Aryl hydrocarbon receptor activity of polyhalogenated carbazoles and the molecular mechanism

被引：34

作者：

Ma, Dan ^{[1
,2
]}

Xie, Heidi Qunhui ^{[1
,2
]}

Zhang, Wanglong ^{[1
,2
]}

Xue, Qiao ^{[1
,2
]}

Liu, Xiuchang ^{[1
,2
]}

Xu, Li ^{[1
,2
]}

Ma, Yongchao ^{[1
,2
]}

Bonefelci-Jorgensen, Eva Cecilie ^{[3
]}

Long, Manhai ^{[3
]}

Zhang, Aiqian ^{[1
,2
]}

Zhao, Bin ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, Res Ctr Ecoenvimnment Sci, State Key Lab Environm Chem & Ecotoxicol, Beijing 100085, Peoples R China

[2] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[3] Aarhus Univ, Dept Publ Hlth, Ctr Arctic Hlth & Mol Epidemiol, DK-8000 Aarhus, Denmark

来源：

SCIENCE OF THE TOTAL ENVIRONMENT | 2019年 / 687卷

基金：

中国国家自然科学基金;

关键词：

Polyhalogenated carbazoles; Aryl hydrocarbon receptor; CH223191; 2,3,7,8-tetrachlorodibenzo-p-dioxin; Luciferase reporter assay; DIBENZO-P-DIOXINS; HALOGENATED CARBAZOLES; THYROID-HORMONE; CHLOROCARBAZOLES; ACTIVATION; GENE; EXPRESSION; SEDIMENTS; TOXICITY; AHR;

D O I：

10.1016/j.scitotenv.2019.05.406

中图分类号：

X [环境科学、安全科学];

学科分类号：

08 ; 0830 ;

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.

引用

页码：516 / 526

页数：11

共 59 条

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