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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 universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi. Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden.
Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
2015 (Engelska)Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 284, nr 2, s. 163-179Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2015. Vol. 284, nr 2, s. 163-179
Nyckelord [en]
Aryl hydrocarbon receptor, Zebrafish embryo, Beta-catenin, 6-Formylindolo[3, 2-b]carbazole 3, 3 ', 4, 4 ', 5-Pentachlorobiphenyl
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
URN: urn:nbn:se:uu:diva-253256DOI: 10.1016/j.taap.2015.02.014ISI: 000353864000007PubMedID: 25711857OAI: oai:DiVA.org:uu-253256DiVA, id: diva2:820821
Forskningsfinansiär
Forskningsrådet FormasCarl Tryggers stiftelse för vetenskaplig forskning
Anmärkning

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

Tillgänglig från: 2015-06-12 Skapad: 2015-05-25 Senast uppdaterad: 2018-01-11Bibliografiskt granskad

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Jönsson, Maria E.

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