Event: 317

Key Event Title


Altered, Cardiovascular development/function

Short name


Altered, Cardiovascular development/function

Biological Context


Level of Biological Organization

Organ term


Organ term

Key Event Components


Process Object Action
abnormal cardiovascular system physiology morphological change
cardiovascular system development cardiovascular system abnormal

Key Event Overview

AOPs Including This Key Event


AOP Name Role of event in AOP
AHR activation to ELS mortality, via VEGF KeyEvent
AhR mediated mortality, via COX-2 KeyEvent



Taxonomic Applicability


Term Scientific Term Evidence Link
Vertebrates Vertebrates High NCBI
Invertebrates Invertebrates High NCBI

Life Stages


Life stage Evidence
Embryo High

Sex Applicability


Term Evidence
Unspecific High

Key Event Description


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

How It Is Measured or Detected


Altered cardiovascular development/function can be measured in numerous ways:

1) As blood flow in the mesencephalic vein by use of time-lapse recording using a digital video camera (Teraoka et al 2008; 2014). Blood flow is measured as the number of red blood cells passing the mesencephalic vein per second (Teraoka et al 2008; 2014). This method is described in detail by Teraoka et al (2002). However, some studies have assessed blood flow through visualized scoring techniques by use of a microscope as (1) same rate as control, (2) slower rate than control, or (3) no flow (Henry et al 1997).

2) As heart area, pericardial edema area, or yolk sac edema area quantified with area analysis by use of a microscope linked digital camera and conventional image software (Dong et al 2010; Teraoka et al 2008; 2014; Yamauchi et al 2006). Images at the same magnification are used to obtain the area measured as number of pixels (Teraoka et al 2008; 2014). This method can use either live individuals or histologic samples. This method is described in detail by Teraoka et al (2003).

3) As basic physical measurements such as heart weight, heart aspect ratio (horizontal length versus vertical length), heart weight to body weight ratio (Fujisawa et al 2014).

4) As incidence of malformation measured as percent occurrence among individuals (Buckler et al 2015; Dong et al 2010; Park et al 2014; Yamauchi et al 2006).This method is described in detail by Dong et al (2010).

5) As heartbeat rate measured by direct observation by use of a microscope (Park et al 2014). This method is described in detail by Park et al (2014).

Domain of Applicability


  • Some form of cardiovascular system is present in members of the clade Bilateria (Bishopric 2005). This clade includes most animal phyla, except for sponges (Porifera), jellyfishes and corals (Cnidaria), placozoans (Placozoa), and comb jellies (Ctenophora).
  • Differences in cardiovascular systems are present among taxa. Vertebrates have closed circulatory systems, while some invertebrate taxa have open circulatory systems (Kardong 2006).

Evidence for Perturbation by Stressor



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.

Bishopric, N.H. (2005). Evolution of the heart from bacteria to man. Ann. N. Y. Acad. Sci. 1047, 13-29.


Buckler J.; Candrl, J.S.; McKee, M.J.; Papoulias, D.M.; Tillitt, D.E.; Galat, D.L. Sensitivity of shovelnose sturgeon (Scaphirhynchus platorynchus) and pallid sturgeon (S. albus) early life stages to PCB-126 and 2,3,7,8-TCDD exposure. Enviro. Toxicol. Chem. 2015, 34(6), 1417-1424.


Carney, S.A.; Prasch, A.L.; Heideman, W.; Peterson, R.E. 2006. Understanding dioxin developmental toxicity using the zebrafish model. Birth Defects Research. A. 76, 7-18.


Cohen-Barnhouse, A.M.; Zwiernik, M.J.; Link, J.E.; Fitzgerald, S.D.; Kennedy, S.W.; Herve, J.C.; Giesy, J.P.; Wiseman, S.; Yang, Y.; Jones, P.D.; Yi, W.; Collins, B.; Newsted, J.L.; Kay, D.; Bursian, S.J. 2011. Sensitivity of Japanese quail (Coturnix japonica), common pheasant (Phasianus colchicus), and white leghorn chicken (Gallus gallus domesticus) embryos to in ovo exposure to TCDD, PeCDF, and TCDF. Toxicol. Sci. 119, 93-102.


