# Developmental Origins of Neurotoxicity of the PFAS GenX

> **NIH NIH R21** · PURDUE UNIVERSITY · 2021 · $212,744

## Abstract

PROJECT SUMMARY / ABSTRACT
Per- and polyfluoroalkyl substances (PFAS) are synthetic fluorine-containing compounds that are present in
many applications due to their non-stick and stain-resistant properties. Longer carbon chain compounds [C8;
e.g., perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS)], were phased out based on
health risks. Shorter carbon chain (<C8) PFAS were produced to minimize environmental persistence and
bioaccumulation. PFAS are an emerging class of environmental chemical contaminants and the replacement
PFAS are not regulated by federal agencies. The developing central nervous system is particularly sensitive to
toxicant exposure and a growing body of evidence suggests developmental neurotoxicity (DNT) may result
from PFAS exposures including increased risk for attention deficit/hyperactivity disorder and reduced motor
and executive functioning. Similar to other PFAS toxicity studies, the limited DNT laboratory studies have
mainly focused on PFOS or PFOA. Some of these DNT studies suggest impacts to the dopaminergic (DA)
system. It is now estimated there are >4000 PFAS with most having limited to no toxicity information available.
Futhermore, some studies including our preliminary data indicate similar toxicity outcomes with some even
being more potent than the C8 compounds. Moreover, most PFAS are present in the environment in a mixture,
which can result in various mixture interactions. As such, a significant gap remains in our basic understanding
of DNT of PFAS and PFAS mixtures, mechanisms and functional impacts to the developing CNS, and the risk
of persistent neurotoxicity in the developmental origins of health and disease paradigm (DOHaD). PFAS of
particular concern are GenX (C6, replacement for PFOA) and PFBS (perfluorobutanesulfonic acid, C4,
replacement for PFOS). These PFAS alternatives are detected in environmental samples and in treated
drinking water. Questions remain on DNT and persistent neurotoxicity of a short-term developmental exposure
(e.g., the DOHaD paradigm). This question is significant considering GenX is reported to be more potent than
PFOA and is likely that co-exposure to GenX and PFOA will occur. Our CENTRAL HYPOTHESIS is that
exposure to GenX at early developmental stages will result in DNT targeting the DA system and persistent
neurotoxicity in adults with the combined effects of GenX and PFOA resulting in an additive toxicity response.
We will first define DNT of GenX using the zebrafish by assessing gross and fine morphological changes,
behavior, and targets associated with the DA system. Results will be compared to PFOA, PFBS, and
GenX/PFOA mixtures and alterations in the serotonergic system (aim 1). Second, we will assess persistent
neurotoxicity of the developmental PFAS exposure in the DOHaD paradigm (aim 2). The zebrafish, a well-
established model to study DNT and neurobehavior, will be used as an integrative vertebrate animal model to
assess short and long-term neuro...

## Key facts

- **NIH application ID:** 10218403
- **Project number:** 1R21ES031646-01A1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Jennifer L. Freeman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $212,744
- **Award type:** 1
- **Project period:** 2021-04-14 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218403

## Citation

> US National Institutes of Health, RePORTER application 10218403, Developmental Origins of Neurotoxicity of the PFAS GenX (1R21ES031646-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10218403. Licensed CC0.

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