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Combination effects...
Combination effects of AHR agonists and Wnt/beta-catenin modulators in zebrafish embryos : Implications for physiological and toxicological AHR functions
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- Wincent, Emma (author)
- Karolinska Institutet,Uppsala universitet,Miljötoxikologi,Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden
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- Stegeman, John J. (author)
- Woods Hole Oceanog Inst, Dept Biol, Woods Hole, MA 02543 USA
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- Jönsson, Maria E. (author)
- Uppsala universitet,Miljötoxikologi
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(creator_code:org_t)
- Elsevier BV, 2015
- 2015
- English.
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In: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 284:2, s. 163-179
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- Aryl hydrocarbon receptor
- Zebrafish embryo
- Beta-catenin
- 6-Formylindolo[3
- 2-b]carbazole 3
- 3 '
- 4
- 4 '
- 5-Pentachlorobiphenyl
Publication and Content Type
- ref (subject category)
- art (subject category)
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