Disease relevance of AHR

• The mechanism of HAH toxicity involves altered gene expression subsequent to activation of the aryl hydrocarbon receptor (AHR), a basic helix-loop-helix-PAS transcription factor [1].
• Thus, the spatial and temporal expression of AhR and Arnt suggests that the developing myocardium and cardiac septa are potential targets of TCDD-induced teratogenicity, and such targets are also consistent with cardiac hypertrophy and septal defects observed following TCDD exposure [2].
• Since high levels of AhR ligands are found in cigarette smoke, and further since smoking is an important risk factor in both osteoporosis and periodontal disease, it may be postulated that AhR ligands are the component of cigarette smoke linking smoking to osteoporosis and periodontal disease [3].

High impact information on AHR

• These studies provide a molecular understanding of species differences in sensitivity to dioxin-like compounds and suggest an approach to using the AHR as a marker of dioxin susceptibility in wildlife [1].
• Here, we show that although chicken and tern AHRs both exhibit specific binding of [(3)H]TCDD, the tern AHR has a lower binding affinity and exhibits a reduced ability to support TCDD-dependent transactivation as compared to AHRs from chicken or mouse [1].
• Cytochrome P-450-mediated arachidonic acid metabolism in chick embryo liver microsomes was increased by both Ah receptor-dependent (2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and beta-naphthoflavone) and independent (phenobarbital) P-450 inducers [4].
• Although the heart is a principal target organ for TCDD toxicity and AhR is expressed throughout embryogenesis, induction of CYP1A was not observed in the chick heart [5].
• In contrast with polychlorinated biphenyls, Ah receptor binding affinities of PBDEs could not be related to the planarity of the molecule, possibly because the large size of the bromine atoms expands the Ah receptor's binding site [6].

Chemical compound and disease context of AHR

• One example of this is the aryl hydrocarbon receptor (AHR), a basic-helix-loop-helix (bHLH)-Per-Arnt-Sim (PAS) transcription factor through which planar aromatic hydrocarbons cause altered gene expression and toxicity [7].
• Binding by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the Ah receptor leads to transcriptional activation of several genes and a toxicity syndrome that includes tumor promotion, wasting, hormonal and immune system dysfunction, and death [8].
• It seems that the mechanism of toxicity of chlorinated chrysene in chick embryos is similar to that of the coplanar PCBs and other Ah receptor ligands [9].

Biological context of AHR

• Phylogenetic analysis of these and other AHR amino acid sequences showed that the bird and mudpuppy AHRs were more closely related to mammalian and fish AHR1 forms than to fish AHR2 [10].
• These data suggest that AhR ligands inhibit osteogenesis probably through inhibition of osteodifferentiation and that this effect can be antagonized by resveratrol [3].
• Aryl hydrocarbon receptor (AhR) ligands are environmental contaminants found in cigarette smoke and other sources of air pollution [3].
• The differential responses of chicken and Eider duck embryos were used to examine the involvement of Ah receptor-mediated enzyme induction in the activation of the environmental and food mutagen 3-amino- 1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) [11].
• 2,3,7,8-Tetrachlorodibenzo-p-dioxin elicits aryl hydrocarbon receptor-mediated apoptosis in the avian DT40 pre-B-cell line through activation of caspases 9 and 3 [12].

Anatomical context of AHR

• Two CYP enzymes induced by Ah receptor ligands were purified recently from chick embryo liver [13].
• The recombinant cell system was compared with the widely used wild-type cell line (H4IIE-wt), which expresses Ah receptor-mediated cytochrome P450 1A induction [14].
• 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and its congeners, such as 3,3',4,4'-tetrachlorobiphenyl (TCB) and 3,3',4,4'-tetrachloroazoxybenzene (TCAOB), act on targets in the immune system, probably by interacting with the Ah-receptor, causing a characteristic pattern of effects typified by inhibition of lymphoid development in the thymus [15].
• The AhR was expressed ubiquitously in cardiac myocytes, while Arnt expression was restricted to myocytes overlying developing septa: atrioventricular canal, outflow tract, and atrial and ventricular septa [2].
• The results suggest a cytochrome P450 1A (CYP1A)-mediated activation of Trp-P-1 in avian heart endothelial cells although involvement of other Ah receptor-regulated enzymes is also possible [11].

Associations of AHR with chemical compounds

• Partial AHR cDNAs encompassing the helix-loop-helix and PAS domains were cloned and sequenced [10].
• In contrast to humans and other mammals, which possess a single AHR, teleosts such as the Atlantic killifish (Fundulus heteroclitus) have at least two AHRs (AHR1 and AHR2) [7].
• Hepatic microsomal ethoxyresorufin O-deethylase-inducing potency in ovo and cytosolic Ah receptor binding affinity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: comparison of four avian species [16].
• The notable frequency of structural variation in the Ah receptor is in contrast to the analogous highly conserved steroid hormone receptors [17].
• To determine if another aryl hydrocarbon receptor agonist produced a similar response, graded doses of TCDD; 3,3',4,4',5-pentachlorobiphenyl (PeCB 126); or 2,2',4,4',5,5'-hexachlorobiphenyl (HxCB 153) were injected into WLB eggs [18].

Regulatory relationships of AHR

• CYP1A5 mRNA was expressed basally in chick embryo liver and was highly inducible by the Ah receptor ligands, 3-methylcholanthrene, beta-naphthoflavone, and 3,4,3', 4'-tetrachlorobiphenyl (TCB), but not by the phenobarbital analog, glutethimide [19].

Other interactions of AHR

• The developmental expression of CYP1A4-associated aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) activity and its association with expression of the Ah receptor had previously been characterized in chick embryo liver [19].

Analytical, diagnostic and therapeutic context of AHR

• We further show through use of chimeric AHR proteins and site-directed mutagenesis that the difference between the chicken and tern AHRs resides in the ligand-binding domain and that two amino acids (Val-325 and Ala-381) are responsible for the reduced activity of the tern AHR [1].
• Use of the gel retardation assay with a synthetic oligonucleotide indicated that in these cases the liganded Ah receptor failed to bind to the DNA recognition sequence [6].
• Fate of Ah-receptor agonists in organic household waste during anaerobic degradation--estimation of levels using EROD induction in organ cultures of chick embryo livers [20].

References