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Developing an Experimental Model of Vascular Toxicity in Embryonic Zebrafish
Citation:
Tal, T. Developing an Experimental Model of Vascular Toxicity in Embryonic Zebrafish. Presented at Society of Toxicology meeting, October 04, 2012.
Impact/Purpose:
presentation for Society of Toxicology meeting October 4, 2012, RTP, NC
Description:
Developing an Experimental Model of Vascular Toxicity in Embryonic Zebrafish Tamara Tal, Integrated Systems Toxicology Division, U.S. EPA Background: There are tens of thousands of chemicals that have yet to be fully evaluated for their toxicity by validated in vivo testing paradigms [1]. As such, there is a substantial need for rapid, cost-effective approaches to prioritize chemicals for further testing, particularly in the realm of developmental toxicity. The vascular system is the first functional organ to develop in the mammalian embryo. It is sensitive to chemical perturbation and vascular toxicity is associated with adverse developmental outcomes including embryo resorption, fetal weight reduction, and skeletal defects [2, 3]. The vascular system forms by de novo synthesis of blood vessels or by angiogenic sprouting from preexisting blood vessels. Angiogenesis relies on a complex set of biological process including endothelial cell differentiation, migration and proliferation, extracellular matrix remodeling, and tube formation [4]. These processes are governed by a constellation of molecular signaling pathways [5] that are sensitive to disruption by environmental chemicals [2, 3, 6, 7] The relationship between environmental chemicals, vascular toxicicty and developmental outcomes has been the focus of recent computational modeling efforts [2, 3]. Using ToxCast data generated in hundreds of cell-based and biochemical assays and following exposure to 309 environmental chemicals, Kleinstreuer et al. predicted a number of environmental chemicals to exert toxicity in developing blood vessels by disruption of key molecular pathways that control angiogenesis [2]. Thus, there is an outstanding need to test predictions generated by the computational vascular toxicity model in a relevant in vivo experimental system. To tackle this problem, we used embryonic zebrafish – a transparent vertebrate model of developmentally toxicity with a rapid developmental profile and substantial genetic homology with mammals [8]. Here, transgenic zebrafish that express enhanced green fluorescent protein in blood vessels were used to visualize and quantify blood vessel formation during development in order to generate a quantitative in vivo model of vascular toxicity. Results: A uniform region of angiogenic intersegmental vessels (ISVs) was targeted for analysis wherein inter- and intra-vessel length was not significantly different among unexposed larvae (Figure 1A). Manual and automated methods of ISV quantification (Figure 1A-B) were developed to generate an in vivo angiogenesis assay. THIS ABSTRACT DOES NOT NECESSARILY REFLECT EPA POLICY.