Time-dependent transcriptomic and biochemical responses of 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are explained by AHR activation time

Reza Farmahin; Doug Crump; Jason M O'Brien; Stephanie P Jones; Sean W Kennedy

doi:10.1016/j.bcp.2016.06.005

Time-dependent transcriptomic and biochemical responses of 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are explained by AHR activation time

Biochem Pharmacol. 2016 Sep 1:115:134-43. doi: 10.1016/j.bcp.2016.06.005. Epub 2016 Jun 11.

Authors

Reza Farmahin¹, Doug Crump², Jason M O'Brien², Stephanie P Jones², Sean W Kennedy³

Affiliations

¹ Centre for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada; Environment and Climate Change Canada, National Wildlife Research Centre, Ottawa, Ontario K1A 0H3, Canada. Electronic address: farmahin@gmail.com.
² Environment and Climate Change Canada, National Wildlife Research Centre, Ottawa, Ontario K1A 0H3, Canada.
³ Centre for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada; Environment and Climate Change Canada, National Wildlife Research Centre, Ottawa, Ontario K1A 0H3, Canada.

PMID: 27301797
DOI: 10.1016/j.bcp.2016.06.005

Abstract

6-Formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are ligands of the aryl hydrocarbon receptor (AHR) and bind to the AHR with high affinity. Until recently, TCDD was considered to be the most potent AHR agonist, but several recent studies indicate that FICZ binds with greater affinity to the AHR than TCDD. To advance our understanding of the similarities and differences of the effects of FICZ and TCDD exposure in chicken embryo hepatocyte (CEH) cultures, we compared relative expression changes of 27 dioxin-responsive genes by the use of a chicken PCR array, porphyrin accumulation and ethoxyresorufin-O-deethylase (EROD) activity at different time points. In addition, an egg injection study was performed to assess the effects of FICZ on the developing chicken embryo. The results of the current study showed: (1) mean EROD-derived relative potency values for FICZ compared to TCDD changed as a function of time (i.e. 9, 0.004, 0.0008 and 0.00008 at 3, 8, 24, and 48h, respectively) in CEH cultures; (2) FICZ exposure did not result in porphyrin accumulation in CEH cultures; (3) concordance between gene expression profiles for FICZ and TCDD was time- and concentration-dependent, and (4) no mortality or morphological abnormalities were observed in chicken embryos injected with 0.87ng FICZ/g egg into the air cell. The results presented herein suggest that while FICZ and TCDD share similar molecular targets, transient versus sustained AHR activation by FICZ and TCDD result in differential transcriptomic responses. Moreover, rapid metabolism of FICZ in hepatocytes resulted in a significant decrease in the induction of EROD activity.

Keywords: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, PubChem CID: 15625); 6-Formylindolo[3,2-b]carbazole (FICZ, PubChem CID: 1863); AHR ligand; Aryl hydrocarbon receptor; Bird; Dioxin; FICZ; Molecular toxicology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carbazoles / metabolism*
Cells, Cultured
Chick Embryo
Cytochrome P-450 CYP1A1 / metabolism
Gene Expression
Hepatocytes / metabolism
Polychlorinated Dibenzodioxins / metabolism*
Polymerase Chain Reaction
Porphyrins / metabolism
Receptors, Aryl Hydrocarbon / agonists*
Receptors, Aryl Hydrocarbon / metabolism
Time Factors
Tissue Array Analysis
Transcriptome

Substances

6-formylindolo(3,2-b)carbazole
Carbazoles
Polychlorinated Dibenzodioxins
Porphyrins
Receptors, Aryl Hydrocarbon
Cytochrome P-450 CYP1A1