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Your Environment. Your Health.

University of Rhode Island

Superfund Research Program

Mechanisms of Exposure

Project Leader: Angela L. Slitt
Co-Investigators: Fatemeh Akhlaghi, Geoffrey D. Bothun
Grant Number: P42ES027706
Funding Period: 2022-2027
View this project in the NIH Research Portfolio Online Reporting Tools (RePORT)

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Project Summary (2022-2027)

This biomedical research project utilizes expertise in pharmacy and chemical engineering to elucidate mechanisms that underlie per- and polyfluorinated alkyl substances (PFAS) absorption, distribution, and excretion (ADE).

PFAS have been widely detected in human serum and excreta. Since the inception of the University of Rhode Island SRP Center, it has become evident that PFAS contamination is global, exposure is ubiquitous, and the need to understand PFAS properties is urgent. There is a large gap in knowledge regarding the mechanisms by which the ~7000 PFAS that are on the commercial market are absorbed, retained, and are eliminated by the living system, with very little understood about the mechanisms that dictate PFAS ADE. Cell-based studies suggest both protein binding (i.e., serum albumin and fatty acid binding proteins) and xenobiotic/drug transporters (i.e., organic anion transporting polypeptide [OATP2B1] and ATP-binding cassette subfamily G member 2 [ABCG2]) are potential mechanisms that dictate PFAS absorption, distribution, and excretion in vivo.

This research project uses mouse knock-out models and cell-based assays to test the hypothesis that protein transporters and protein binding are critical factors for PFAS ADE and tissue distribution through accomplishing the following three aims. Aim 1: Determine the contribution of OATP2B1 as a critical uptake mechanism for cellular PFAS uptake, tissue distribution and elimination. Aim 2: Determine the contribution of serum albumin and fatty acid binding proteins as critical mechanisms for PFAS uptake, tissue retention, and elimination. Aim 3: Determine the contribution of ABCG2 as a critical efflux mechanism that influences PFAS ADE.

Ultimately the team aims to validate critical mechanisms using in vivo, rodent-based tools and in vitro humanized tools. The findings of the project help guide the prioritization and selection of key toxicological mechanisms that can be targeted in larger screening efforts. Key mechanisms identified by this research project informs Assessing the Contribution of Polyfluoroalkyl Precursors to Diverse PFAS Exposures near Contaminated Sites, Critical Effects Associated with Developmental PFAS Exposure Profiles, and Passive Samplers in Support of Remediation, Detection and Bioaccumulation of PFAS and is incorporated into bioaccumulation modeling. Those three projects in turn inform this project about new PFAS to characterize in the proposed in vitro models.

Additionally, this research project provides an interdisciplinary training experience through the Research Experience and Training Coordination Core (RETCC) and supports the Community Engagement Core (CEC) through participation in bidirectional communications about findings and PFAS science. This work significantly advances the mechanistic understanding of PFAS ADE, especially in relationship to predicative physiochemical properties of emerging PFAS, which addresses SRP’s mandate to develop techniques to assess the effects of hazardous substances on human health. It also uses a mechanistic approach to identify underlying genetic risk or dietary factors that modulate PFAS ADE, which addresses SRP’s mandates to develop methods for assessing the risks hazardous substances pose to human health and to develop biological, chemical, and physical methods of decreasing hazardous substances and their toxicity.

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