Upstream eventdimerization, AHR/ARNT
Increase, COX-2 expression
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2||adjacent||High||Moderate|
|Danio rerio||Danio rerio||High||NCBI|
|Oryzias latipes||Oryzias latipes||High||NCBI|
|Gallus gallus||Gallus gallus||Low||NCBI|
Life Stage Applicability
Key Event Relationship Description
- The AhR/ARNT heterodimer is able to interact with dioxin-responsive elements (DREs) on the DNA causing the up-regulation in dioxin-responsive genes (Whitlock et al 1996).
- DREs in the promoter region of COX-2 allow the AhR/ARNT heterodimer to up-regulate expression of COX-2 (Degner et al 2007; Jonsson et al 2012).
Evidence Supporting this KER
- Putative DREs have been identified in the promoter region of COX-2 in zebrafish and presumably exist in other species and taxa (Degner et al 2007; Jonsson et al 2012).
- DREs are well characterized and numerous other genes that have DREs in their promoter region are known to be up-regulated by the AhR/ARNT heterodimer (Denison et al 1988).
- Expression of COX-2 is up-regulated in response to exposure to ligands that activate AhR causing dimerization with ARNT (Dong et al 2010; Teraoka et al 2008; 2014).
- Knockdown of ARNT1 prevents interaction of AhR with DREs and the up-regulation in dioxin-responsive genes (Antkiewicz et al 2006; Prasch et al 2004).
- Depletion of ARNT lessens or prevents interaction of AhR with DREs and the up-regulation in dioxin-responsive genes (Prasch et al 2004).
- However, expressions of COX-2 have not yet been investigated following targeted knockdown of either AhR or ARNT1 preventing dimerization and interaction with DREs.
Uncertainties and Inconsistencies
- In chicken (Gallus gallus), and presumably other species of birds, COX-2 is believed to be up-regulated by the AhR through non-genomic mechanisms that are independent of the AhR/ARNT heterodimer (Fujisawa et al 2014). DREs are not believed to be present in the promoter region of COX-2 in chicken (Fujisawa et al 2014).
- However, nothing is known regarding the presence or absence of DREs in the promoter region of COX-2 in species or taxa other than zebrafish.
- Amounts of COX-2 protein have not been investigated and therefore only increases in expressions of transcript are known.
Quantitative Understanding of the Linkage
- Limited dose-response information is available regarding dimerization of AhR/ARNT leading to increased expression of COX-2.
- In Japanese medaka (Oryzias latipes), abundance of transcript of COX-2 followed a dose-dependent increase to waterborne concentrations of the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Dong et al 2010).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Dimerization of AhR/ARNT leading to increased expression of COX-2 has only been investigated in zebrafish, Japanese medaka, and chicken (Dong et al 2010; Teraoka et al 2008; 2014; Fugisawa et al 2014).
- Due to the presence of a functional AhR/ARNT pathway and COX-2 genes among all vertebrate taxa, it is acknowledged that this key event relationship is likely applicable to vertebrates in general and possibly some invertebrates.
Antkiewicz, D.S.; Burns, C.G.; Carney, S.A.; Peterson, R.E.; Heideman, W. 2005. Heart malformation is an early response to TCDD in embryonic zebrafish. Toxicol. Sci. 84, 368-377.
Degner, S.C.; Kemp, M.Q.; Hockings, J.K.; Romagnolo, D.F. (2007). Cyclooxygenase-2 promoter activation by the aromatic hydrocarbon receptor in breast cancer MCF-7 cells: Repressive effects of conjugated linoleic acid. Nutri. Canc. 56 (2), 248-257.
Denison, M.S.; Fisher, J.M.; Whitlock, J.P. (1988). The DNA recognition site for the dioxin-Ah receptor complex, Nucleotide sequence and functional analysis. J. Biol. Chem. 263, 17221-17224.
Dong, W.; Matsumura, F.; Kullman, S.W. (2010). TCDD induced pericardial edema and relative COX-2 expression in medaka (Oryzias latipes) embryos. Toxicol. Sci. 118 (1), 213-223.
Fujisaw, N.; Nakayama, S.M.M.; Ikenaka, Y.; Ishizuka, M. 2014. TCDD-induced chick cardiotoxicity is abolished by a selective cyclooxygenase-2 (COX-2) inhibitor NS398. Arch. Toxicol. 88, 1739-1748.
Jonsson, M.E.; Kubota, A.; Timme-Laragy, A.R.; Woodin, B.; Stegeman, J.J. (2012). Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish. Toxicol. Appl. Pharmacol. 265 (2), 166-174.
Prasch, A.L.; Teraoka, H.; Carney, S.A.; Dong, W.; Hiraga, T.; Stegeman, J.J.; Heideman, W.; Peterson, R.E. 2003. Toxicol. Sci. Aryl hydrocarbon receptor 2 mediated 2,3,7,8-tetrachlorodibenzo-p-dioxin developmental toxicity in zebrafish. 76 (1), 138-150.
Teraoka, H.; Kubota, A.; Kawai, Y.; Hiraga, T. (2008). Prostanoid signaling mediates circulation failure caused by TCDD in developing zebrafish. Interdis. Studies Environ. Chem. Biol. Resp. Chem. Pollut. 61-80.
Teraoka, H.; Okuno, Y.; Nijoukubo, D.; Yamakoshi, A.; Peterson, R.E.; Stegeman, J.J.; Kitazawa, T.; Hiraga, T.; Kubota, A. (2014). Involvement of COX2-thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish. Aquat. Toxicol. 154, 19-25.
Whitlock, J.P.; Okino, S.T.; Dong, L.Q.; Ko, H.S.P.; Clarke Katzenberg, R.; Qiang, M.; Li, W. 1996. Induction of cytochrome P4501A1: a model for analyzing mammalian gene transcription. Faseb. J. 10, 809-818.