Summary: Researchers have found that per- and polyfluorinated alkyl substances ( PFAS ) alter the expression of specific genes in brain-like cells, potentially contributing to neurotoxicity. Perfluorooctanoic acid ( PFOA ) was one of the six tested compounds that caused the most significant changes, downregulating genes essential for neuron survival and upregulating those linked to cell death.
Despite shared substance traits, PFAS vary widely in their natural effects, making it important to study each element separately. These findings may help determine biological PFAS exposure symbols and prioritize safer alternatives to phasing out harmful substances.
Important Information:
- Gene Expression Impact: PFAS exposure impacts over 700 chromosomes, affecting cerebral work.
- Most Dangerous Mixture: PFOA has a significant impact on genes involved in neuron survival and neural growth.
- Marker Genes Identified: Eleven genes constantly respond to all six tested PFAS, suggesting usage as publicity signs.
Origin: University at Buffalo
Per- and polyfluorinated alkyl substances ( PFAS ) earn their “forever chemical” moniker by persisting in water, soil and even the human brain.  ,
PFAS is particularly concerning because of its unique ability to cross the blood-brain challenge and build up in brain tissue, but the main process of their neurotoxicity needs to be more investigated.  ,
To address this, researchers at the University at Buffalo recently found 11 genes that may hold the key to understanding how the brain responds to these widespread chemicals found in everyday objects.
Regardless of the type of PFAS compounds tested, it was discovered that some genes, some of which are involved in procedures critical for neuronal health, were constantly exposed to PFAS, either expressing more or less, regardless of the type of PFAS substances.
For instance, all ingredients resulted in the expression of one gene that controls neuronal cell success but not another that controls neuronal cell death.
” Our studies indicate these chromosomes may be signs to identify and track PFAS-induced neurotoxicity in the future”, says direct co-corresponding artist G. Ekin Atilla-Gokcumen, PhD, Dr. Marjorie E. Winkler Distinguished Professor in the Department of Chemistry, within the UB College of Arts and Sciences.
However, the study, published in the Dec. 18 problem of , ACS Chemical Neuroscience, found hundreds more genes whose expression changed in various directions based on the substance tested.
Additionally, there was no correlation between the degree to which PFAS accumulates in a cell and the extent to which it causes differential gene expression.  ,
Together, these findings suggest that different molecular structures within each PFAS type cause changes in gene expression.  ,
” PFAS, despite sharing certain chemical characteristics, come in different shapes and sizes, leading to variability in their biological effects. Thus, knowledge on how our own biology reacts to the different types of PFAS is of major biomedical relevance”, says the study’s other co-corresponding author, Diana Aga, PhD, SUNY Distinguished Professor and Henry M. Woodburn Chair in the Department of Chemistry, and director of the UB RENEW Institute.
” Depending on their chain length or headgroup, PFAS can have very different effects on cells”, Atilla-Gokcumen adds. They should not be viewed as a single large class of compounds, but as individual compounds that need to be studied.
Other authors include Omer Gokcumen, PhD, professor in the Department of Biological Sciences. The U.S. Environmental Protection Agency ( EPA ) provided funding for the study.
Ups and downs of gene expression
PFAS aren’t immediately toxic. We’re exposed to them practically every day, including through drinking water and food packaging, and don’t notice.
Further upstream in the cellular process than just whether a cell lives or dies, according to Atilla-Gokcumen.
The team decided to focus on how PFAS affects the gene expression of neuronal-like cells, as well as how PFAS affects lipids, which are molecules that help make up the cell membrane, among other important functions.
Exposure to different PFAS for 24 hours resulted in modest but distinct changes in lipids, and over 700 genes to express differently.
Perfluorooctanoic acid ( PFOA ), one of the six PFAS types tested and recently deemed hazardous by the EPA, was by far the most harmful.
