Grantee Research Project Results

2019 Progress Report: System toxicological approaches to define and predict the toxicity of Per and Polyfluoroalkyl Substances

EPA Grant Number: R839481
Title: 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 , East Carolina University , University of Pittsburgh
EPA Project Officer: Packard, Benjamin H
Project Period: May 1, 2019 through May 7, 2025
Project Period Covered by this Report: May 1, 2019 through April 30,2020
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 and validated an ever-growing library of PFAS compounds for testing. These include 65 bona fide standards, a carbon length series of carboxylate and sulfonated compounds and we received the EPA 430 compound PFAS library. We have used the high throughput zebrafish assay to screen dozens of individual PFASs and mixtures to date. These compounds are the highest purity standard solutions available. We also determined that 0.5% methanol exposure concentration does not induce any abnormal behavior effects in this study and it is suitable alternate vehicle standard. We also completed our first dietary study by contaminating a commercial diet with PFAS. This was a 43-day dietary exposure study at three exposure levels starting at 17-dpf. We have isolated organs for analytical measures, and have grown to adulthood for behavioral testing and fecundity measures. The mouse developmental immunotoxicology experiments will begin with at least one of the understudied PFAS discovered in the Cape Fear River of North Carolina since GenX and other per- and polyfluoroalkyl compounds are detected in drinking water and in the blood of human study volunteers. Our work with one of these understudied PFAS, 'Nafion Byproduct 2,' has demonstrated that it is a potent systemic toxicant and immunotoxicant when given to adult mice. We also designed 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:

No journal articles submitted with this report: View all 38 publications for this project

Supplemental Keywords:

zebrafish, toxicity, development, modeling, bioaccumulation, dietary, pharmacokinetic

Relevant Websites:

Systems Toxicological Assessments of PFAS Exit

Progress and Final Reports:

Original Abstract

The 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.