heterocyclic moieties in PHCZs relative to that in TCDD dramatically decreased the complex stability provided by inter-molecular interactions. Moreover, two distinguished docking poses adopted by the nine PHCZs were found, in which one was illustrated by 2367-CCZ and 27-BCZ while the other symbolized by TCDD and the left seven agonists. The differential antagonizing effects of CH223191 on PHCZ-induced AhR activity supported such pose differentiation. The present experimental and in silico data provide new direct evidence of PHCZ-AhR interaction which sheds light on AhR-associated toxicological study and risk assessment of PHCZs. (C) 2019 Published by Elsevier B.V.
机译：多卤咔唑（PHCZs）是一类根据先前研究确定具有持久性和生物蓄积性的污染物。但是，尚未完全了解PHCZ的毒性作用和机理。在这项研究中，通过使用二恶英响应元件驱动的荧光素酶报告基因分析法，筛选了11种PHCZ，包括4种氯咔唑，4种溴咔唑和2种溴/氯咔唑潜在的芳烃受体（AhR）活性。我们发现九个PHCZs以浓度依赖的方式显着激活了AhR。它们的AhR活化能力比最有效的AhR配体2,3,7,8-四氯二苯并-对-二恶英（TCDD）低1000至100,000倍。九种PHCZ的相对AhR活化潜能依次为2,3,6,7-四氯9H-咔唑> 2,7-二溴9H-咔唑> 1,3,6-三溴-9H-咔唑> 1， 3,6,8-四氯-9H-咔唑> 1,3,6,8-四溴-9H-咔唑> 1-溴-3,6-二氯-9H-咔唑> 3,6-二溴-9H-咔唑> 3-bromo-9H-咔唑> 1,8-dibromo-3,6-dichloro-9H-咔唑，部分与诱导AhR介导的CYP1A1表达相符。计算机分析表明，由于九种PHCZ具有高度的结构相似性，因此它们可以与TCDD停靠在同一口袋中。但是，相对于TCDD，PHCZs中杂环部分的缩合尺寸显着降低了分子间相互作用所提供的复杂稳定性。此外，发现了九个PHCZ采取的两个不同的对接姿势，其中一个由2367-CCZ和27-BCZ表示，另一个由TCDD和左七个激动剂表示。 CH223191对PHCZ诱导的AhR活性的不同拮抗作用支持了这种姿势分化。目前的实验数据和计算机模拟数据提供了PHCZ-AhR相互作用的新直接证据，为与AhR相关的毒理学研究和PHCZs的风险评估提供了启示。 （C）2019由Elsevier B.V.发布

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  • 来源
    《The Science of the Total Environment》 |2019年第15期|516-526|共11页
  • 作者

    Ma Dan; Xie Heidi Qunhui; Zhang Wanglong; Xue Qiao; Liu Xiuchang; Xu Li; Ma Yongchao; Bonefelci-Jorgensen Eva Cecilie; Long Manhai; Zhang Aiqian; Zhao Bin;

  • 作者单位

    Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

    Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

    Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

    Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

    Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

    Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

    Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

    Aarhus Univ, Dept Publ Hlth, Ctr Arctic Hlth & Mol Epidemiol, DK-8000 Aarhus, Denmark;

    Aarhus Univ, Dept Publ Hlth, Ctr Arctic Hlth & Mol Epidemiol, DK-8000 Aarhus, Denmark;

    Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

    Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China|Univ Chinese Acad Sci, Beijing 100049, Peoples R China;

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  • 正文语种 eng
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  • 关键词

    Polyhalogenated carbazoles; Aryl hydrocarbon receptor; CH223191; 2,3,7,8-tetrachlorodibenzo-p-dioxin; Luciferase reporter assay;

    机译：聚卤代咔唑;芳基烃受体;CH223191;2,3,7,8-四氯二苯并苯并二恶英;荧光素酶报告分析;

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