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Event Title

Cardiovascular development/function, Altered
Short name: Cardiovascular development/function, Altered

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Aryl hydrocarbon receptor activation leading to embryolethality via cardiotoxicty KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
chicken Gallus gallus Strong NCBI
mouse Mus musculus Strong NCBI
zebrafish Danio rerio Strong NCBI

Level of Biological Organization

Biological Organization

How this Key Event works

This key event applies to the disruption of cardiogenesis early enough in embryogenesis to result in gross morphological alterations leading to reduced cardiac function.

With respect to dioxin-like compounds that are strong AHR agonists, the malformations that have been observed following embryonic exposure are summarized in table 1.

Table 1: Cardiotoxic effects of strong AHR-agonists

Zebrafish Embryo Chicken Embryo Mouse
  • Reduced extension of common cardinal vein
  • Reduced blood flow
  • Reduced heart rate
  • Disrupted erythropoiesis
  • Decreased heart volume
  • Pericardial edema
  • Overt heart malformations
  • Enlarged left ventricle
  • Increased heart rate
  • Increased myosin content
  • Reduced β-adrenergic responsiveness
  • Increased ANF mRNA
  • Arrhythmia
  • Increased apoptosis
  • Reduced myocyte proliferation
  • Pericardial edema
  • Overt heart malformations
  • Reduced heart-to-body weight
  • Reduced myocyte proliferation
  • Vascular remodeling

21 Days old

  • Increased heart-to-body weight
  • Increased left ventricle weight
  • Reduced heart rate
  • Cardiac hypertrophy
  • Increased ANF mRNA
  • Increased risk of heart disease

ANF= cardiac atrial natriuretic factor; an indicator of cardiac stress. Source: (Kopf and Walker 2009)

How it is Measured or Detected

Evidence Supporting Taxonomic Applicability

Birds, fish and mammals are all susceptible to cardiotoxicity following embryonic chemical exposure.


1. Carro, T., Dean, K., and Ottinger, M. A. (2013a). Effects of an environmentally relevant polychlorinated biphenyl (PCB) mixture on embryonic survival and cardiac development in the domestic chicken. Environ. Toxicol. Chem. 23(6), 1325-1331.

2. Carro, T., Taneyhill, L. A., and Ottinger, M. A. (2013b). The effects of an environmentally relevant 58 congener polychlorinated biphenyl (PCB) mixture on cardiac development in the chick embryo. Environ. Toxicol. Chem.

3. DeWitt, J. C., Millsap, D. S., Yeager, R. L., Heise, S. S., Sparks, D. W., and Henshel, D. S. (2006). External heart deformities in passerine birds exposed to environmental mixtures of polychlorinated biphenyls during development. Environ. Toxicol. Chem. 25(2), 541-551.

4. Heid, S. E., Walker, M. K., and Swanson, H. I. (2001). Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation. Toxicol. Sci 61(1), 187-196.

5. 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.

6. 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.

7. 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.