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 to elucidate how smoking, viral infection, or other vascular toxicants lead to heart attack. This work also demonstrated an informatic method to identify transcription factors that govern transcriptional responses. Over the past year, we also developed an immortalized kidney podocyte culture model to illuminate how kidney diseases arise, such as diabetic nephropathy and lupus nephritis. Immortalized podocyte cell lines were established by introducing the SV40 Large T gene into primary cells, and improving culture conditions. We also improved our LUHMES immortalized human dopaminergic neuron model by characterizing several biomarkers. These biomarkers respond to diverse neurotoxicants (Tong et al., submitted), particularly those that impair characteristic neuronal susceptibility pathways, iron transport and oxidative stress (Tong 2018) Thus, these biomarkers will facilitate screening chemical libraries to identify neurodegenerative toxicants that may cause Parkinsons disease or other neurodegenerative diseases.