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 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 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 morpholine-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.

Signaling Events Downstream of AHR Activation That Contribute to Toxic Responses: The Functional Role of an AHR-Dependent Long Noncoding RNA ( slincR ) Using the Zebrafish Model

“…In zebrafish, several publications have supported the hypothesis that xenobiotic activation of the AHR leads to a disruption in Wnt/β-catenin signaling, and that this disruption in Wnt signaling has a causal role in AHR-mediated toxicities (Mathew et al. 2008; Wincent et al. 2015).…”

“…For example, crosstalk between AHR and Wnt/β-catenin signaling pathways is well established (Schneider et al. 2014; Wincent et al. 2015).…”

Protective roles of FICZ and aryl hydrocarbon receptor axis on alveolar bone loss and inflammation in experimental periodontitis

“…Several signalling pathways were reported to be involved in the study of agents promoting osteogenic differentiation of PDLCs, including JNK, p38 MARK and so on (Niu et al, ; Tang et al, ). Wnt/β‐catenin signalling pathway has been widely investigated in the osteogenesis process, and it was reported to have a crosstalk with AhR signalling in the development of zebrafish embryos (Wincent, Stegeman, & Jonsson, ). In this study, FICZ might promote the osteogenesis of PDLCs via the activation of Wnt/β‐catenin.…”

The Role of Aryl-Hydrocarbon Receptor (AhR) in Osteoclast Differentiation and Function

“…Homeostasis in bone remodeling depends on relative levels of bone formation and resorption, which in turn depend primarily on the relative activities of osteoblasts (OB) and osteoclasts (OC). In this context, AhR signaling leads to modulation of the NF-κB, Wnt, and MAP kinase pathways; influences the function and differentiation of OB and OC; and results in altered bone remodeling [ 16 , 17 , 18 , 19 , 20 ]. The overall effect of AhR activation in OB is suppressed cell differentiation.…”