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Evaluation of 147 perfluoroalkyl substances for immunotoxic and other (patho)physiological activities through phenotypic screening of human primary cells
Citation:
Houck, K., K. Friedman, M. Feshuk, G. Patlewicz, M. Smeltz, M. Clifton, B. Wetmore, S. Velichko, A. Berenyi, AND E. Berg. Evaluation of 147 perfluoroalkyl substances for immunotoxic and other (patho)physiological activities through phenotypic screening of human primary cells. ALTEX. Society ALTEX Edition, Kuesnacht, Switzerland, 40(2):248-270, (2023). https://doi.org/10.14573/altex.2203041
Impact/Purpose:
This product will test how a collection of PFAS impact immunotoxicity endpoints measured in complex human cell system assays. An NTP systematic review concluded PFOA and PFOS were "presumed to be an immune hazard to humans", emphasizing the importance of evaluating NAMs that may predict potential for such hazard. The first and second PFAS screening sets, totaling 150 samples, will be tested in the Dixcoverx BioMAP phenotypic screening platform. These assays include 148 measured endpoints covering a wide variety of mechanistic effects involved in immunotoxicity and other endpoints. Results will be compared to an extensive database of drugs and environmental chemicals previously profiled in these assays.
Description:
A structurally diverse set of 147 per- and polyfluoroalkyl substances (PFAS) was screened in a panel of 12 human primary cell systems by measuring 148 biomarkers relevant to (patho)physiological pathways to inform hypotheses about potential mechanistic effects of data-poor PFAS in human model systems. This analysis focused on immunosuppressive activity, which was previously reported as an in vivo effect of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), by comparing PFAS responses to four pharmacological immunosuppressants. The PFOS response profile had little correlation with reference immunosuppressants, suggesting in vivo activity does not occur by similar mechanisms. The PFOA response profile did share features with the profile of dexamethasone, although some distinct features were lacking. Other PFAS, including 2,2,3,3-tetrafluoropropyl acrylate, demonstrated more similarity to the reference immunosuppressants but with additional activities not found in the reference immunosuppressive drugs. Correlation of PFAS profiles with a database of environmental chemical responses and pharmacological probes identified potential mechanisms of bioactivity for some PFAS, including responses similar to ubiquitin ligase inhibitors, deubiquitylating enzyme (DUB) inhibitors, and thioredoxin reductase inhibitors. Approximately 21% of the 147 PFAS with confirmed sample quality were bioactive at nominal testing concentrations in the 1-60 micromolar range in these human primary cell systems. These data provide new hypotheses for mechanisms of action for a subset of PFAS and may further aid in development of a PFAS categorization strategy useful in safety assessment.
URLs/Downloads:
DOI: Evaluation of 147 perfluoroalkyl substances for immunotoxic and other (patho)physiological activities through phenotypic screening of human primary cells
https://pubmed.ncbi.nlm.nih.gov/36129398/