PUBLICATION
Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions
- Authors
- Wincent, E., Stegeman, J.J., Jönsson, M.E.
- ID
- ZDB-PUB-150226-12
- Date
- 2015
- Source
- Toxicology and applied pharmacology 284(2): 163-79 (Journal)
- Registered Authors
- Stegeman, John J.
- Keywords
- 3,3',4,4',5-pentachlorobiphenyl,PCB126, 6-formylindolo[3,2-b]carbazole, AHR, FICZ, aryl hydrocarbon receptor, beta-catenin, zebrafish embryo
- MeSH Terms
-
- Animals
- Benzazepines/toxicity
- Carbazoles/toxicity
- Embryo, Nonmammalian/drug effects*
- Embryo, Nonmammalian/metabolism
- Heterocyclic Compounds, 3-Ring/toxicity
- Indoles/toxicity
- Polychlorinated Biphenyls/toxicity
- Receptors, Aryl Hydrocarbon/agonists*
- Wnt Proteins/metabolism*
- Zebrafish
- Zebrafish Proteins/metabolism
- beta Catenin/antagonists & inhibitors
- beta Catenin/metabolism*
- PubMed
- 25711857 Full text @ Tox. App. Pharmacol.
- CTD
- 25711857
Citation
Wincent, E., Stegeman, J.J., Jönsson, M.E. (2015) Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions. Toxicology and applied pharmacology. 284(2):163-79.
Abstract
Wnt/β-catenin signaling regulates essential biological functions and acts in developmental toxicity of some chemicals. The aryl hydrocarbon receptor (AHR) is well-known to mediate developmental toxicity of persistent dioxin-like compounds (DLCs). Recent studies indicate a crosstalk between β-catenin and the AHR in some tissues. However the nature of this crosstalk in embryos is poorly known. We observed that zebrafish embryos exposed to the β-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3',4,4',5-pentachlorobiphenyl (PCB126). This led us to investigate AHR interaction with β-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of β-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a β-catenin activator, 1-azakenpaullone, alone or with AHR agonists, either PCB126 or 6-formylindolo[3,2-b]carbazole (FICZ). Alone 1-azakenpaullone and XAV939 both were embryo-toxic, and we found that in presence of FICZ, the toxicity of 1-azakenpaullone decreased while the toxicity of XAV939 increased. This rescue of 1-azakenpaullone effects occurred in the time window of Ahr2-mediated toxicity and was reversed by morpholine-oligonucleotide knockdown of Ahr2. Regarding PCB126, addition of either 1-azakenpaullone or XAV939 led to lower mortality than with PCB126 alone but surviving embryos showed severe edemas. 1-Azakenpaullone induced transcription of β-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of β-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating β-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping