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Identification of vascular disruptor compounds by a tiered analysis in zebrafish embryos and mouse embryonic endothelial cells
McCollum, C., J. Conde Vancells, C. Hans, M. Vazquez-Chantada, N. Kleinstreuer, T. Tal, T. Knudsen, S. Shah, F. Merchant, R. Finnell, J. Gustafsson, R. Cabrera, AND M. Bondesson. Identification of vascular disruptor compounds by a tiered analysis in zebrafish embryos and mouse embryonic endothelial cells. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 70:60-69, (2017).
The large number of diverse chemicals in production or in the environment has motivated medium to high throughput in vitro or small animal approaches to efficiently profile chemical-biological interactions and to utilize this information to assess risks of chemical exposures on human health and the environment, particularly for reproductive toxicity testing. This study utilized an in vivo zebrafish embryo vascular model in conjunction with a mouse endothelial cell model to identify vascular disruptor compounds (VDCs) from the U.S. Environmental Protection Agency (EPA) ToxCast Phase I chemical inventory, primarily consisting of pesticides and antimicrobials. In transgenic zebrafish expressing green fluorescent protein in the vasculature, 161 compounds were screened and 34 were initially identified by visual inspection as VDCs, of which 28 were then confirmed as VDCs by quantitative image analysis. Exposure to these chemicals invoked a plethora of vascular perturbations in the zebrafish embryo, including malformed intersegmental vessels, uncondensed caudal vein plexus, hemorrhages and cardiac edema. Testing of the zebrafish VDCs for their capacity to inhibit endothelial tube formation in the murine yolk-sac-derived endothelial cell line C166 identified 22 compounds that both disrupted zebrafish vascular development and murine endothelial tubulogenesis. Putative molecular targets for the VDCs were examined using EPA’s Toxicological Prioritization Index (ToxPi) tool and a predictive signature based on a proposed adverse outcome pathway (AOP) for developmental vascular toxicity. The VDCs identified here perturbed chemokine signaling, extracellular matrix composition and the vascular endothelial growth factor (VEGF) pathway. In conclusion, our screening approach of chemicals from the ToxCast Phase I library identified 22 novel vascular disruptors across species, some of which were active at nanomolar concentrations.
This manuscript describes one aspect of a collaborative study from the Texas-Indiana Virtual STAR Center, "Data-Generating in vitro and in silico Models of Developmental Toxicity in Embryonic Stem Cells and Zebrafish" (11/01/2009 - 10/31/2013). The goal is to contribute to a more reliable chemical risk assessment through development of high throughput in vitro and in silico screening models of developmental toxicity, specifically using murine embryonic stem cells and transgenic zebrafish embryos. The results will contribute to large-scale screening efforts based on developmental vascular toxicity and systems modeling of dysmorphogenesis.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL CENTER FOR COMPUTATIONAL TOXICOLOGY