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Relationship: 1567

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

Altered, Cardiovascular development/function leads to Increase, Early Life Stage Mortality

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Altered, Cardiovascular development/function

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Early Life Stage Mortality

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 reduced VEGF	adjacent	High	Low	Arthur Author (send email)	Open for citation & comment	WPHA/WNT Endorsed
Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2	adjacent	High	Low	Allie Always (send email)	Open for citation & comment	WPHA/WNT Endorsed
Aryl hydrocarbon receptor activation leading to early life stage mortality via sox9 repression induced cardiovascular toxicity	adjacent	High	Low	Allie Always (send email)	Under development: Not open for comment. Do not cite	Under Review

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
mammals	mammals	High	NCBI
fish	fish	High	NCBI
chicken	Gallus gallus	High	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

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

Changes in heart morphology can result in decreased cardiac output and are associated with myocardial disease, abnormalities in cardiac loading, rhythm disorders, ischemia (restriction in blood supply to tissues, causing a shortage of oxygen and glucose needed for cellular metabolism), and cardiac compression. Severe cardiac dysfunction can result in congestive fetal heart failure (inability of the heart to deliver adequate blood flow to organs) leading to fluid build-up in tissues and cavities (edema and effusion, respectively). Fluid buildup exerts a positive pressure on fetal cardiac chambers, which further limits the diastolic ventricular filling reserve, potentiating the diminished cardiac output and leading to fetal death (Thakur et al. 2013).

It remains unclear whether edema plays an essential role in causing fetal death, or whether it simply accelerates the rate of deterioration; nonetheless, it is a reliable indicator of cardiotoxicity.

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

The connection between altered cardiovascular developement during embryogenesis, diminished cardiac output and embryonic death have been well studied (Thakur et al. 2013; kopf and Walker 2009)

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. More help

The most common cause of infant death due to birth defects is congenital cardiovascular malformation (Kopf and Walker 2009)
At low doses of dioxin-like compounds, disrupted heart looping (Henshel et al. 1993), congenital heart defects, (Cheung et al. 1981) and impaired contraction of cardiac myocytes (Canga et al. 1993) were observed in chick embryos without the onset of edema. Whereas at higher doses edema and embryo death are increased (Walker et al. 1997).
Changes in heart morphology consistent with dilated cardiomyopathy (decreased cardiac output and ventricular cavity expansion) were observed in chick embryos exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) followed by progression to congestive heart failure.
Changes in heart morphology and decreases in cardiac output and peripheral blood flow precede heart failure in Zebrafish (Antkiewicz et al. 2005; Belair et al. 2001; Henry et al. 1997; Plavicki et al. 2013)
When mannitol is used as a protective agent against chemical-induced edema in zebrafish, cardiotoxic effects are still observed; therefore, edema is secondary to cardiotoxicity (Antkiewicz et al. 2005; Plavicki et al. 2013)
Edema is a hallmark sign of cardio-developmental toxicity in fish, chick, and mammalian species exposed to strong AHR agonists early in embryogenesis (Carney et al. 2006)
- Note that it presents as pericardial and yolk sac edema in fish, pericardial, peritoneal and subcutaneous edema on chicks, and peritoneal and subcutaneous edema in mice.

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

There is no doubt that severely altered cardiovascular development early in embryogenesis causes embryonic death, however the precise sequence of events leading to heart failure remains to be elucidated.

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

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. More help

The extent of remodeling and reduction in cardiac output required to cause fatality has not been determined.

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

Cardiovasular remodelling and cardiac failure leading to embryo death has been observed in mammals (kopf and Walker 2009, Thakur et al.2013), fish (kopf and Walker 2009) and chickens (kopf and Walker 2009). Although the chick is preferenrially used as a lab model for developemental studies, this KER likely extends to other avian species aswell.

References

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

1. Thakur, V., Fouron, J. C., Mertens, L., and Jaeggi, E. T. (2013). Diagnosis and management of fetal heart failure. Can. J Cardiol. 29(7), 759-767.

2. Kopf, P. G., and Walker, M. K. (2009). Overview of developmental heart defects by dioxins, PCBs, and pesticides. J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol. Rev. 27(4), 276-285.

3. Antkiewicz, D. S., Burns, C. G., Carney, S. A., Peterson, R. E., and Heideman, W. (2005). Heart malformation is an early response to TCDD in embryonic zebrafish. Toxicol. Sci. 84(2), 368-377.

4. Belair, C. D., Peterson, R. E., and Heideman, W. (2001). Disruption of erythropoiesis by dioxin in the zebrafish. Dev. Dyn. 222(4), 581-594.

5. Canga, L., Paroli, L., Blanck, T. J., Silver, R. B., and Rifkind, A. B. (1993). 2,3,7,8-tetrachlorodibenzo-p-dioxin increases cardiac myocyte intracellular calcium and progressively impairs ventricular contractile responses to isoproterenol and to calcium in chick embryo hearts. Mol. Pharmacol. 44(6), 1142-1151.

6. Cheung, M. O., Gilbert, E. F., and Peterson, R. E. (1981). Cardiovascular teratogenicity of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin in the chick embryo. Toxicol. Appl. Pharmacol. 61(2), 197-204.

7. Henry, T. R., Spitsbergen, J. M., Hornung, M. W., Abnet, C. C., and Peterson, R. E. (1997). Early life stage toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in zebrafish (Danio rerio). Toxicol. Appl. Pharmacol. 142(1), 56-68.

8. Henshel, D. S., Hehn, B. M., Vo, M. T., and Steeves, J. D. (1993). A short-term test for dioxin teratogenicity using chicken embryos. In Environmental Toxicology and Risk Assessment: Volume 2 (J.W.Gorsuch, F.J.Dwyer, C.G.Ingersoll, and T.W.La Point, Eds.), pp. 159-174. American Society of Testing and materials, Philedalphia.

9. Plavicki, J., Hofsteen, P., Peterson, R. E., and Heideman, W. (2013). Dioxin inhibits zebrafish epicardium and proepicardium development. Toxicol. Sci. 131(2), 558-567.

10. Carney, S. A., Prasch, A. L., Heideman, W., and Peterson, R. E. (2006). Understanding dioxin developmental toxicity using the zebrafish model. Birth Defects Res. A Clin Mol. Teratol. 76(1), 7-18.

11. Walker, M. K., and Catron, T. F. (2000). Characterization of cardiotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chemicals during early chick embryo development. Toxicol. Appl. Pharmacol. 167(3), 210-221.

12. Walker, M. K., Pollenz, R. S., and Smith, S. M. (1997). Expression of the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator during chick cardiogenesis is consistent with 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced heart defects. Toxicol. Appl. Pharmacol. 143(2), 407-419.