Elonen, G.E.; Spehar, R.L.; Holcombe, G.W.; Johnson, R.D.; Fernandez, J.D.; Erickson, R.J.; Tietge, J.E.; Cook, P.M. Comparative toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin to seven freshwater fish species during early life-stage development. Enviro. Toxico. Chem. 1998, 17, 472-483.


Goldstone, H.M.H.; Stegeman, J.J. (2008). Molecular mechanisms of 2,3,7,8-tetrachlorodibenzo-p-dioxin cardiovascular embryotoxicity. Drug. Metab. Rev. 38, 261-289.


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


Huang, L.; Wang, C.; Zhang, Y.; Li, J.; Zhong, Y.; Zhou, Y.; Chen, Y.; Zuo, Z. (2012). Benzo[a]pyrene exposure influences the cardiac development and the expression of cardiovascular relative genes in zebrafish (Daniorerio) embryos. Chemosphere. 87 (4), 369-375.


Johnson, R.D.; Tietge, J.E.; Jensen, K.M.; Fernandez, J.D.; Linnum, A.L.; Lothenbach, D.B.; Holcombe, G.W.; Cook, P.M.; Christ, S.A.; Lattier, D.L.; Gordon, D.A. Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin to early life stage brooke trout (Salvelinus fontinalis) following parental dietary exposure. Enviro. Toxicol. Chem. 1998, 17 (12), 2408-2421.


Kardong, K.V. (2006). Vertebrates: comparative anatomy, function, evolution. McGraw-Hill Higher Eduction. Boston, USA.


Lemly, A.D. (2002). Symptoms and implications of selenium toxicity in fish: the Belews Lake case example. Aquat. Toxicol. 57 (1-2), 39-49.


Park, Y.J.; Lee, M.J.; Kim, H.R.; Chung, K.H.; Oh, S.M. Developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in artificially fertilized crucian carp (Carassius auratus) embryo. Sci. Totl. Enviro. 2014, 491-492, 271-278.

Teraoka, H.; Dong, W.; Hiraga, T. (2003). Zebrafish as a novel experimental model for development toxicology. Congenit. Anom. 43, 123-132.


Teraoka, T.; Dong, W.; Ogawa, S.; Tsukiyama, S.; Okuhara, Y.; Niiyama, M.; Ueno, N.; Peterson, R.E. (2002). 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in the zebrafish embryo: Altered regional blood flow and impaired lower jaw development. Toxicol. Sci. 65, 192-199.


Tillitt, D.E.; Buckler, J.A.; Nicks, D.K.; Candrl, J.S.; Claunch, R.A.; Gale, R.W.; Puglis, H.J.; Little, E.E.; Linbo, T.L.; Baker, M. Sensitivity of lake sturgeon (Acipenser fulvescens) early life stages to 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3,3’,4,4’,5-pentachlorobiphenyl. 2015. Enviro. Toxicol. Chem. DOI: 10.1002/etc.3614.


Toomey, B.H.; Bello, S.; Hahn, M.E.; Cantrell, S.; Wright, P.; Tillitt, D.; Di Giulio, R.T. TCDD induces apoptotic cell death and cytochrome P4501A expression in developing Fundulus heteroclitus embryos. Aquat. Toxicol. 2001, 53, 127-138.


Walker, M.K.; Spitsbergen, J.M.; Olson, J.R.; Peterson, R.E. 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) toxicity during early life stage development of lake trout (Salvelinus namaycush). Canad. J. Fisheries Aqua. Sci. 1991, 48, 875-883.


Yamauchi, M.; Kim, E.Y.; Iwata, H.; Shima, Y.; Tanabe, S. Toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in developing red seabream (Pagrus major) embryos: an association of morphological deformities with AHR1, AHR2 and CYP1A expressions. Aquat. Toxicol. 2006, 16, 166-179.


Zabel, E.W; Cook, P.M.; Peterson, R.E. Toxic equivalency factors of polychlorinated dibenzo-p-dioxin, dibenzofuran and biphenyl congeners based on early-life stage mortality in rainbow trout (Oncorhynchus mykiss). Aquat Toxicol. 1995. 31, 315-328.