Aryl hydrocarbon receptor (AHR): “pioneer member” of the basic-helix/loop/helix per - Arnt - sim (bHLH/PAS) family of “sensors” of foreign and endogenous signals

Abstract

The basic-helix-loop-helix Per-Arnt-Sim (bHLH/PAS) family comprises many transcription factors, found throughout all three kingdoms of life; bHLH/PAS members “sense” innumerable intracellular and extracellular “signals” — including endogenous compounds, foreign chemicals, gas molecules, redox potential, photons (light), gravity, heat, and osmotic pressure. These signals then initiate downstream signaling pathways involved in responding to that signal. The term “PAS”, abbreviation for “Per-Arnt-Sim” was first coined in 1991. Although the mouse Arnt gene was not identified until 1991, evidence of its co-transcriptional binding partner, aryl hydrocarbon receptor (AHR), was first reported in 1974 as a “sensor” of foreign chemicals, up-regulating cytochrome P450 family 1 (CYP1) and other enzyme activities that usually metabolize the signaling chemical. Within a few years, AHR was proposed also to participate in inflammation. The mouse [Ah] locus was shown (1973–1989) to be relevant to chemical carcinogenesis, mutagenesis, toxicity and teratogenesis, the mouse Ahr gene was cloned in 1992, and the first Ahr(−/−) knockout mouse line was reported in 1995. After thousands of studies from the early 1970s to present day, we now realize that AHR participates in dozens of signaling pathways involved in critical-life processes, affecting virtually every organ and cell-type in the animal, including many invertebrates.

Cross‐talk between monocyte invasion and astrocyte proliferation regulates scarring in brain injury

“…We reasoned that this pathway may be less active in the condition when monocytes do not invade and, hence, be higher in WT mice in our proteome. One candidate that caught our attention is ARNT2 (Fig B), an essential co‐factor for the canonical signaling pathway of the Aryl hydrocarbon receptor (AhR) signaling . As AhR has previously been shown to repress Ccl2 and other chemokines in astrocytes , and given Ccl2 attracts CCR2 + monocytes , we stained for AhR and reactive astrocytes at 5 dpi (Fig ).…”

Cytochrome P450 Induction and Xeno‐Sensing Receptors Pregnane X Receptor, Constitutive Androstane Receptor, Aryl Hydrocarbon Receptor and Peroxisome Proliferator‐Activated Receptor α at the Crossroads of Toxicokinetics and Toxicodynamics

“…The specific role of AHR in the regulation of CYP1 and some other xenobiotic‐metabolizing enzymes by polycyclic aromatic hydrocarbons became apparent in the 1970s and 1980s . With a few exceptions , AHR seems to have a smaller role in regulating other CYPs, as compared especially with PXR, but regulates a number of important phase II enzymes such as specific UGT, SULT and aldo‐keto reductase (AKR) enzymes .…”

“…Additionally, AHR has been suggested as a target for potential anticancer therapies . Since the 1990s, the participation of AHR signalling pathway has been demonstrated for several endogenous functions and processes, from reproduction to senescence , and some examples are shown in table .…”

Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect sensitivity to developmental polychlorinated biphenyl exposure in mice: relevance to studies of human neurological disorders

“…The AHR is a ligand-activated transcription factor that binds to coplanar PCBs, dioxins, and polycyclic aromatic hydrocarbons and has been linked to numerous developmental and metabolic pathways, including those in the nervous system (reviewed in Nebert 2017). The AHR regulates the three members of the CYP1 family (CYP1A1, CYP1A2, and CYP1B1), which have orthologs in the mouse.…”

“…Ahr b mice have high affinity for planar molecules, whereas Ahr d mice are considered nonresponders with poor affinity for those ligands (Denison and Faber 2017; Nebert 2017). The focus of this project was to explore mechanisms of neurotoxicity in three genotypes of mice varying at the Ahr and Cyp loci by examining changes in thyroid hormone signaling and gene expression in brain regions required for normal motor function: the dorsal striatum, cerebellum, and cortex.…”