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Increase, COX-2 expression leads to Altered, Cardiovascular development/function
Key Event Relationship Overview
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 increased COX-2||adjacent||Moderate||Moderate||Allie Always (send email)||Open for citation & comment||WPHA/WNT Endorsed|
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 Collection Strategy
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.
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.
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.