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How Does Stress Modify Chemical Toxicity? A High Throughput In Vitro Screening Approach to Advance New Approach Method (NAM) Testing of Differences in Susceptibility
Citation:
Word, L., C. Willis, S. Padilla, C. Weitekamp, K. Carstens, L. Everett, B. Knapp, R. Judson, AND J. Harrill. How Does Stress Modify Chemical Toxicity? A High Throughput In Vitro Screening Approach to Advance New Approach Method (NAM) Testing of Differences in Susceptibility. American Society for Cellular and Computational Toxicology (ASCCT) 12th Annual Meeting - Spotlight on NAMs: Elevating New Approaches in Risk Assessment, Silver Spring, MD, October 23 - 25, 2023. https://doi.org/10.23645/epacomptox.24769035
Impact/Purpose:
Presentation to the American Society for Cellular and Computational Toxicology (ASCCT) 12th Annual Meeting October 2023. Our research aims to further the ability of NAMs to screen chemicals for their interactions with stressed biological systems, which is particularly relevant to Environmental Justice (EJ) communities due to their higher levels of chronic stress. This work is being presented at a conference that is focused on New Approach Methodology (NAM) development.
Description:
Stress plus chemical exposure may produce effects not observed with chemical exposure alone, which would be of particular concern for environmental justice (EJ) since EJ communities experience higher levels of chronic stress. Therefore, there is a need for New Approach Methodologies (NAMs) that can rapidly screen chemicals for their interaction with stressed biological systems. We are exploring this interaction using in vitro chemical screening by phenotypic profiling of human osteosarcoma cells that express fluorescent nuclear and cytoskeletal fusion proteins (U-2 OS_FP). These cells have glucocorticoid receptor, which is the target of the stress hormone, cortisol, and the cells were transitioned to a serum-free media so that we will have control over cortisol dosing during the experiment. The U-2 OS_FP cells will be co-exposed to a mixture of cortisol and toxicants in a time- and concentration-dependent screen to evaluate cellular phenotypic changes. We are screening 147 chemicals, including chemicals that are relevant to environmental justice (n=73), chemicals that impact the glucocorticoid receptor (n=22) or overlapping gene pathways (n=25), are carcinogenic (n=20), endocrine disruptors (n=15), and/or induce cell stress responses (n=13). These chemicals will be evaluated for effects under conditions of low vs high stress (cortisol) levels. Then, zebrafish embryos will be exposed to a subset of these chemicals to evaluate phenotypic and behavioral effects of chemical exposure accompanied by high or low cortisol levels during development. This will improve NAM modeling of how stress may impact adverse outcomes from chemical exposure. This does not necessarily represent the views of the U.S.EPA.
URLs/Downloads:
DOI: How Does Stress Modify Chemical Toxicity? A High Throughput In Vitro Screening Approach to Advance New Approach Method (NAM) Testing of Differences in Susceptibility
ASCCT_IMPACT OF STRESS ON CHEMICAL TOXICITY_LJW_10-19-23.PDF (PDF, NA pp, 5237.85 KB, about PDF)