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

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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 human cell culture models and methods to illuminate toxicology and human diseases. For example, we validated an iPSC-derived endothelial cell model by showing it responds to tobacco smoke very much like primary endothelial cells according to gene expression profiles and cytokine profiles.(Chu et al, 2020) This endothelial cell model is also being used in collaboration with the NIEHS Cardiovascular Program to elucidate how environmental toxicants and drugs cause vascular toxicity and heart attacks. Methods: We developed and filed a patent application on a high-throughput method to screen chemical libraries using multiplex gene expression, called APLS. (Gerhold et al. US #63/196,438) With R. Huangs Group we also developed a Point of Departure algorithm (POD) for public access to analyze concentration-response transcriptomic data to identify dose-responsive genes and the concentration where each is up- or down-regulated by a treatment. Over the past two years, we developed an immortalized kidney podocyte culture (regeneration) model to illuminate how kidneys adapt to glomerular toxicities and disease such as diabetic nephropathy and lupus nephritis. We also refined our LUHMES immortalized human dopaminergic neuron model by characterizing several biomarkers and neuronal susceptibility pathways including, iron metabolism and oxidative stress (Tong 2018) This model will enable screening chemical libraries to identify neurodegenerative toxicants that may cause Parkinsons disease or other neurodegenerative diseases.