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Combination effects of AHR agonists and Wnt/beta-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
2015 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 284, no 2, 163-179 p.Article in journal (Refereed) Published
Abstract [en]

Wnt/beta-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 beta-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 beta-catenin inhibitor XAV939 display effects phenocopying those of the dioxin-like 3,3',4,4',5-pentachlorobiphenyl (PCB126). This led us to investigate the AHR interaction with beta-catenin during development and ask whether developmental toxicity of DLCs involves antagonism of p-catenin signaling. We examined phenotypes and transcriptional responses in zebrafish embryos exposed to XAV939 or to a beta-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-oligonudeotide 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 beta-catenin-associated genes, while PCB126 and FICZ blocked this induction. The data indicate a stage-dependent antagonism of p-catenin by Ahr2 in zebrafish embryos. We propose that the AHR has a physiological role in regulating beta-catenin during development, and that this is one point of intersection linking toxicological and physiological AHR-governed processes. (C) 2015 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
2015. Vol. 284, no 2, 163-179 p.
Keyword [en]
Aryl hydrocarbon receptor, Zebrafish embryo, Beta-catenin, 6-Formylindolo[3, 2-b]carbazole 3, 3 ', 4, 4 ', 5-Pentachlorobiphenyl
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:uu:diva-253256DOI: 10.1016/j.taap.2015.02.014ISI: 000353864000007PubMedID: 25711857OAI: oai:DiVA.org:uu-253256DiVA: diva2:820821

Correction in: Toxicology and Applied Pharmacology, 2015, Volume: 288, Issue: 2, Pages: 280-280, DOI: 10.1016/j.taap.2015.07.021

Available from: 2015-06-12 Created: 2015-05-25 Last updated: 2015-11-24Bibliographically approved

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