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Constructing, Quantifying, and Validating an Adverse Outcome Pathway for Vascular Developmental Toxicity
Citation:
Kleinstreuer, N., T. Knudsen, T. Tal, T. Heinonen, J. Franzosa, N. Baker, S. Padilla, E. Carney, AND W. CASEY. Constructing, Quantifying, and Validating an Adverse Outcome Pathway for Vascular Developmental Toxicity. Presented at World Congress on Alternatives and Animal use in the Life Sciences, Prague, CZECH REPUBLIC, August 24 - 28, 2014.
Impact/Purpose:
This work describes the development of a proposed adverse outcome pathway for vascular development and the testing of the AOP using many different approaches.
Description:
Constructing, Quantifying, and Validating an Adverse Outcome Pathway for Vascular Developmental Toxicity The adverse outcome pathway (AOP) for embryonic vascular disruption1 leading to a range of adverse prenatal outcomes was recently entered into the AOP wiki and accepted as part of the OECD workplan. This talk will explain how the AOP was built based on molecular initiating events (MIEs) corresponding to genes from critical pathways (hypoxia/growth factor signaling, chemokine networks, extracellular matrix interactions and vessel remodeling/stabilization) with evidence of abnormal embryonic vascular development in the mammalian phenotype browser of the Mouse Genome Informatics database (http://www.informatics.jax.org/). ToxCast high throughput screening (HTS) data2 for assays mapping to targets in the AOP were used to prioritize >1000 chemicals for their potential to disrupt vascular development. A subset of these chemicals are being further tested in a wide range of systems. Preliminary results from functional validation of AOP targets, quantification of MIEs and key cellular events3, and compound hazard predictions will be discussed. This abstract does not necessarily reflect EPA policy. This project was funded in whole or in part with Federal funds from the EPA, CSS Research Program, Lockheed-Martin, and NIEHS, NIH under Contract No.HHSN27320140003C. References 1Knudsen, T. B. & Kleinstreuer, N. C. Disruption of embryonic vascular development in predictive toxicology. Birth Defects Res C Embryo Today 93, 312-323, doi:10.1002/bdrc.20223 (2011). 2Kavlock, R. et al. Update on EPA's ToxCast program: providing high throughput decision support tools for chemical risk management. Chemical research in toxicology 25, 1287-1302, doi:10.1021/tx3000939 (2012). 3Kleinstreuer, N. et al. A computational model predicting disruption of blood vessel development. PLoS computational biology 9, e1002996, doi:10.1371/journal.pcbi.1002996 (2013).