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

National Center For Advancing Translational Sciences

Investigators

Linked publications & trials

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 group has used the Toxmatrix method (Tong 2018) to identify pathways that render neurons susceptible to 32 neurodegenerative toxicants investigated. Toxmatrix interactions identified iron transport, and oxidative metabolism as characteristic neuronal toxicity pathways. Transcriptional profiling of neurotoxicants has identified seven transcriptionally-induced biomarker genes that are particularly responsive to toxicants that cause, or increase risk for, Parkinsons disease (PD). These chemical interactions, culture conditions, and biomarkers, are being used to develop a qHTS assay to screen chemical libraries to identify potential neurodegenerative toxicants. The Genomic Toxicology and Computational Toxicology groups have also advanced high-throughput gene expression technology. In 2018, we worked with Computational Toxicology to adapt our Point-of-Departure (POD) algorithm to RNAseq, and applied it to identify endothelial cell gene responses to chemicals from tobacco smoke that lead to heart attack and stroke. The POD algorithm revealed multiple toxico-dynamic effects of individual chemicals that accumulated as the toxicant concentration was increased; a reductive analysis of the toxicological principle The dose makes the poison.