The Aryl Hydrocarbon ReceptorsansXenobiotics: Endogenous Function in Genetic Model Systems

Abstract

For more than 30 years, the aryl hydrocarbon receptor [Ah receptor (AHR)] has been extensively scrutinized as the cellular receptor for numerous environmental contaminants, including polychlorinated dioxins, dibenzofurans, and biphenyls. Recent evidence argues that this description is incomplete and perhaps myopic. Ah receptor orthologs have been demonstrated to mediate diverse endogenous functions in our close vertebrate relatives as well as our distant invertebrate ancestors. Moreover, these endogenous functions suggest that xenobiotic toxicity may be best understood in the context of intrinsic AHR physiology. In this literature review, we survey the emerging picture of endogenous AHR biology from work in the vertebrate and invertebrate model systems Mus musculus, Caenorhabditis elegans, and Drosophila melanogaster.

Transcriptional Factor Aryl Hydrocarbon Receptor (Ahr) Controls Cardiovascular and Respiratory Functions by Regulating the Expression of the Vav3 Proto-oncogene

“…For example, it has been described that Ahr is important for vasculogenesis, a process that may contribute to alterations in peripheral vascular resistance if not working properly (63). It has been also proposed that the Ahr deficiency may promote hypertension by defective fluid shear stress responses in arterioles (64). However, these defects cannot explain the rest of the sympathetic and respiratory changes seen in Ahr-deficient mice.…”

Genome-wide B1 retrotransposon binds the transcription factors dioxin receptor and Slug and regulates gene expression in vivo

“…Ligand-bound AhR translocates from the cytosol to the nucleus, heterodimerizes with the AhR nuclear translocator (ARNT), and binds to xenobiotic responsive elements (XREs) located in the promoter of target genes (17). Recent evidence implicates AhR in cell proliferation and differentiation, organ homeostasis, cell adhesion, cell migration, and cancer (18)(19)(20). These functions presumably require AhR to be integrated in regulatory pathways that control gene expression in coordination with other transcription factors.…”

Phosphodiesterases link the aryl hydrocarbon receptor complex to cyclic nucleotide signaling

“…There is evidence for nucleocytoplasmic shuttling of AHR in the absence of exogenous ligand [17][18][19]. Studies using AHR knockout mice suggest that the developmental role of AHR does not require addition of ligands [20] and TCDD-independent functions of AHR have been observed in different species [21]. Oesch-Bartlomowicz et al (for additional reading see OeschBartlomowicz `s review elsewhere in this issue) showed that cAMP, in a similar way to TCDD, is able to induce translocation of AHR to the nucleus [22].…”