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North Carolina State University

Superfund Research Program

Uncovering the Mechanisms of PFAS-Induced Immunotoxicity: An Important Public Health Endpoint

Project Leader: Seth W. Kullman
Co-Investigators: Jamie C. DeWitt (Oregon State University), Jeffrey Yoder
Grant Number: P42ES031009
Funding Period: 2020-2025
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Project Summary (2020-2025)

Per- and polyfluoroalkyl substances (PFAS) are considered contaminants of emerging concern for myriad reasons, but one of the most pressing is that only a handful of the nearly 5,000 PFAS that are known to exist have been evaluated for their toxicologic potential, even though numerous communities are being impacted by their presence in environmental media, especially drinking water. Studies of humans exposed to perfluoroocatonic acid (PFOA) and perfluorooctane sulfonate (PFOS), two PFAS detected with high frequency and concentration in human and environmental samples, have provided compelling evidence that the immune system is a sensitive target of PFAS. Additional work with experimental animal models supports the hypothesis that PFAS induce immunotoxicity and alter responses of both the adaptive and innate immune systems. While PFOA and PFOS are presumed to be immune hazards to humans, several gaps in knowledge exist, notably the mechanism(s) by which these PFAS induce immunotoxicity and the extent to which most PFAS of emerging concern perturb immune function. The objectives of this project are twofold: (1) explore molecular changes underlying PFAS-induced immunotoxicity in select animal models and human cell lines to identify impacted signaling pathways and networks and (2) determine the immunotoxicological profile, including mechanistic underpinnings, of PFAS of emerging concern relative to the few well-studied PFAS. The researchers’ global hypothesis is that PFAS-mediated immune suppression results from modulation of immune cell metabolic functions. This hypothesis is being evaluated by (Aim 1) quantifying the impact of PFAS exposure on B cell development and antibody production in a mouse model and (Aim 2) identifying the impact of PFAS exposure on phagocytotic cell function using a zebrafish in vivo model and human in vitro cell line models. This project addresses significant gaps in what is known about the mechanisms by which PFAS induce immunotoxicity, thus improving management of a known PFAS health risk, immune suppression, and accelerating development of immune therapies for affected individuals. Additionally, the large number of untested PFAS also means that methods for rapid prioritization are critical for informing appropriate regulatory measures; this project is uncovering molecular initiating events underlying altered immune responses to facilitate novel, immune-mechanism-based prioritization strategies for PFAS recently detected in North Carolina and elsewhere.

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