Relationship: 1567



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

Upstream event


Altered, Cardiovascular development/function

Downstream event


Increase, Early Life Stage Mortality

Key Event Relationship Overview


AOPs Referencing Relationship


Taxonomic Applicability


Term Scientific Term Evidence Link
mammals mammals High NCBI
fish fish High NCBI
chicken Gallus gallus High NCBI

Sex Applicability


Sex Evidence
Unspecific High

Life Stage Applicability


Term Evidence
Embryo High

Key Event Relationship Description


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 Supporting this KER


Biological Plausibility


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


  • 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


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.

Quantitative Understanding of the Linkage


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

Response-response Relationship




Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability


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.



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.