Chemical genomics profiling of environmental chemical modulation of human nuclear receptors.
Chemical genomics profiling of environmental chemical modulation of human nuclear receptors.
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DOI：
10.1289/ehp.1002952
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发表时间：
2011-08
影响因子：
10.4
通讯作者：
Austin CP
中科院分区：
文献类型：
--
作者：
Huang R;Xia M;Cho MH;Sakamuru S;Shinn P;Houck KA;Dix DJ;Judson RS;Witt KL;Kavlock RJ;Tice RR;Austin CP
背景资料：排放到环境中的化学品数量庞大且不断增加，这就要求采用更有效和更具成本效益的方法来评估环境化学品毒性。美国Tox 21计划通过提出毒性测试的替代策略来应对这一挑战，其中定量高通量筛选（qHTS）范式已被采用为使用广泛的测定筛选大型化学文库生成数据的主要工具。目的：本研究的目的是开发方法来评价这些测定产生的数据，以指导Tox 21项目未来的测定选择和优先级排序。研究方法：我们针对一组10种人核受体（AR、ERα、FXR、GR、LXRβ、PPARγ、PPARδ、RXRα、TRβ和VDR）检查了Tox 21中试阶段收集的约3，000种环境化学品（qHTS格式）数据的重现性、生物活性特征与受体配体结合结构域序列同源性的一致性以及结构-活性关系。结果：我们确定该试验在生物学相关性方面是适当的。我们发现，与拮抗剂模式测定相比，激动剂模式测定的重复化合物具有更好的一致性，这可能是由于后者测定中细胞毒性的干扰。这项工作还使我们能够制定数据驱动的策略，以区分真实信号和伪影，并根据数据质量确定分析的优先级。结论：结果表明，qHTS的可行性，以确定潜在的环境相关的化学品相互作用的关键毒性途径与人类疾病的诱导。
Background: The large and increasing number of chemicals released into the environment demands more efficient and cost-effective approaches for assessing environmental chemical toxicity. The U.S. Tox21 program has responded to this challenge by proposing alternative strategies for toxicity testing, among which the quantitative high-throughput screening (qHTS) paradigm has been adopted as the primary tool for generating data from screening large chemical libraries using a wide spectrum of assays. Objectives: The goal of this study was to develop methods to evaluate the data generated from these assays to guide future assay selection and prioritization for the Tox21 program. Methods: We examined the data from the Tox21 pilot-phase collection of approximately 3,000 environmental chemicals profiled in qHTS format against a panel of 10 human nuclear receptors (AR, ERα, FXR, GR, LXRβ, PPARγ, PPARδ, RXRα, TRβ, and VDR) for reproducibility, concordance of biological activity profiles with sequence homology of the receptor ligand binding domains, and structure–activity relationships. Results: We determined the assays to be appropriate in terms of biological relevance. We found better concordance for replicate compounds for the agonist-mode than for the antagonist-mode assays, likely due to interference of cytotoxicity in the latter assays. This exercise also enabled us to formulate data-driven strategies for discriminating true signals from artifacts, and to prioritize assays based on data quality. Conclusions: The results demonstrate the feasibility of qHTS to identify the potential for environmentally relevant chemicals to interact with key toxicity pathways related to human disease induction.
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影响因子：
4.1
作者：
Huang, Ruili;Southall, Noel;Austin, Christopher P.
通讯作者：
Austin, Christopher P.
影响因子：
3.1
作者：
Cleator, Susan J.;Ahamed, Eliyaz;Palmieri, Carlo
通讯作者：
Palmieri, Carlo
影响因子：
64.5
作者：
Shiau, AK;Barstad, D;Greene, GL
通讯作者：
Greene, GL
影响因子：
64.8
作者：
Kersten, S;Desvergne, B;Wahli, W
通讯作者：
Wahli, W
影响因子：
7.8
作者：
Kohonen, Teuvo
通讯作者：
Kohonen, Teuvo