ZFIN ID: ZDB-PUB-150226-12
Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions
Wincent, E., Stegeman, J.J., Jönsson, M.E.
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.
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.