Upstream eventIncrease, COX-2 expression
Altered, Cardiovascular development/function
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2||adjacent||Moderate||Moderate|
|Danio rerio||Danio rerio||High||NCBI|
|Oryzias latipes||Oryzias latipes||High||NCBI|
|Gallus gallus||Gallus gallus||High||NCBI|
Life Stage Applicability
Key Event Relationship Description
- 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 Supporting this KER
- 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.
- 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
- 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.
Quantitative Understanding of the Linkage
- 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).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- 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.
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.