Knudsen Thomas B, Kleinstreuer Nicole C
National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Birth Defects Res C Embryo Today. 2011 Dec;93(4):312-23. doi: 10.1002/bdrc.20223.
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.
21世纪的毒性测试正朝着使用高通量筛选分析方法发展，以便快速针对数百个分子靶点和生物途径测试数千种化学物质，并提供关于化学物质对人类细胞和小型模式生物影响的机制信息。第一代产前发育毒性预测模型揭示了一个复杂的生物过程网络，与血管生成和血管新生有许多联系。本综述探讨胚胎血管发育的破坏作为导致发育毒性的潜在不良结局途径。我们简要回顾胚胎血管发育以及血管发育的重要信号（局部生长因子和细胞因子，如血管内皮生长因子-A和转化生长因子-β、纤溶酶原激活系统中的成分以及趋化性趋化因子）。遗传学研究表明，干扰这些信号可导致不同程度的不良后果，从先天性血管发育异常到胎儿畸形和胚胎致死。血管发育、稳定和重塑所需的分子靶点和细胞行为适合进行体外评估。对于沙利度胺、雌激素、内皮素、二噁英、类维生素A、香烟烟雾和金属等化合物，有证据表明它们会对这些过程产生化学干扰。虽然并非所有具有发育毒性的化合物都显示出体外血管生物活性特征，但许多“推定的血管破坏化合物”会引发不良发育后果。因此，从不良结局途径的角度看待胚胎血管发育，有助于识别有用信息，以评估与风险评估相关的不良结局，并有效利用资源进行验证。
