Impact of Environmental Chemicals on Key Transcription Regulators and Correlation to Toxicity End Points within EPA's ToxCast Program
Impact of Environmental Chemicals on Key Transcription Regulators and Correlation to Toxicity End Points within EPA's ToxCast Program
复制标题
DOI：
10.1021/tx900325g
复制
发表时间：
2010-03-01
影响因子：
4.1
通讯作者：
Houck, Keith A.
中科院分区：
文献类型：
--
作者：
Martin, Matthew T.;Dix, David J.;Houck, Keith A.
接触环境化学品会增加人类和野生动物的疾病负担，其程度难以估计，因此难以减轻。迫切需要有能力评估现有化学品的影响，因为这些化学品的毒性数据很少或根本没有，或者在化学品开发和使用的早期阶段以及在可能的接触发生之前预测这种影响。然而，目前的毒性评价方法，以满足这一需求的能力是有限的低通量和高成本。在EPA的ToxCast项目的背景下，我们评估了一种新型细胞生物传感器系统（Factorial（1）），该系统能够快速，高内容地评估化合物对基因调控网络的影响。Factorial生物传感器将顺式和陷阱调节的转录因子报告构建体的文库与高度均质的检测方法相结合，从而能够同时评估多重转录因子活性。在这里，我们展示了该技术的应用，确定生物活性配置文件，通过定量评估309环境化学品对25个核受体和48个转录因子反应元件的影响。我们证明了跨核受体及其反应元件的连贯转录因子活性，并且Nrf2活性（氧化应激的标志物）与化学物质的整体混杂性高度相关。此外，作为ToxCast计划的一部分，我们确定了与体内终点相关的分子靶点，并代表了可以作为潜在毒性途径生物标志物和体内毒性预测建模输入的作用模式。
Exposure to environmental chemicals adds to the burden of disease in humans and wildlife to a degree that is difficult to estimate and, thus, mitigate. The ability to assess the impact of existing chemicals for which little to no toxicity data are available or to foresee such effects during early stages of chemical development and use, and before potential exposure occurs, is a pressing need. However, the capacity of the current toxicity evaluation approaches to meet this demand is limited by low throughput and high costs. In the context of EPA's ToxCast project, we have evaluated a novel cellular biosensor system (Factorial(1)) that enables rapid, high-content assessment of a compound's impact on gene regulatory networks. The Factorial biosensors combined libraries of cis- and traps-regulated transcription factor reporter constructs with a highly homogeneous method of detection enabling simultaneous evaluation of multiplexed transcription factor activities. Here, we demonstrate the application of the technology toward determining bioactivity profiles by quantitatively evaluating the effects of 309 environmental chemicals on 25 nuclear receptors and 48 transcription factor response elements. We demonstrate coherent transcription factor activity across nuclear receptors and their response elements and that Nrf2 activity, a marker of oxidative stress, is highly correlated to the overall promiscuity of a chemical. Additionally, as part of the ToxCast program, we identify molecular targets that associate with in vivo end points and represent modes of action that can serve as potential toxicity pathway biomarkers and inputs for predictive modeling of in vivo toxicity.