# Comparative neurotoxicity of PFAS

> **NIH NIH R01** · PURDUE UNIVERSITY · 2024 · $656,288

## Abstract

Project Summary
Exposure to per- and polyfluoroalkyl substances (PFAS) is highly prevalent in the US population and has been
associated with neurodevelopmental and neurodegenerative diseases particularly via changes in dopaminergic
(DA) neurons. Conventional PFAS chemicals are being rapidly replaced by novel chemicals with unknown long-
term neurotoxicity necessitating the comparison of neurotoxicity of various PFAS. The goal of the proposed
research is to evaluate and compare the impact of a developmental exposure to selected PFAS chemicals
including the legacy PFAS, PFOA, and its PFAS replacements, PFBA and GenX, at low doses on the plasticity
of neuronal compartments; and subsequently characterize their vulnerability to established neurotoxins
promoting DA neuron degeneration. There are limited studies comparing developmental neurotoxicity of PFAS
and the lasting impacts on the central nervous system, especially replacement PFAS due to the scarcity of
longitudinal epidemiological studies. Our studies using the zebrafish model suggest although lethality decreases
in PFAS with shorter carbon chain length and addition of side chains common in replacement PFAS,
perturbations on development, behavior, and dopamine (DA) concentrations occur at lower dose exposures in
PFAS replacements (e.g., PFBA and GenX). These findings were further corroborated using dopaminergic-like
cells differentiated from SH-SY5Y and floor plate progenitor cells derived for human induced pluripotent stem
cells (hiPSCs). Collectively, PFOA seems to have a distinctive neurotoxic mechanism compared to PFBA and
GenX, while all three PFAS can result in persistent alterations at various sub-cellular compartments and perturb
calcium (Ca) homeostasis. We will thus test our CENTRAL HYPOTHESIS that low dose PFAS exposure disrupts
communication between different cellular compartments via altered intracellular Ca concentrations, leading to
systematic disruptions in multiple cellular compartments, interrupting the formation of the neuronal network, and
increasing risk of neuron damage and degeneration. We will use a combination of the zebrafish animal model
and DA neurons derived from hiPSC to evaluate immediate impact of developmental PFAS exposure (SA1) and
latent long-term neurotoxicity (SA2) emphasizing the dopaminergic pathway. Throughout SA1 and SA2, we will
determine changes in neuronal vulnerability to established neurotoxins for altered viability and accumulation of
degenerative markers, such as synuclein aggregates. Sub-cellular and network Ca activity will be recorded and
correlated to reveal driving pathogenic mechanisms for abnormal neuronal activity and neurodegeneration
induced by developmental PFAS exposure, while exploring normalization options (SA3). Collectively, we will
determine unique and shared neurotoxicity associated with selected PFAS; reveal sub-cellular compartments
most compromised and conferring to the neurodegenerative-like phenotype; and explore the feasib...

## Key facts

- **NIH application ID:** 10883045
- **Project number:** 1R01ES035429-01A1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Jennifer L. Freeman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $656,288
- **Award type:** 1
- **Project period:** 2024-06-11 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883045

## Citation

> US National Institutes of Health, RePORTER application 10883045, Comparative neurotoxicity of PFAS (1R01ES035429-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10883045. Licensed CC0.

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