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EMBRYONIC VASCULAR DISRUPTION ADVERSE OUTCOMES: LINKING HIGH THROUGHPUT SIGNALING SIGNATURES WITH FUNCTIONAL CONSEQUENCES
Ellis-Hutchings, R., R. Settivari, A. McCoy, N. Kleinstreuer, J. Franzosa, T. Knudsen, AND E. Carney. EMBRYONIC VASCULAR DISRUPTION ADVERSE OUTCOMES: LINKING HIGH THROUGHPUT SIGNALING SIGNATURES WITH FUNCTIONAL CONSEQUENCES. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 70:82-96, (2017). https://doi.org/10.1016/j.reprotox.2017.05.005
• Agency Research Drivers - Predicting toxicity to the embryo is important for protecting human health. Chemical exposures to the pregnant mother may impact the developing child, leading to adverse outcomes such as birth defects, childhood developmental disorders, and adult disease. To protect children’s environmental health under EDSP or TSCA, research is needed to understand how chemicals may alter development at critical windows of susceptibility. • Science Challenge – Development of the cardiovascular system is sensitive to drug or chemical perturbation and is a potential mechanism of teratogenesis. Data concerning chemical-target interactions underlying developmental vascular toxicity are limited. An integrative approach, involving computational, cellular, and animal models, is necessary to build charactierize potential impacts of environmental chemical exposures on vascular development • Research Approach – The present study evaluated two chemicals (5HPP-33 and TNP-470) across high throughput assay technology platforms. These high throughput data were compared with functional assays in rats and zebrafish. • Results – Both compounds were clearly identified as putative vascular disruptive compounds in the ToxCastDB. The functional assays confirmed disruption of angiogenesis and embryogenesis. However, the functional assays revealed differences in relative potency and adverse effects to the embryo. • Anticipated Impact/Expected use – This study demonstrates a tiered approach by which complex functional in vitro assays can be used to evaluate HTS signatures to prioritize further in vivo testing.
Embryonic vascular disruption is an important adverse outcome pathway (AOP) given the knowledge that chemical disruption of early cardiovascular system development leads to broad prenatal defects. High throughput screening (HTS) assays provide potential building blocks for AOP development although linking these in vitro data to in vivo apical endpoints remains challenging. The present study evaluated two anti-angiogenic agents, 5HPP-33 and TNP-470, across ToxCastDB (> 870 assay endpoints from 11 high throughput assay technology platforms pointing to a range of high-level cell responses and approximately 300 signaling pathways) and anchored the results from in vitro profiling to three complex in vitro functional assays: the rat aortic explant assay (AEA), rat whole embryo culture (WEC), and the zebrafish embryotoxicity (ZET) assay. Both compounds were clearly identified as putative vascular disruptive compounds (pVDCs) in the ToxCastDB and confirmed by the functional assays for disruption of angiogenesis and embryogenesis. However, the functional assays revealed differences in their relative potency and adverse effects to the embryo. Whereas 5HPP-33 was embryolethal in WEC and ZET assays, TNP-470 produced caudal extension defects at lower concentrations. This study demonstrates a tiered approach by which complex functional in vitro assays can be used to evaluate HTS signatures to prioritize further in vivo testing.