Project 3 is one of two biomedical projects proposed for new URI-led Center ? Sources, Transport, Exposure and Effects of PFASs (STEEP) ? that is being created to aid the Superfund Research Program (SRP) in addressing the emerging problem of poly- and perfluorinated alkyl substances (PFASs) contamination. PFASs are considered emerging environmental pollutants, notably found at high concentrations at sites contaminated by aqueous fire fighting foams, such as Cape Cod. Human exposure to PFASs has been linked to immunotoxicity, cancer, as well as metabolic and dyslipidemia. Specific to metabolic disorders, PFASs are known to highly partition to the liver and links have been established between PFAS serum levels, specifically perfluorooctanic acid (PFOA) and perfluorosulfonic acid (PFOS), and liver injury. While insightful, these two common PFASs represent only a fraction of PFASs that exist within the contaminated sites and have been detected in humans (for example by Grandjean, STEEP Project 2; and Sunderland, STEEP Project 1). Understanding the mechanisms driving the biological response to PFASs are still emerging. The goal of this work is to (i) address whether environmental exposure to PFASs contributes an additional increase risk for obesity-induced fatty liver disease and metabolic disorders, and (ii) identify the physicochemical and partitioning behavior of PFASs that contribute to bioaccumulation. The overarching hypotheses are (1) that PFAS exposure will increase diet-induced hepatic steatosis and inflammation, which is potentially via increased adiposity and altered adipokine secretion, and (2) that the biological responses (e.g. liver weight) and biomarkers (e.g. oxidative stress gene expression) can be correlated with the protein, lipid, and/or membrane partitioning behavior of PFASs. These hypotheses will be tested by (Aim 1) evaluating the potential of PFASs to impact hepatic lipid accumulation, adipogenesis and adipokine secretion, (Aim 2) evaluating postnatal and adult PFAS exposure as an additional risk factor for obesity-induced hepatic steatosis and adipocyte dysfunction, and (Aim 3) determining the physicochemical properties of PFASs and their partitioning behavior to fat and in protein phases. Furthermore, through this project significant gaps in ATSDR guidance related to PFASs will be addressed pertaining to (i) outcomes with early in life PFAS exposure, (ii) mechanistic biomarkers for PFAS exposure in addition to liver endpoints, (iii) risk factors common to the United States population that might impact response to PFAS exposure (i.e. diet; obesity), and (iv) accurate measurements of physicochemical properties that are needed to predict bioaccumulation and toxicity.

Public Health Relevance

Perfluoroalkyl substances (PFASs) are emerging environmental pollutants, notably found at high concentrations at sites contaminated by aqueous fire fighting foams, such as Cape Cod. Human exposure to PFASs has been linked to immunotoxicity, cancer, as well as metabolic and dyslipidemia. This project will investigate metabolic abnormalities caused by PFASs in rodent models and determine the physicochemical and partitioning properties that attribute to these abnormalities and are needed for predictive bioaccumulation models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
1P42ES027706-01
Application #
9258544
Study Section
Special Emphasis Panel (ZES1)
Project Start
2017-09-01
Project End
2022-03-31
Budget Start
2017-08-15
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Rhode Island
Department
Type
DUNS #
144017188
City
Kingston
State
RI
Country
United States
Zip Code
02881
Grandjean, Philippe (2018) Health Status of Workers Exposed to Perfluorinated Alkylate Substances. J Occup Environ Med 60:e562
Sun, Qi; Zong, Geng; Valvi, Damaskini et al. (2018) Plasma Concentrations of Perfluoroalkyl Substances and Risk of Type 2 Diabetes: A Prospective Investigation among U.S. Women. Environ Health Perspect 126:037001
Grandjean, Philippe (2018) Delayed discovery, dissemination, and decisions on intervention in environmental health: a case study on immunotoxicity of perfluorinated alkylate substances. Environ Health 17:62
Barouki, R; Melén, E; Herceg, Z et al. (2018) Epigenetics as a mechanism linking developmental exposures to long-term toxicity. Environ Int 114:77-86
DeWitt, Jamie C; Blossom, Sarah J; Schaider, Laurel A (2018) Exposure to per-fluoroalkyl and polyfluoroalkyl substances leads to immunotoxicity: epidemiological and toxicological evidence. J Expo Sci Environ Epidemiol :
Sunderland, Elsie M; Hu, Xindi C; Dassuncao, Clifton et al. (2018) A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects. J Expo Sci Environ Epidemiol :
Budtz-Jørgensen, Esben; Grandjean, Philippe (2018) Application of benchmark analysis for mixed contaminant exposures: Mutual adjustment of perfluoroalkylate substances associated with immunotoxicity. PLoS One 13:e0205388
Grandjean, Philippe; Abdennebi-Najar, Latifa; Barouki, Robert et al. (2018) Timescales of developmental toxicity impacting on research and needs for intervention. Basic Clin Pharmacol Toxicol :
Hu, Xindi C; Dassuncao, Clifton; Zhang, Xianming et al. (2018) Can profiles of poly- and Perfluoroalkyl substances (PFASs) in human serum provide information on major exposure sources? Environ Health 17:11
Jensen, Richard Christian; Glintborg, Dorte; Timmermann, Clara Amalie Gade et al. (2018) Perfluoroalkyl substances and glycemic status in pregnant Danish women: The Odense Child Cohort. Environ Int 116:101-107

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