Screening Chemicals for Estrogen Receptor Bioactivity Using a Computational Model
Screening Chemicals for Estrogen Receptor Bioactivity Using a Computational Model
复制标题
DOI：
10.1021/acs.est.5b02641
复制
发表时间：
2015-07-21
影响因子：
11.4
通讯作者：
Thomas, Russell S.
中科院分区：
文献类型：
--
作者：
Browne, Patience;Judson, Richard S.;Thomas, Russell S.
美国环境保护署（EPA）正在考虑高通量和计算方法来评估环境化学品的内分泌生物活性。在这里，我们描述了一个多步骤的，基于性能的验证新方法，并证明这些新的工具是足够强大的使用：在内分泌干扰物筛选计划（EDSP）。将18种雌激素受体（ER）ToxCast高通量筛选试验的结果整合到一个计算模型中，该模型可以区分生物活性与试验特异性干扰和细胞毒性。模型评分范围为0（无活性）至1（17 β-雌二醇的生物活性）。评价了参考化学品的ToxCast ER模型性能，以及现行实践中EDSP Tier 1筛选试验的结果。与参考化学品相比，ToxCast ER模型的准确度为86%至93%，EDSP 1级指南和其他子宫营养研究的预测结果的准确度为84%至100%。高通量测定和ToxCast ER模型预测的性能表明，这些方法正确识别活性和非活性参比化学品，提供相对ER生物活性的测量，并快速识别具有潜在内分泌生物活性的化学品，用于额外的筛选和测试。EPA正在接受1812种化学品的ToxCast ER模型数据，作为EDSP Tier 1 ER结合、ER反式激活和子宫营养测定的替代品。
The U.S. Environmental Protection Agency (EPA) is considering high-throughput and Computational Methods to evaluate the endocrine bioactivity of environmental Chemicals. Here we describe a multistep, performance-based validation of new methods and demonstrate that these new tools are sufficiently robust to be used: in the Endocrine Disruptor Screening Program (EDSP). Results from 18 estrogen receptor (ER) ToxCast high-throughput screening assays were integrated into a computational model that can discriminate bioactivity from assay-specific interference and cytetoxicity. Model scores range from 0 (no activity) to 1 (bioactivity of 17 beta-estradiol). ToxCast ER model performance was evaluated for reference chemicals, as well as results of EDSP Tier 1 screening assays in current practice. The ToxCast ER model accuracy was 86% to 93% when compared to reference chemicals and predicted results of EDSP Tier 1 guideline and other uterotrophic studies with 84% to 100% accuracy. The performance of high-throughput assays and ToxCast ER model predictions demonstrates that these methods correctly identify active and inactive reference chemical, provide a measure of relative ER bioactivity, and rapidly identify chemicals with potential endocrine bioactivities for additional Screening and testing. EPA is accepting ToxCast ER model data for 1812 chemicals as alternatives for EDSP Tier 1 ER binding,, ER transactivation, and uterotrophic assays.