AhR-mediated changes in global gene expression in rat liver progenitor cells

Abstract

Although the tumor-promoting effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), coplanar polychlorinated biphenyls (PCBs), and related compounds in liver tissue are primarily attributed to the activation of the aryl hydrocarbon receptor (AhR), the underlying molecular mechanisms are still unclear. Liver progenitor (oval) cells have been suggested to constitute a potential target for hepatocarcinogenic chemicals. To better understand AhR-driven pathways, we analyzed the transcriptional program in response to coplanar PCB 126 in contact-inhibited rat liver progenitor WB-F344 cells using high-density microarrays. After 6-h treatment, we identified 145 significantly deregulated genes considered to be direct AhR-dependent target genes. The number of differentially regulated genes increased to 658 and 968 genes after 24 and 72 h, respectively. Gene ontology analysis revealed that these genes were primarily involved in drug and lipid metabolism, cell cycle and growth control, cancer developmental processes, cell-cell communication, and adhesion. Interestingly, the Wnt and TGF-β signaling pathways, both being involved in developmental and tumorigenic processes, belonged to the most affected pathways. AhR- and ARNT-dependent regulation of selected target genes of interest was then confirmed using TCDD as a model AhR agonist, together with pharmacological inhibition of the AhR and by RNA-interference techniques. We demonstrated AhR-dependent regulation of emerging and novel AhR target genes, such as Fst, Areg, Hbegf, Ctgf, Btg2, and Foxq1. Among them, the transcription factor Foxq1, recently suggested to contribute to tumor promotion and/or progression, was found to be regulated at both mRNA and protein levels by AhR/ARNT activation.

The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation

“…Transcriptome analysis of control or TCDD-treated rat liver cells revealed that TGF-b and Wnt signaling pathways were 2 of the most influenced pathways by AHR activation. 47 These data are intriguing and support our current study that orbital fibroblasts require AHR ligand-dependent activation of the AHR to attenuate b-catenin/Wnt signaling.…”

Mining Gene Expression Data for Pollutants (Dioxin, Toluene, Formaldehyde) and Low Dose of Gamma-Irradiation

“…Formaldehyde promotes the formation of protein-protein and DNA-protein crosslinks [43], [44]. 2,3,7,8-tetrachlorodibenzo-p-dioxin, which is not directly genotoxic, binds to the aryl hydrocarbon receptor AhR, an intracellular protein that is a transcriptional enhancer affecting the expression of important genes [10], [45], [46].…”

Intersection of AHR and Wnt Signaling in Development, Health, and Disease

“…The AHR-ARNT heterodimer binds to dioxin response elements (DREs) in the promoter region of downstream target genes and directly upregulates their expression [38]. Activated AHR is also capable of downregulating expression, and multiple studies have reported a larger number of genes being downregulated rather than upregulated following AHR activation [41,42,43,44,45,46,47]. However, it is less clear whether transcriptional downregulation is the result of AHR binding directly to the promoter, or if it is an indirect effect due to (1) AHR-induced upregulation of transcriptional inhibitors or (2) AHR-induced degradation of other transcriptional activators (discussed below).…”

“…The biological significance of these findings is not known. Microarray analysis of the multipotent stem cell-like cell line, WB-F344, after exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB126, an AHR agonist) also found Wnt5a to be downregulated, along with Wnt4 , Fzd1 , and Fzd4 (Table 1 and Table 2) [47]. Numerous other genes linked to Wnt signaling were also downregulated including Lef1 and Axin2 .…”