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Disruption of Embryonic Vascular Development in Predictive Toxicology
Citation:
KNUDSEN, T. B. AND N. C. KLEINSTREUER. Disruption of Embryonic Vascular Development in Predictive Toxicology. Anthony M. DeLise (Guest Editor) (ed.), Birth Defects Research, Part C: Embryo Today: Reviews. John Wiley & Sons, Ltd., Indianapolis, IN, 93(4):312-323, (2011).
Impact/Purpose:
First-generation predictive models for prenatal developmental toxicity from HTS have predicted a complex web of biological processes with many connections to important signals for vascular development (local growth factors and cytokines such as VEGF-A and TGF-beta, components in the plasminogen activator system, and chemotactic chemokines). Evidence for environmental disruption of these processes is accumulating for a number of mechanistically diverse compounds. Although not all environmental chemicals with developmental toxicity show an in vitro vascular bioactivity signature, many ‘putative Vascular Disruptor Compounds’ (pVDCs) invoke adverse developmental consequences. For a subset of these chemicals, the disruption of blood vessel development may be part of an AOP that can be applied to predictive toxicology and mechanistic modeling of prenatal developmental toxicity. As such, an AOP perspective of embryonic vascular development can help identify useful information for assessing adverse outcomes relevant to risk assessment and efficient use of resources for validation.
Description:
Toxicity testing in the 21st century is moving toward using high-throughput screening assays to rapidly test thousands of chemicals against hundreds of molecular targets and biological pathways, and to provide mechanistic information on chemical effects in human cells and small model organisms. First-generation predictive models for prenatal developmental toxicity have revealed a complex web of biological processes with many connections to vasculogenesis and angiogenesis. This review examines disruption of embryonic vascular development as a potential adverse outcome pathway leading to developmental toxicity. We briefly review embryonic vascular development and important signals for vascular development (local growth factors and cytokines such as vascular endothelial growth factor-A and TGF-beta, components in the plasminogen activator system, and chemotactic chemokines). Genetic studies have shown that perturbing these signals can lead to varying degrees of adverse consequences, ranging from congenital angiodysplasia to fetal malformations and embryolethality. The molecular targets and cellular behaviors required for vascular development, stabilization and remodeling are amenable to in vitro evaluation. Evidence for chemical disruption of these processes is available for thalidomide, estrogens, endothelins, dioxin, retinoids, cigarette smoke, and metals among other compounds. Although not all compounds with developmental toxicity show an in vitro vascular bioactivity signature, many ‘putative vascular disruptor compounds’ invoke adverse developmental consequences. As such, an adverse outcome pathway perspective of embryonic vascular development can help identify useful information for assessing adverse outcomes relevant to risk assessment and efficient use of resources for validation.
