To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:1350

Relationship: 1350

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

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

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2 adjacent High Moderate Markus Hecker (send email) Open for citation & comment WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Danio rerio Danio rerio High NCBI
Oryzias latipes Oryzias latipes High NCBI
Gallus gallus Gallus gallus Low NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Embryo High
Development High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help
  • 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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help
  • 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).
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help
  • 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.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help
  • 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.

References

List of the literature that was cited for this KER description. More help

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.