Upstream eventActivation, AhR
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Aryl hydrocarbon receptor activation leading to uroporphyria||adjacent||High||High|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
The molecular mechanism for AHR-mediated activation of gene expression is presented in Figure 1. In its unliganded form, the AHR is part of a cytosolic complex containing heat shock protein 90 (HSP90), the HSP90 co-chaperone p23 and AHR-interacting protein (AIP). Upon ligand binding, the AHR migrates to the nucleus where it dissociates from the cytosolic complex and forms a heterodimer with Ahr nuclear translocator (ARNT). The AHR-ARNT complex then binds to a xenobiotic response element (XRE) found in the promoter of an AHR-regulated gene and recruits co-regulators such as CREB binding protein/p300, steroid receptor co-activator (SRC) 1, SRC-2, SRC-3 and nuclear receptor interacting protein 1, leading to induction of gene expression.
Evidence Supporting this KER
WOE is strong for this KER.
There is a strong mechanistic understanding of AHR-mediated induction of CYP1A genes.
Include consideration of temporal concordance here
It is well established that the extent of CYP1A induction is directly proportional to the strength of ligand binding to the AHR. Two sites within the ligand binding domain (LBD)of the AHR have been identified (positions 375 and 319 in mammals; equivalent to positions 380 and 324 in birds) as being responsible for the range of binding affinities of dioxin-like compound (DLCs) and their corresponding efficacy (transactivation potential). A similar investigation in sturgeon (fish) revealed that the residue at position 388 of the LBD of AHR2 was responsible for differences in sensitivity between White Sturgeon and Lake Sturgeon, both of which are endangered species. Furthermore, Hestermann et al. described that compounds with a high intrinsic efficacy demonstrate a 1:1 relationship between AHR binding affinities and CYP1A protein induction.
Uncertainties and Inconsistencies
There are no knowledge gaps or inconsistencies/conflicting lines of evidence for this KER.
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
The relationship between chemical structure and response potencies of AHR ligands has been well studied. With additional knowledge of intrinsic efficacy, it is possible to build a computational model of receptor action to predict transactivation potential, as demonstrated by Hestermann et al.. This model was able to explain the less-than additive effect of some DLC mixtures on AHR activation. Quantitative structure-activity relationships (QSARs) have also been developed.
As mentioned above, the identity of two amino acids within the LBD of the AHR can also be used to predict transactivation sensitivity. This quality has been studied extensively in birds, resulting in the categorization of bird species into 3 groups: type 1, high sensitivity (e.g. chicken); type 2, moderate sensitivity (e.g. ring-necked pheasant); and type 3, low sensitivity (e.g. Japanese quail). Furthermore, a non-invasive method for RNA extraction using plucked feathers has been determined, making it possible to predict the sensitivity of any bird species to AHR agonists, and mediating the selection of priority species for risk assessment purposes.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Multiple AHR isoforms have been isolated and characterized in mammals, fish and birds. Mammals possess a single AHR that controls the expression of CYP1A2, while birds and fish possess 2 AHR isoforms (AHR-1 and AHR-2), with AHR-1 being homologous to the mammalian AHR. The avian orthologue to CYP1A2 is CYP1A5. Most fish species only express a single CYP1A gene.
- ↑ 1.0 1.1 1.2 Fujii-Kuriyama, Y., and Kawajiri, K. (2010). Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli. Proc.Jpn.Acad.Ser.B Phys.Biol.Sci. 86, 40-53.
- ↑ Mimura, J., and Fujii-Kuriyama, Y. (2003). Functional role of AhR in the expression of toxic effects by TCDD. Biochimica et Biophysica Acta - General Subjects 1619, 263-268.
- ↑ 3.0 3.1 Murray, I. A., Reen, R. K., Leathery, N., Ramadoss, P., Bonati, L., Gonzalez, F. J., Peters, J. M., and Perdew, G. H. (2005). Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity. Arch. Biochem. Biophys. 442 (1), 59-71.
- ↑ 4.0 4.1 4.2 Karchner, S. I., Franks, D. G., Kennedy, S. W., and Hahn, M. E. (2006). The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. U. S. A 103 (16), 6252-6257.
