Aryl hydrocarbon receptor activity of polyhalogenated carbazoles and the molecular mechanism

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  • Dan Ma, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China, University of Chinese Academy of Sciences, Kina
  • Heidi Qunhui Xie, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China, University of Chinese Academy of Sciences, Kina
  • Wanglong Zhang, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China, University of Chinese Academy of Sciences, Kina
  • Qiao Xue, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China, University of Chinese Academy of Sciences, Kina
  • Xiuchang Liu, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China, University of Chinese Academy of Sciences, Kina
  • Li Xu, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China, University of Chinese Academy of Sciences, Kina
  • Yongchao Ma, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China, University of Chinese Academy of Sciences, Kina
  • Eva Cecilie Bonefeld-Jørgensen
  • Manhai Long
  • Aiqian Zhang, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China, University of Chinese Academy of Sciences, Kina
  • Bin Zhao, State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center of Eco-Environment Sciences, Chinese Academy of Sciences, Beijing 100085, China, University of Chinese Academy of Sciences, Kina

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.

OriginalsprogEngelsk
TidsskriftScience of the Total Environment
Vol/bind687
Sider (fra-til)516-526
Antal sider11
ISSN0048-9697
DOI
StatusUdgivet - 15 okt. 2019

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