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A gene expression biomarker identifies in vitro and in vivo ERα modulators in a human gene expression compendium
Citation:
Vanduyn, N., B. Chorley, R. Tice, AND R. Judson. A gene expression biomarker identifies in vitro and in vivo ERα modulators in a human gene expression compendium. FutureTox III, Arlington, VA, November 19 - 20, 2015.
Impact/Purpose:
We propose the use of gene expression profiling to complement the chemical characterization currently based on HTS assay data and present a case study relevant to the Endocrine Disruptor Screening Program.
Description:
We propose the use of gene expression profiling to complement the chemical characterization currently based on HTS assay data and present a case study relevant to the Endocrine Disruptor Screening Program. We have developed computational methods to identify estrogen receptor α (ERα) modulators in an existing database of whole-genome microarray data. The ERα biomarker consisted of 46 ERα-regulated genes with consistent expression patterns across 7 known ER agonists and 3 known ER antagonists. The biomarker was evaluated as a predictive tool using the fold-change rank-based Running Fisher algorithm by comparison to annotated gene expression data sets from experiments carried out in MCF-7 cells. Using 141 comparisons from chemical- and hormone-treated cells, the biomarker gave a balanced accuracy for prediction of ERα activation or suppression of 94% or 93%, respectively. The biomarker was able to correctly classify 18 out of 21 OECD ER reference chemicals including “very weak” agonists and replicated 105 out of 114 predictions based on the 18 in vitro ERα-associated HTS assays currently employed by ToxCast/Tox21. Importantly, the biomarker accurately predicted 48 out of 56 chemicals evaluated in vivo with uterotrophic assays. These results demonstrate that the gene expression-based ERα biomarker can accurately identify ERα modulators in MCF-7 cells and could be considered as a potential “Tier 0” screening model prior to ToxCast/Tox21 HTS assays, and as a potential replacement of one or more of the current ToxCast ER assays. This abstract does not represent EPA policy.