Relationship: 1350



dimerization, AHR/ARNT leads to Increase, COX-2 expression

Upstream event


dimerization, AHR/ARNT

Downstream event


Increase, COX-2 expression

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Directness Weight of Evidence Quantitative Understanding
AhR activation leading to early life stage mortality directly leads to Strong Moderate

Taxonomic Applicability


Term Scientific Term Evidence Link
Danio rerio Danio rerio Strong NCBI
Oryzias latipes Oryzias latipes Strong NCBI
Gallus gallus Gallus gallus Weak NCBI

Sex Applicability


Sex Evidence
Unspecific Strong

Life Stage Applicability


Term Evidence
Embryo Strong
Development Strong

How Does This Key Event Relationship Work


  • 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). 

Weight of Evidence


Biological Plausibility


  • 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).

Empirical Support for Linkage


  • 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 or 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).

Evidence Supporting Taxonomic 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.