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Identification of vascular disruptor compounds by 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 analysis in zebrafish embryos and mouse embryonic endothelial cells. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 70:60-69, (2017).
• 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 – This study used a zebrafish model, a mouse cell model, and a computational model to identify putative vascular disruptor compounds from the U.S. Environmental Protection Agency ToxCast Phase I chemical inventory. • Results – In the zebrafish model, 161 compounds were screened and of which 28 were confirmed as disrupting vascular development. These chemicals were then evaluated in the mouse cell model, and 22 compounds were identified that disrupted vascular development in both models. Putative mechanisms for these chemicals were examined using EPA’s Toxicological Prioritization Index tool and based on a proposed adverse outcome pathway (AOP) for developmental vascular toxicity. The chemicals identified here perturbed chemokine signaling, extracellular matrix composition and the vascular endothelial growth factor pathway. • Anticipated Impact/Expected use – In conclusion, this integrated screening approach may help identify chemicals with vascular disruptor potential.
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.
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