Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5845988 | Toxicology and Applied Pharmacology | 2015 | 17 Pages |
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 3,3â²,4,4â²,5-pentachlorobiphenyl (PCB126). This led us to investigate the 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 the 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 morpholino-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.
Keywords
qPCRXAV939T-cell factor/lymphoid enhancer-binding factorPCNAAZPDLCsZGA6-formylindolo[3,2-b]carbazole3-methylcholanthreneAHR2PCB126FICZGSK3βCYP1TCDDAHRDPFhpfAPC2,3,7,8-Tetrachlorodibenzo-p-dioxin3,3′,4,4′,5-pentachlorobiphenylDMSO3-MCquantitative real-time RT-PCRadenomatosis polyposis coliProliferating Cell Nuclear Antigenbeta-cateninDioxin-like compoundsZebrafish embryoDimethyl sulfoxidedays post-fertilizationhours post-fertilizationzygotic genome activationmorpholinoGlycogen synthase kinase 3βaryl hydrocarbon receptor
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Authors
Emma Wincent, John J. Stegeman, Maria E. Jönsson,