The human aryl hydrocarbon receptor (hAHR) and mouse aryl hydrocarbon receptor (mAHRb) share limited (58%) transactivation domain (TAD) sequence identity. Compared to the mAHRb allele, the hAHR displays 10-fold lower relative affinity for prototypical ligands, such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). However, in previous studies, we have demonstrated that the hAHR can display a higher relative ligand-binding affinity than the mAHRb for specific AHR ligands, such as indirubin. Each receptor has also been shown to differentially recruit LXXLL coactivator motif proteins and to utilize different TAD subdomains in gene transactivation. Using hepatocytes isolated from C57BL/6J mice (Ahrb/b) and AHRTtr transgenic mice, which express hAHR protein specifically in hepatocytes, we investigated whether the hAHR and mAHRb differentially regulate genes. DNA microarray and quantitative PCR analysis of Ahrb/b and AHRTtr primary mouse hepatocytes treated with 10nM TCDD revealed that a number of established AHR target genes such as Cyp1a1 and Cyp1b1 are significantly induced by both receptors. Remarkably, of the 1752 genes induced by mAHRb and 1186 genes induced by hAHR, only 265 genes (~18%) were significantly activated by both receptors in response to TCDD. Conversely, of the 1100 and 779 genes significantly repressed in mAHRb and hAHR hepatocytes, respectively, only 462 (~49%) genes were significantly repressed by both receptors in response to TCDD treatment. Genes identified as differentially expressed are known to be involved in a number of biological pathways, including cell proliferation and inflammatory response, which suggest that compared to the mAHRb, the hAHR may play contrasting roles in TCDD-induced toxicity and endogenous AHR-mediated gene regulation.
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