Identification of potential endocrine disrupting chemicals using gene expression biomarkers

Recent technological advances have moved the field of toxicogenomics from reliance on microarray platforms to high-throughput transcriptomic (HTTr) technologies that measure global gene expression. Gene expression biomarkers are emerging as useful tools for interpreting gene expression profiles to identify perturbations of targets of xenobiotic chemicals including those that act as endocrine disrupting chemicals (EDCs). Gene expression biomarkers are lists of similarly-regulated genes identified in global gene expression comparisons of cells or tissues 1) exposed to known agonists or antagonists of the transcription factor (TF) and 2) after expression of the TF itself is knocked down/knocked out or overexpressed. Estrogen receptor alpha (ER alpha) and androgen receptor (AR) biomarkers have been shown to be very accurate at identifying both agonists (94-97%) and antagonists (93-98%) in microarray data derived from human breast or prostate cancer cell lines. Importantly, the biomarkers have been shown to accurately replicate the results of computational models that predict ERa or AR modulation using multiple ToxCast HT screening assays. An integrated screening strategy using sets of biomarkers that simultaneously predict various EDC targets in relevant cell lines should simplify chemical screening without sacrificing accuracy. The biomarker predictions can be put into the context of the adverse outcome pathway framework to help prioritize chemicals with the greatest risk of potential adverse outcomes in the endocrine systems of animals and people.