- ↑ 5.0 5.1 Farmahin, R., Jones, S. P., Crump, D., Hahn, M. E., Giesy, J. P., Zwiernik, M. J., Bursian, S. J., and Kennedy, S. W. (2014). Species-specific relative AHR1 binding affinities of 2,3,4,7,8-pentachlorodibenzofuran explain avian species differences in its relative potency. Comp Biochem. Physiol C. Toxicol. Pharmacol 161C, 21-25.
- ↑ Ema, M., Ohe, N., Suzuki, M., Mimura, J., Sogawa, K., Ikawa, S., and Fujii-Kuriyama, Y. (1994). Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors. J.Biol.Chem. 269, 27337-27343.
- ↑ Poland, A., Palen, D., and Glover, E. (1994). Analysis of the four alleles of the murine aryl hydrocarbon receptor. Mol.Pharmacol. 46, 915-921.
- ↑ Backlund, M., and Ingelman-Sundberg, M. (2004). Different structural requirements of the ligand binding domain of the aryl hydrocarbon receptor for high- and low-affinity ligand binding and receptor activation. Mol.Pharmacol. 65, 416-425.
- ↑ Pandini, A., Denison, M. S., Song, Y., Soshilov, A. A., and Bonati, L. (2007). Structural and functional characterization of the aryl hydrocarbon receptor ligand binding domain by homology modeling and mutational analysis. Biochemistry 46, 696-708.
- ↑ Pandini, A., Soshilov, A. A., Song, Y., Zhao, J., Bonati, L., and Denison, M. S. (2009). Detection of the TCDD binding-fingerprint within the Ah receptor ligand binding domain by structurally driven mutagenesis and functional analysis. Biochemistry 48, 5972-5983.
- ↑ Doering, J. A., Farmahin, R., Wiseman, S., Beitel, S. C., Kennedy, S. W., Giesy, J. P., and Hecker, M. (2015). Differences in activation of aryl hydrocarbon receptors of white sturgeon relative to lake sturgeon are predicted by identities of key amino acids in the ligand binding domain. Environ. Sci. Technol. 49 (7), 4681-4689.
- ↑ 12.0 12.1 Hestermann, E. V., Stegeman, J. J., and Hahn, M. E. (2000). Relative contributions of affinity and intrinsic efficacy to aryl hydrocarbon receptor ligand potency. Toxicol. Appl. Pharmacol 168 (2), 160-172.
- ↑ Gu, C., Goodarzi, M., Yang, X., Bian, Y., Sun, C., and Jiang, X. (2012). Predictive insight into the relationship between AhR binding property and toxicity of polybrominated diphenyl ethers by PLS-derived QSAR. Toxicol. Lett. 208 (3), 269-274.
- ↑ Li, F., Li, X., Liu, X., Zhang, L., You, L., Zhao, J., and Wu, H. (2011). Docking and 3D-QSAR studies on the Ah receptor binding affinities of polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). Environ. Toxicol. Pharmacol. 32 (3), 478-485.
- ↑ Farmahin, R., Manning, G. E., Crump, D., Wu, D., Mundy, L. J., Jones, S. P., Hahn, M. E., Karchner, S. I., Giesy, J. P., Bursian, S. J., Zwiernik, M. J., Fredricks, T. B., and Kennedy, S. W. (2013). Amino acid sequence of the ligand-binding domain of the aryl hydrocarbon receptor 1 predicts sensitivity of wild birds to effects of dioxin-like compounds. Toxicol. Sci. 131 (1), 139-152.
- ↑ Jones, S. P., and Kennedy, S. W. (2015). Feathers as a source of RNA for genomic studies in avian species. Ecotoxicology. 24 (1), 55-60.
- Hahn, M.E. 2002. Aryl hydrocarbon receptors: diversity and evolution. Chemico-Biol. Interact. 141, 131-160.
- Goldstone, H. M. H., and Stegeman, J. J. (2006). A revised evolutionary history of the CYP1A subfamily: Gene duplication, gene conversion, and positive selection. Journal of Molecular Evolution 62(6), 708-717.
- Rifkind, A. B. (2006). CYP1A in TCDD toxicity and in physiology - With particular reference to CYP dependent arachidonic acid metabolism and other endogenous substrates. Drug Metabolism Reviews 38(1-2), 291-335.