Combination effects of AHR agonists and Wnt/beta-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions
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
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.
Aryl hydrocarbon receptor, Zebrafish embryo, Beta-catenin, 6-Formylindolo[3, 2-b]carbazole 3, 3 ', 4, 4 ', 5-Pentachlorobiphenyl
Pharmacology and Toxicology
IdentifiersURN: 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.2015.07.0212015-06-122015-05-252015-11-24Bibliographically approved