# Optimizing a human relevant mouse model to study adverse health effects of PFAS

> **NIH NIH R21** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $212,603

## Abstract

PROJECT SUMMARY
Millions of Americans are exposed daily to per- and polyfluoroalkyl substances (PFAS) due to the current and
historical use of these chemicals in consumer and industrial products. PFAS exposure in humans is associated
with liver disease and serum hyperlipidemia (increased serum cholesterol, in particular). However, understanding
the mechanism(s) linking PFAS exposure to dyslipidemia is hindered by 1) the ability of PFAS to activate
peroxisome proliferator activated receptor α (PPARα), a receptor activated by fibrate drugs that reduces serum
triacylglycerides, 2) apparently disparate effects of PFAS on serum lipids in human and rodents (in which PFAS
can decrease serum lipids), 3) lack of understanding if/how PFAS congeners exert distinct effects on lipid
homeostasis, and 4) species differences in nuclear receptors that regulate PFAS-induced effects. Our
overarching objective is to determine the mechanisms by which PFAS disrupt systemic lipid homeostasis. Our
research focuses on nuclear receptors that are activated by PFAS and are directly involved in lipid regulation:
PPARα, constitutive androstane receptor (CAR), and pregnane X receptor (PXR). PPARα activation decreases
hepatic and serum lipids while CAR and PXR activation can have the opposite effect. There are two major
chemical classes of PFAS: perfluoroalkyl carboxylic acids (PFCA) and perfluoroalkyl sulfonic acids (PFSA). We
used a human-relevant model in vitro to show that PFCA and PFSA activate human PPARα (huPPARα) with
differing efficacies. Using mice expressing huPPARα and fed an American diet, we showed that: 1)
perfluorooctanoic acid (PFOA) activates hepatic huPPARα in vivo at body burdens found in humans, 2) CAR
and PXR also are strongly activated, 3) PFOA increases liver lipids and serum cholesterol, and 4) PFOA’s effects
are sex-dependent. Given the strength of the PFAS-induced CAR/PXR signal, the potential for CAR/PXR to
differentiate the effects of PFCAs and PFSAs, and that CAR/PXR also are activated in a species-specific manner,
we propose that the most human relevant in vivo model should be multi-humanized. Thus, our Specific Aims are
as follows. In Aim 1, we will refine our novel mouse model to investigate human relevant mechanisms of PFAS
action by incorporating human CAR (huCAR) and PXR (huPXR) into the huPPARα mouse and update our novel
“What we eat in America” diet. In Aim 2, we will test the contribution of huPPARα to PFAS-induced toxicological
effects in vivo in the context of huCAR and huPXR by comparing effects in huPPARα+:huCAR+:huPXR+ and
PPARαNull(mouse/human):huCAR+:huPXR+ mice exposed to human-relevant PFAS levels. We will test the hypotheses
that a) activation of PPARα by PFAS limits their capacity to stimulate hepatic steatosis and serum hyperlipidemia
by counteracting effects of CAR/PXR activation and b) PFAS structure will determine the balance of
huPPARα:huCAR/huPXR activation resulting in differences in toxicological effects. Results will fi...

## Key facts

- **NIH application ID:** 10885292
- **Project number:** 1R21ES035475-01A1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Jennifer J Schlezinger
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $212,603
- **Award type:** 1
- **Project period:** 2024-03-04 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885292

## Citation

> US National Institutes of Health, RePORTER application 10885292, Optimizing a human relevant mouse model to study adverse health effects of PFAS (1R21ES035475-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10885292. Licensed CC0.

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