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 develops improved cell culture models and methods to illuminate toxicology and human diseases. Over the past year, we have established a model for kidney podocyte culture to illuminate how kidney diseases, such as diabetic nephropathy and lupus nephritis, arise. We also adapted a cellular dopaminergic neuron model that enables us to screen chemical libraries to identify neurodegenerative toxicants. Specifically, the Genomic Toxicology group has used the Toxmatrix method (Tong 2018) to identify two pathways, iron transport and oxidative metabolism, as characteristic neuronal susceptibility pathways. These insights led us to develop a neuronal model, biomarker genes, and assay methods to identify candidate toxicants that may cause Parkinsons disease or other neurodegenerative diseases. The Genomic Toxicology and Computational Toxicology groups have also advanced high-throughput gene expression technology. We worked with Computational Toxicology to analyze RNAseq dose-response data using a novel Point-of-Departure (POD) algorithm. The POD algorithm was applied 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.