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Neurotoxic Effects of Human-Relevant Per- and Polyfluoroalkyl Substance Mixtures: A Multi-Omics Investigation of Memory Loss

Award Number: R21ES038702
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2026
PERIOD OF PERFORMANCE END DATE: 07/06/2028

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Neurotoxic Effects of Human-Relevant Per- and Polyfluoroalkyl Substance Mixtures: A Multi-Omics Investigation of Memory Loss - PROJECT SUMMARY/ABSTRACT Among older adults, Alzheimer's Disease and Related Dementias (ADRD) is the leading cause of dementia in the United States. A combination of genetic risk factors and exposures to environmental toxicants across the lifespan is thought to contribute to the etiology, progression, and severity of the decline in cognitive function, including memory loss, associated with ADRD. Laboratory and epidemiological findings demonstrate that ex- posure to per- and polyfluoroalkyl substances (PFAS) can cause or exacerbate memory loss. However, it is unknown how PFAS mixtures affect gene expression in brain regions relevant to memory. Because epide- miological studies cannot address this knowledge gap, there is a critical need to (1) assess changes in the brain region-dependent gene expression relevant to memory in animal models following exposure to a human- relevant PFAS mixture and (2) identify individual PFAS associated with these genes. Identifying individual PFAS relevant to memory is important because environmental factors, unlike genetic risk factors for ADRD, are modifiable. Our long-term goal is to characterize the contribution of environmental exposures to PFAS to ADRD and ultimately prevent ADRD by utilizing system-level exposomics and transcriptomics data. The overall objective of this project is to identify individual PFAS contributing to altered gene expression in the hippocam- pus and associated regions and memory loss following exposure to a complex, human-relevant PFAS mixture in mice. Our central hypothesis is that oral exposure to a human-relevant PFAS mixture dose-dependently im- pairs memory in mice by altering brain region-specific gene expression, with brain levels of individual PFAS compounds corresponding to more pronounced changes in the expression of these genes. This hypothesis builds on published evidence that PFAS are present in the brain and that PFAS exposure can exacerbate cog- nitive decline. To test this hypothesis, we will orally expose male and female mice to human-relevant doses of a PFAS mixture and employ a spatial network analysis approach to integrate data across the Specific Aims to identify PFAS associated with changes in gene expression in the hippocampus and adjacent brain regions. We will test our central hypothesis by (1) characterizing the dose-dependent disposition of PFAS in tissues, (2) in- vestigating the dose-dependent effects of PFAS exposure on hippocampus-dependent memory, and (3) char- acterizing the association between individual PFAS and differentially expressed genes in the brain, particularly genes relevant to memory, in PFAS-exposed mice. The proposed research is innovative because it employs a novel spatial network approach to investigate the interplay between a PFAS mixture and the brain transcrip- tome in mice. The successful completion of these aims will identify specific PFAS compounds linked to altered gene expression, particularly those involved in memory, in the brains of adult mice experiencing memory loss. These findings will inform future mechanistic studies investigating the link between PFAS exposure and memory loss relevant to ADRD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $427,625 )
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Environmental Health	000	1	7/8/2026	NEW	$427,625
														Subtotal = $427,625

Grand Total All Awards = $427,625

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Neurotoxic Effects of Human-Relevant Per- and Polyfluoroalkyl Substance Mixtures: A Multi-Omics Investigation of Memory Loss

Award Number: R21ES038702

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/07/2026

PERIOD OF PERFORMANCE END DATE: 07/06/2028

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