No other compound has had more than 147 genes altered by PFOA despite its modest uptake. Specifically, PFOA decreased the expression of genes involved in synaptic growth and neural function.  ,
Altogether, the six compounds caused changes in biological pathways involved in hypoxia signaling, oxidative stress, protein synthesis and amino acid metabolism, all of which are crucial for neuronal function and development.  ,
Eleven of the genes were found to express the same way, either more or less, to all six compounds. Mesencephalic astrocyte-derived neurotrophic factor, which is crucial for the survival of neuronal cells and has been shown to reverse the symptoms of neurodegenerative diseases in rats, was one of the genes that was consistently downregulated.
The thioredoxin-interacting protein, which has been linked to neuronal cell death, was one of the genes that was consistently upregulated.
Each of these 11 genes showed consistent regulation across all PFAS that we tested. Although this consistent response points to potential potential PFAS exposure, further investigation is required to understand how these genes respond to various other PFAS, according to Atilla-Gokcumen.
Identifying the least-worst options
PFAS can be harmful, but there are still good alternatives to find.
The compounds can perhaps be replaced in applications like food packaging, but their effectiveness in firefighting and semiconductor manufacturing, for example, may need to continue long term.
That’s why studies like this are crucial, Atilla-Gokcumen says. The varied reactions that most genes had to various substances, as well as the lack of correlation between the level of gene change expression they cause and PFAS uptake into cells, highlights how individual each of these substances are.  ,
We can prioritize eliminating the worst offenders while looking for safer alternatives if we understand why some PFAS are more harmful than others. For example, alternatives like short-chain PFAS are being explored, as they tend to persist less in the environment and accumulate less in biological systems.
However, some applications may have a lower return on investment because of their lessening persistence, and there are concerns about potential unknowable health effects that warrant further investigation.
” Further research is needed to ensure these substitutes are genuinely safer and effective for specific applications”, Atilla-Gokcumen explains.
” This study represents a significant step in the direction of this objective.”
About this news about neuroscience and genetics
Author: Tom Dinki
Source: University at Buffalo
Contact: Tom Dinki – University at Buffalo
Image: The image is credited to Neuroscience News
Original Research: Open access.
Marjorie E. Winkler et al.,” Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells through Transcriptomics and Lipidomics.” ACS Chemical Neuroscience
Abstract
Transcriptomics and lipidomics analysis to investigate the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells
Per- and polyfluorinated alkyl substances ( PFAS ) are widespread environmental pollutants that bioaccumulate in tissues and pose risks to human health. Neurodegenerative and behavioral disorders are increasingly linked to PFAS, but their underlying causes of neuronal function are largely unexplored.
In this study, we utilized SH-SY5Y neuroblastoma cells, differentiated into neuronal-like cells, to investigate the impact of six PFAS compounds─perfluorooctanoic acid ( PFOA ), perfluorooctanesulfonic acid ( PFOS), perfluorodecanoic acid ( PFDA ), perfluorodecanesulfonic acid ( PFDS ), 8: 2 fluorotelomer sulfonate ( 8: 2 FTS), and 8: 2 fluorotelomer alcohol ( 8: 2 FTOH) ─on neuronal health.
Following a 30 μM exposure for 24 h, PFAS accumulation ranged from 40–6500 ng/mg of protein. Transcriptomic analysis revealed 721 differentially expressed genes ( DEGs ) across treatments ( padj , <, 0.05 ), with 11 DEGs shared among all PFAS exposures, indicating potential biomarkers for neuronal PFAS toxicity.
PFOA-treated cells showed downregulation of genes involved in synaptic growth and neural function, while PFOS, PFDS, 8: 2 FTS, and 8: 2 FTOH exposures resulted in the upregulation of genes related to hypoxia response and amino acid metabolism.
Lipidomic profiling further revealed significant increases in fatty acid levels with 8: 2 FTS and a depletion of triacylglycerols with 8: 2 FTOH treatments.
These findings provide insights into the molecular processes that may be responsible for PFAS-induced neuronal dysfunction and suggest that the neurotoxic effects of PFAS are structurally dependent.
