Environmental impact on vascular development predicted by high-throughput screening.
Environmental impact on vascular development predicted by high-throughput screening.
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DOI：
10.1289/ehp.1103412
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发表时间：
2011-11
影响因子：
10.4
通讯作者：
Knudsen TB
中科院分区：
文献类型：
--
作者：
Kleinstreuer NC;Judson RS;Reif DM;Sipes NS;Singh AV;Chandler KJ;Dewoskin R;Dix DJ;Kavlock RJ;Knudsen TB
背景资料：了解暴露于环境化学品对胚胎发育的健康风险是一项重大挑战，因为这些化合物的化学景观多种多样，数据匮乏。美国环境保护署（EPA）ToxCast™项目中的高通量筛选（HTS）提供了关于不断扩大的化学库的大量数据，该化学库目前由I期（完成）和II期（正在进行）中的> 500种体外试验中的> 1，000种独特化合物组成。这一公开数据集可用于评估对许多不同生物靶点的浓度依赖性效应，并建立原型毒性途径的预测模型，以帮助做出评估人类发育健康和疾病的决策。目的：我们挖掘ToxCast I期数据集，以识别血管形成和重塑的潜在化学破坏的特征。方法：ToxCast第一阶段使用9种检测技术平台的467种HTS检测方法筛选了309种化学品。该分析测量化学品和分子靶标（受体、酶）之间的直接相互作用，以及对报告基因活性或细胞后果的下游影响。我们根据个体血管生物活性评分对化学品进行了排名，并使用ToxPi（毒理学优先指数）曲线对排名进行了可视化。结果如下：炎症趋化因子信号传导、血管内皮生长因子途径和纤溶酶原激活系统中的靶点受到某些化学物质的强烈干扰，我们发现与美国EPA ToxRefDB（毒理学参考数据库）体内数据库（包含产前大鼠和家兔指南研究）中的发育效应呈正相关。我们观察到明显不同的相关模式的化学品与兔与大鼠的影响，尽管衍生的体外签名的基础上，人类细胞和无细胞的生化目标，这意味着保护，但物种之间的发展途径的潜在差异贡献。抗血管生成沙利度胺类似物和其他体外血管靶点的后续分析显示，体外活性与此处测试的最活跃的环境化学品一致。结论：我们预测，血管的发展是一个目标的环境化学品作为假定的血管干扰化合物（pVDC），并确定了潜在的物种差异敏感的血管发育途径。
Background: 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 the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of > 1,000 unique compounds across > 500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease. Objective: We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling. Methods: ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles. Results: Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U.S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns 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 antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here. Conclusions: We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways.
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影响因子：
7.5
作者：
Li M;Huang SJ
通讯作者：
Huang SJ
影响因子：
--
作者：
Houck, Keith A.;Dix, David J.;Berg, Ellen L.
通讯作者：
Berg, Ellen L.
影响因子：
7.4
作者：
Hansen, JM;Choe, HS;Harris, C
通讯作者：
Harris, C
影响因子：
56.9
作者：
Ito, Takumi;Ando, Hideki;Handa, Hiroshi
通讯作者：
Handa, Hiroshi
DOI：
10.1161/atvbaha.108.162925
发表时间：
2008-11
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Keeley EC;Mehrad B;Strieter RM
通讯作者：
Strieter RM