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

National Center For Advancing Translational Sciences

Investigators

Linked publications, trials & patents

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 human cell culture models and methods to illuminate toxicology and human diseases. For example, we are collaborating with the NIEHS Cardiovascular Health Effects Innovation Team to evaluate twelve suspected cardiovascular toxicants for adverse effects on heart and vasculature. Methods: My lab is using primary human endothelial cell models and co-culture vascular models to elucidate how environmental toxicants and drugs cause vascular toxicity and heart attacks through impacts on vascular failure modes. By transcriptomic- and cytokine-profiling of cultured human endothelial cells, for example, we found that ephedra suppresses tPA and Osteoprotegerin secretion suggesting a procoagulant effect. We have developed an endothelium-dependent coagulation assay using human platelet-rich plasma and a coagulation biochip replete with fluid flow for study of endothelial cell-platelet interactions. BPA caused increased expression of CYP1A1 and CYP1B1 genes, whereas perfluorohexanoic A (PFHxA) caused a clear oxidative stress response. These responses suggest mechanistic bases for vascular failure modes such as perturbations of vasoactivity, coagulation, or inflammation and atherosclerosis. Anti-inflammatory drugs Anakinra and Etanercept caused cultured vascular endothelial cells to secrete at least twenty pro-inflammatory cytokines, prompting a re-examination of in vivo effects of these drugs. Dr. Zhi-Bin Tong has developed a high-throughput 3D LUHMES culture and differentiation method for screening libraries in 1536-well format. Using this 3D method with a LUHMES MT1G::Luciferase reporter cell line he has screened the LOPAC library and the Tox21-10K Library. He has confirmed over 100 hits and established AC50 values and cytotoxicity IC50 values for these actives. Hits from this assay are candidate causative agents for Parkinsons disease or other neurodegenerative diseases, and are under further characterization for mechanisms of toxicity. Additionally, I continue to collaborate with Amy Leblancs team to characterize canine tumorigenesis. Our current focus is to understand metastasis and drug resistance mechanisms using dogs, and to identify promising drug targets and drug combinations for translation to human patients. Public Health Impact Statement During the course of a lifetime, most people are exposed to many different environmental chemicals. These substances can be found in food, water, household cleaning products and elsewhere. In some cases, these chemicals can be toxic, and in others, researchers lack sufficient data about safety. Medicines also contain chemicals, and in fact, more than 30 percent of promising pharmaceuticals have failed in human clinical trials because they are found to be toxic, despite promising pre-clinical studies in animal and other models. The Tox21 Program works to create alternative methods for assessing chemical toxicity that are less expensive and time-consuming than traditional approaches will improve how scientists evaluate environmental chemicals and develop new medicines to benefit public health.