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Identifying developmental vascular disruptor compounds using a predictive signature and alternative toxicity models
Tal, T., N. Kleinstreuer, T. Toimela, R. Sarkanen, T. Heinonen, T. Knudsen, AND S. Padilla. Identifying developmental vascular disruptor compounds using a predictive signature and alternative toxicity models. Presented at Future TOX II, Chapel Hill, NC, January 16 - 17, 2014.
Identifying Developmental Vascular Disruptor Compounds Using a Predictive Signature and Alternative Toxicity Models Presenting Author: Tamara Tal Affiliation: U.S. EPA/ORD/ISTD, RTP, NC, USA Chemically induced vascular toxicity during embryonic development can result in a wide range of adverse prenatal outcomes. We constructed an embryonic vascular disruption adverse outcome pathway (AOP) based on molecular initiating events corresponding to genetic models with phenotypic evidence of abnormal embryonic vascular development in the Mouse Genome Informatics database. ToxCast high throughput screening data for 25 assays mapping to targets in the AOP were used to prioritize >1000 chemicals for their potential to disrupt vascular development. A subset of 38 chemicals were selected to test computational predictions. TG(flk1:GFP) zebrafish embryos were used to visualize and quantify blood vessel formation during development. Manual and automated methods of vessel quantification were developed, and the assay was evaluated with anti-angiogenic reference compounds PTK787 and AG1478, small molecule inhibitors of VEGFR2 and EGFR, respectively. 38 chemicals have been evaluated for overt toxicity including pesticides, flame retardants, and endocrine active compounds. The test chemicals were also evaluated in a functional angiogenesis assay comprised of a human endothelial cell and fibroblast co-culture system. Chemical rankings were well correlated among the predictive signature, zebrafish overt toxicity, and in vitro tubulogenesis assays. Taken together, the zebrafish model meets a critical need for an in vivo platform that can assess predictions generated by computational models of developmental vascular toxicity. This abstract does not necessarily reflect EPA policy.
Abstract will be presented at the Future TOXII Meeting, January 16-17, 2014, Chapel Hill, NC
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
GENETIC AND CELLULAR TOXICOLOGY BRANCH