Toxicology in the 21st Century Program (Tox21) - Genomic Toxicology

National Center For Advancing Translational Sciences

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Abstract

The Tox21 Program is a multiagency collaborative effort among the Environmental Protection Agency (EPA), Food and Drug Administration (FDA), the National Toxicology Program (NTP) at the National Institute of Environmental Health Sciences (NIEHS), and NCATS to advance in vitro toxicological testing. The Tox21 Program is comprised of three NCATS teams: Systems Toxicology, Genomic Toxicology, and Computational Toxicology. The Genomic Toxicology team has evaluated and established a superior model for neurons, LUHMES cells, human conditionally immortalized dopaminergic neurons), compared to popular models, SH-SY5Y glioblastoma cells, and commercially available stem cell-derived neurons. We published evidence that LUHMES differentiation occurs faster and more completely, and that differentiated LUHMES cells manifest greater sensitivity to 11 known and suspected neurotoxicants than undifferentiated LUHMES or the other models. The Genomic Toxicology team has also advanced development of high-throughput gene expression technologies in order to build a reference gene expression database from hundreds of thousands of toxicological samples. Our automated solid-state RASL-seq technology (ssRASL-seq) was expanded to address 2,600 human genes in 384-well format. ssRASL-seq experiment rapidity was improved by establishing two Illumina DNA sequencing instruments within the NCATS Genomic Toxicology group. Data analyses were enhanced for ssRASL-seq and RNA-seq by establishing three resources: a robust gene expression database, a method for identifying transcription factors that regulate groups of genes, and an automatic heuristic algorithm that identifies the genes that show a dose-dependent response to each treatment and quantitating the Point Of Departure (POD, the concentration at which a gene shows a statistically robust response). This automated POD algorithm is crucial to expand gene expression to interpret dose-response studies that are the foundations of Toxicology and Pharmacology. These software tools have been applied to elucidate RASL-seq data from: 61 mitochondrial toxicants, 18 tobacco component chemicals, and 18 antiviral drugs. The Tox21 Genomic Toxicology team has also quantified gene expression responses of endothelial cells, both HUVEC primary cells and endothelial cells derived from iPC stem cells, to 18 tobacco chemicals. This study determined the POD responses among 347 human genes using RASL-Seq.