These 11 genes may help us better understand forever chemicals' effects on the brain

This unique ability to cross the blood-brain barrier and accumulate in brain tissue makes PFAS particularly concerning, but the underlying mechanism of their neurotoxicity needs to be studied further.

To that end, a new study by University at Buffalo researchers has identified 11 genes that may hold the key to understanding the brain's response to these pervasive chemicals commonly found in everyday items.

These genes, some involved in processes vital for neuronal health, were found to be consistently affected by PFAS exposure, either expressing more or less, regardless of the type of PFAS compounds tested. For example, all compounds caused a gene key for neuronal cell survival to express less, and another gene linked to neuronal cell death to express more.

"Our findings indicate these genes may be markers to detect and monitor PFAS-induced neurotoxicity in the future," says lead co-corresponding author G. Ekin Atilla-Gokcumen, PhD, Dr. Marjorie E. Winkler Distinguished Professor in the Department of Chemistry, within the UB College of Arts and Sciences.

Still, the study, published in the Dec. 18 issue of ACS Chemical Neuroscience, found hundreds more genes whose expression changed in different directions based on the compound tested. Plus, there was no correlation between the level at which PFAS accumulates in a cell and the extent to which it causes differential gene expression.

Taken together, this suggests that distinct molecular structures within each type of PFAS drives 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. "We should not be viewing them as one large class of compounds, but really as compounds that we need to investigate individually."

Other authors include Omer Gokcumen, PhD, professor in the Department of Biological Sciences. The study was supported by the U.S. Environmental Protection Agency (EPA).

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.

"Therefore, researchers need to find points of assessment further upstream in the cellular process than just whether a cell lives or dies," Atilla-Gokcumen says.

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.

Of the six types of PFAS tested, perfluorooctanoic acid (PFOA) -- once commonly used in nonstick pans and recently deemed hazardous by the EPA -- was by far the most impactful. Despite its small uptake, PFOA altered the expression of almost 600 genes -- no other compound altered more than 147. 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. One of the genes that was consistently downregulated was mesencephalic astrocyte derived neurotrophic factor, which is important for the survival of neuronal cells and has been shown to reverse symptoms of neurodegenerative diseases in rats. One of the genes consistently upregulated was thioredoxin interacting protein, which has been linked to neuronal cell death.

"Each of these 11 genes exhibited consistent regulation across all PFAS that we tested. This uniform response suggests that they may serve as promising markers for assessing PFAS exposure, but further research is needed to know how these genes respond to other types of PFAS," Atilla-Gokcumen says.

Identifying the least-worst options

As harmful as PFAS can be, the reality is that good substitutes have yet to be found.

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 reaction most genes had to different compounds, as well as the lack of correlation between PFAS uptake into cells and the extent of gene change expression they cause, underscores just how unique each of these compounds are.

"If we understand why some PFAS are more harmful than others, we can prioritize phasing out the worst offenders while seeking safer substitutes. 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, their reduced persistence may come at the cost of effectiveness in certain applications, and there are concerns about potential unknown health effects that require further investigation. Further research is needed to ensure these substitutes are genuinely safer and effective for specific applications," Atilla-Gokcumen explains. "This research is a major step towards achieving this goal."