Grantee Research Project Results
2020 Progress Report: System toxicological approaches to define and predict the toxicity of Per and Polyfluoroalkyl Substances
EPA Grant Number: R839481Title: System toxicological approaches to define and predict the toxicity of Per and Polyfluoroalkyl Substances
Investigators: Tanguay, Robyn L. , Field, Jennifer , Reif, David , Truong, Lisa , Ng, Carla , DeWitt, Jamie
Institution: Oregon State University , North Carolina State University , University of Pittsburgh , East Carolina University
EPA Project Officer: Packard, Benjamin H
Project Period: May 1, 2019 through May 7, 2025
Project Period Covered by this Report: May 1, 2020 through April 30,2021
Project Amount: $1,981,500
RFA: National Priorities: Per- and Polyfluoroalkyl Substances (2018) RFA Text | Recipients Lists
Research Category: Water Quality
Objective:
- Study the toxicity of a large collection of volatile and non-volatile PFASs and PFAS mixtures with the zebrafish assay. Hypothesis: PFAS compounds with similar structures will bind to the same biomolecular targets, induce expression of the same or highly overlapping gene sets, and induce similar toxic responses.
- Conduct developmental immunotoxicity (DIT) studies in mice. Hypotheses: Developmental exposure to PFASs will compromise antigen-specific antibody responses (a measure of adaptive immunity) and natural killer cell cytotoxicity (a measure of innate immunity). Developmental findings in the mouse will accord with developmental findings in the zebrafish.
- Create pharmacokinetic models that can explain and predict the concentrations of PFASs in the organs of mice and adult zebrafish as a function of exposure dose and chemical structure. Hypotheses: The bioaccumulation and internal distribution of PFASs depend on passive diffusion, transporter-mediated membrane uptake and efflux, and protein binding. The interaction of PFASs with proteins and membranes will depend on i) the presence of polar or charged functional groups and on ii) the length of the linear fluorinated alkyl chain.
Progress Summary:
We have secured, validate and tested the toxicity of an ever-growing library of PFAS compounds. These include 58 Wellington Laboratories PFAS analytical standards, a 139 member US EPA PFAS Library, an additional 25 commercial reference standards and a series of PFAS mixtures. We also completed three adult zebrafish dietary studies by contaminating a commercial diet with PFAS. These were 43-day dietary exposure studies at several exposure levels starting at 17-dpf. We have isolated organs for analytical measures, and have grown to adulthood for behavioral testing and fecundity measures. We began developmental immunotoxicity (DIT) studies in mice with "PFMOAA" (perfluoro-2-methoxyacetic acid), a three carbon perfluoroether carboxylic acid. We have updated the adult PBPK model originally developed in Khazaee & Ng 201810, and on a tiered approach to exploit the large amount of data that is being generated using the larval zebrafish. The updating of the full PBPK model for adult zebrafish requires collecting updated data for both zebrafish physiology and for PFAS-specific parameters. Some of the PFAS-protein interaction parameters will be initially modeled, in the same manner as the mouse interaction parameters, and the resulting predictions of tissue distribution. We completed the browser architecture to accommodate data streams from multiple labs so that results can be securely shared as analyses develop toward publications.
Future Activities:
- Continue to perform screening-level toxicological evaluations of PFASs in zebrafish.
- Complete unbiased transcriptomics following PFAS exposures
- Complete analysis of long lasting effects of dietary PFAS exposures
- Measure the body burden and tissue levels of PFAS following exposures
- Complete mouse developmental immunotoxicology experiments
- Develop PFAS pharmacokinetic models for select PFAS compounds
- Broadly disseminate research findings
Journal Articles on this Report : 9 Displayed | Download in RIS Format
| Other project views: | All 38 publications | 12 publications in selected types | All 12 journal articles |
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Cao D, Rericha Y, Pawley C, Truong L, Tanguay R, Field J. Background per-and polyfluoroalkyl substances (PFAS) in laboratory fish diet:Implications for zebrafish toxicological studies. SCIENCE OF THE TOTAL ENVIRONMENT 2022;842(156831). |
R839481 (2020) |
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Cousins I, DeWett J, Gluge J, Goldenman G, Herzke D, Lohmann R, Ng C, Scheringer M, Wang Z. The high persistence of PFAS is sufficient for their management as a chemical class. ENVIRONMENTAL SCIENCE-PROCESSES & IMPACTS 2020;22(12):2307-2312. |
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Ducatman A, LaPier J, Fuoco R, DeWett J. Official health communications are failing PFAS-contaminated communities. ENVIRONMENTAL HEALTH 2022;21(1). |
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Logmann R, Cousins I, DeWitt J, Gluge J, Goldenman G, Herzke D, Lindstrom A, Miller M, Ng C, Patton S, Scheringer M, Trier X, Wang Z. Are Fluoropolymers Really of Low Concern for Human and Environmental Health and Separate from Other PFAS?. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2020;54(20):12820-12828. |
R839481 (2020) |
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McDonnough C, Li W, Bischel H, De Silva O, DeWitt J. Widening the Lens on PFASs:Direct Human Exposure to Perfluoroalkyl Acid Precursors (pre-PFAAs). ENVIRONMENTAL SCIENCE & TECHNOLOGY 2022;56(10):6004-6013. |
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Rericha Y, Cao D, Truong L, Simonich M, Field J, Tanguay R. Behavior Effects of Structurally Diverse Per-and Polyfluoroalkyl Substances in Zebrafish. CHEMICAL RESEARCH IN TOXICOLOGY 2021;34(6):1409-1416. |
R839481 (2020) |
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Rericha Y, Truong L, Leong C, Cao D, Field J, Tanguay R. Dietary Perfluorohexanoic Acid (PFHxA) Exposures in Juvenile Zebrafish Produce Subtle Behavioral Effects across Generations. TOXICS 2022;10(7):372 |
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Rericha Y, Cao D, Truong L, Simonich M, Field J, Tanguay R. Sulfonamide functional head on short-chain perfluorinated substance drives developmental toxicity. ISCIENCE 2022;25(2). |
R839481 (2020) |
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Truong L, Reircha Y, Thunga P, Marvel S, Wallis D, Simonich M, Field J, Cao D, Reif D, Tanguay R. Systematic developmental toxicity assessment of a structurally diverse library of PFAS in zebrafish. JOURNAL OF HAZARDOUS MATERIALS 2022;431. |
R839481 (2020) R839481 (2022) |
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Supplemental Keywords:
zebrafish, toxicity, development, modeling, bioaccumulation, dietary, pharmacokineticRelevant Websites:
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- Final Report
- 2024
- 2023 Progress Report
- 2022 Progress Report
- 2021 Progress Report
- 2019 Progress Report
- Original Abstract
12 journal articles for this project