# Mechanisms of Exposure

> **NIH NIH P42** · UNIVERSITY OF RHODE ISLAND · 2022 · $268,461

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 3 MECHANISMS
Project 3 (P3–Mechanisms) is a biomedical project utilizing 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 detected in human serum and excreta. Since the inception of STEEP I,
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. P3–Mechanisms will use
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; and Aim 3: Determine the contribution
of ABCG2 as a critical efflux mechanism that influences PFAS ADE. The outcome of the proposed work will be
the validation of critical mechanisms using in vivo, rodent based tools and in vitro humanized tools. The findings
of the project will help guide the prioritization and selection of key toxicological mechanisms that can be targeted
in larger screening efforts. Key mechanisms identified by P3–Mechanisms will inform P1–Exposure, P2–
Critical Effects, and P4–Detection and will be incorporated into bioaccumulation modeling. Projects 1, 2, and
4 will inform P3–Mechanisms about new PFAS to characterize in the proposed in vitro models. P3–
Mechanisms will provide an interdisciplinary training experience through STEEP’s RETCC and will support the
Community Engagement Core (CEC) through participation in bidirectional communications about findings and
PFAS science. This work will significantly advance our mechanistic understanding of PFAS ADE, especially in
relationship to predicative physiochemical properties of emerging PFAS, which addresses SRP Mandate #2
(techniques of assessing the effects of hazardous substances on human health). It uses a mechanistic approach
to identify underlying genetic risk or dietary factors that modulate PFAS ADE, which addresses the broad SRP
Mandate # 3 (development of metho...

## Key facts

- **NIH application ID:** 10352512
- **Project number:** 2P42ES027706-06
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** Angela L Slitt
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $268,461
- **Award type:** 2
- **Project period:** 2017-09-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352512

## Citation

> US National Institutes of Health, RePORTER application 10352512, Mechanisms of Exposure (2P42ES027706-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10352512. Licensed CC0.

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