2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons pose a significant health risk to fish and wildlife, as well as to humans. The developing embryo is generally the most sensitive stage of an organism to the toxic effects of TCDD. In developing zebra fish, the most prominent signs of TCDD exposure are pericardial and yolk sac edema. In many other fish species, the vascular endothelium has been found to be highly sensitive to induction of cytochrome P4501A (CYP1A) by TCDD and vascular permeability is increased by TCDD in lake trout larvae. The overarching hypothesis to be tested in this proposal is that edema in TCDD exposed zebra fish larvae is the result of adverse effects of TCDD in the vascular endothelium. Four hypotheses to be tested in the developing zebra fish are that: (1) the dose-response relationship for TCDD induced CYPIA expression in the vascular endothelium correlates to that for edema, (2) TCDD exposure increases vascular permeability, either overall or within specific tissues, (3) TCDD exposure causes premature regression of specific vessels that normally regress during development resulting in edema, and (4) transgenic zebra fish constitutively expressing elevated levels of CYP1A in the vascular endothelium will develop edema without TCDD exposure. The knowledge gained through testing each of these hypotheses will provide insight into endothelium-specific mechanisms of TCDD toxicity.
| Bello, S M; Heideman, W; Peterson, R E (2004) 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits regression of the common cardinal vein in developing zebrafish. Toxicol Sci 78:258-66 |
