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Environmental Impact on Vascular Development Predicted by High Throughput Screening
KLEINSTREUER, N. C., R. S. JUDSON, D. M. REIF, N. S. SIPES, A. V. SINGH, K. J. CHANDLER, R. DEWOSKIN, D. J. DIX, R. J. KAVLOCK, AND T. B. KNUDSEN. Environmental Impact on Vascular Development Predicted by High Throughput Screening. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 119(11):1596-1603, (2011).
This public dataset can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can help in decision-making for assessments to human developmental health and disease.
Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High throughput screening (HTS) in EPA’s ToxCastTM project provides vast data on a chemical library consisting of 309 unique compounds across over 500 in vitro assays. The present study mined the ToxCast dataset and identified signatures for potential chemical disruption of blood vessel formation and remodeling. Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen activating system were strongly perturbed, and positive correlations were found with developmental effects from the ToxRefDB in vivo database containing prenatal rat and rabbit guideline studies. Distinctly different correlative patterns were observed for chemicals with effects in rabbits versus rats, despite derivation of in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with anti-angiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here. These predictions implicate the embryonic vasculature as a target for environmental chemicals acting as putative Vascular Disruptor Compounds (pVDCs) and illuminates potential species differences in sensitive vascular developmental pathways.