title: Combination effects of AHR agonists and Wnt/β-catenin modulators in zebrafish embryos: Implications for physiological and toxicological AHR functions.
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 3,3',4,4',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.
authors.affiliation: Department of Environmental Toxicology, Uppsala University, 75236 Uppsala, Sweden; Institute of Environmental Medicine, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Wincent
authors.affiliation: Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543-1050, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Stegeman
authors.affiliation: Department of Environmental Toxicology, Uppsala University, 75236 Uppsala, Sweden. Electronic address: maria.jonsson@ebc.uu.se.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Jönsson
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000633:toxicity; D002227:Carbazoles / Q000633:toxicity; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000633:toxicity; D007211:Indoles / Q000633:toxicity; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C111855:6-formylindolo(3,2-b)carbazole; D001552:Benzazepines; D002227:Carbazoles; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D018336:Receptors, Aryl Hydrocarbon; D051153:Wnt Proteins; C544261:XAV939; D029961:Zebrafish Proteins; D051176:beta Catenin; C119620:kenpaullone; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: 3,3′,4,4′,5-Pentachlorobiphenyl; 6-Formylindolo[3,2-b]carbazole; Aryl hydrocarbon receptor; Beta-catenin; Zebrafish embryo