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Relationship: 1351
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).
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Increase, COX-2 expression leads to Altered, Cardiovascular development/function
Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER).
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Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER).
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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.
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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 | Moderate | Moderate | Allie Always (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.
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Sex Applicability
An indication of the the relevant sex for this KER.
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| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
An indication of the the relevant life stage(s) for this KER.
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| 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.
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- The precise role that COX-2 plays in altered cardiovascular development/function has not been investigated. However, the prostaglandin synthesis pathway, of which COX-2 is a rate limiting step, is known to have roles in development of the heart (Dong et al 2010; Huang et al 2007; Teraoka et al 2008; 2014).
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.
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Evidence Supporting this KER
Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP.
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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.
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- The prostaglandin synthesis pathway, of which COX-2 is a rate limiting step, is known to have roles in development of the heart and therefore altered levels of expression of COX-2 could be expected to result in altered development of the heart.
Empirical Evidence
Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient.
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- Blocking induction of COX-2 through knockdown of COX-2 or through selective antagonists of COX-2 in zebrafish, Japanese medaka (Oryzias latipes), and chicken (Gallus gallus) prevents alteration in cardiovascular development and function by 2,3,7,8-TCDD, including prevention of pericardial edema, changes in heart size, and reduction in blood blow (Dong et al 2010; Teraoka et al 2008; 2014).
- Knockdown of and selective antagonists of thromboxane A synthase 1 (CYP5A), which is down-stream of COX-2 in the prostaglandin synthesis pathway, prevents alteration in cardiovascular development and function by 2,3,7,8-TCDD (Teraoka et al 2008).
COX-2 Cardiovascular Development Roles:
- Transgenic mice (Mus musculus) that over express COX-2 display altered cardiac remodeling that results in cardiomyocyte hypertrophy (Streicher et al 2010). However, significantly impaired cardiac function was not observed in the strain of transgenic mice investigated in this study (Streicher et al 2010).
- Embryos of zebrafish (Danio rerio) exposed to the COX-2 inducers, aristolochic acid and doxorubicin, develop hypertrophy of the heart, disorganization of cardiomyocytes, and loss of endocardium (Huang et al 2007). These effects result in reduced function of the heart and eventually cause death in zebrafish (Huang et al 2007).
- COX-2 has also been demonstrated to have roles in cardiovascular development in humans, chicken (Gallus gallus), and Japanese medaka (Oryzias latipes) (Fujisawa et al 2014; Gullestad & Aukrust 2005; Hocherl et al 2002; Huang et al 2007; Wong et al 1998).
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.
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- Intermediary steps between increased expression of COX-2 and altered heart development and function have not been investigated.
- The precise role of COX-2 and the prostaglandin synthesis pathway in early development of the heart is not 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.
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Quantitative Understanding of the Linkage
Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE.
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- There is an R2 of 0.84 between relative COX-2 mRNA and altered heart development measured as pericardial area in embryos of Japanese medaka exposed to the COX-2 inducer, 2,3,7,8-teterachlorodibenzo-p-dioxin (TCDD) (Dong et al 2010).
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.
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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?).
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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.
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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.
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- Links between induction of COX-2 and alteration of cardiovascular development and function has only been demonstrated in zebrafish, Japanese medaka, and chicken (Dong et al 2010; Teraoka et al 2008; 2014).
- However, it is acknowledged that this key event relationship could be applicable to all vertebrate taxa and some invertebrate taxa based on presence of COX-2 genes and a cardiovascular system.
References
List of the literature that was cited for this KER description.
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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.
Huang, C.C.; Chen, P.C.; Huang, C.W.; Yu, J. (2007). Aristolochic acid induces heart failure in zebrafish embryos that is mediated by inflammation. Toxicol. Sci. 100, 486-494.
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.