Chemicals forever in the brain? New study reveals silent invasion

University at Buffalo researchers reveal molecular insights into the neurotoxic effects of PFAS.

Per- and polyfluorinated alkyl substances (PFAS), often referred to as “forever chemicals,” are known for their persistence in water, soil, and even the human brain.

There are significant concerns about their ability to cross the blood-brain barrier and accumulate in brain tissues, but the mechanisms underlying their neurotoxic effects remain poorly understood.

A recent study by researchers at the University at Buffalo identified 11 genes that could play a crucial role in understanding how the brain responds to these persistent and widely used chemicals in the environment.

These genes, some of which are involved in processes vital to neuronal health, were found to be consistently affected by PFAS exposure, whether expressed more or less, regardless of the type of PFAS compound tested. For example, all compounds caused lower expression of a key gene for neuronal cell survival, and higher expression of another gene linked to neuronal cell death.

“Our results indicate that these genes could be markers to detect and monitor PFAS-induced neurotoxicity in the future,” says co-corresponding senior author G. Ekin Atilla-Gokcumen, PhD, Dr. Marjorie E. Winkler, professor emeritus in the Department of Chemistry. , within the UB College of Arts and Sciences.

However, the study, published in ACS Chemical Neurosciencediscovered hundreds of additional genes whose expression changed in different directions depending on the compound tested. Additionally, there was no correlation between the level at which PFAS accumulates in a cell and the extent to which they cause differential gene expression.

Taken together, this suggests that distinct molecular structures within each type of PFAS drive changes in gene expression.

“PFAS, although they share some chemical characteristics, come in different shapes and sizes, leading to variability in their biological effects. Thus, knowledge of how our own biology responds to different types of PFAS is of major biomedical importance,” says the study’s other co-corresponding author, Diana Aga, PhD, SUNY Distinguished Professor and the Henry M. Woodburn Chair in the Department of Chemistry. , and director of the UB RENEW Institute.

“Depending on their chain length or head group, PFAS can have very different effects on cells,” adds Atilla-Gokcumen. “We shouldn’t think of them as a large class of compounds, but rather as compounds that we need to study individually. »

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

Ups and downs in gene expression

PFAS are not immediately toxic. We are exposed to it almost every day, particularly through drinking water and food packaging, without realizing it.

“Therefore, researchers need to find assessment points further upstream of the cellular process than just whether a cell lives or dies,” says 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 be expressed differently.

Among the six types of PFAS tested, perfluorooctanoics acid (PFOA) – once commonly used in nonstick pans and recently deemed unsafe by the EPA – was by far the most impactful. Despite its low absorption, PFOA altered the expression of nearly 600 genes – no other compound altered more than 147. Specifically, PFOA decreased the expression of genes involved in synaptic growth and function. neuronal.

In total, all 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 be expressed the same way, more or less, for all six compounds. One of the genes consistently downregulated was mesencephalic astrocyte-derived neurotrophic factor, which is important for neuronal cell survival and has been shown to reverse the symptoms of neurodegenerative diseases in rats. One of the consistently upregulated genes was thioredoxin-interacting protein, which has been associated with neuronal cell death.

“Each of these 11 genes showed consistent regulation across all PFASs we tested. This uniform response suggests that they could serve as promising markers for assessing PFAS exposure, but more research is needed to learn how these genes respond to other types of PFAS,” says Atilla-Gokcumen.

Identify the least worst options

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

These compounds may perhaps be replaced in applications such as food packaging, but their effectiveness in firefighting and semiconductor manufacturing, for example, may need to continue in the long term.

That’s why studies like this are crucial, says Atilla-Gokcumen. The varied response of most genes to different compounds, as well as the lack of correlation between the uptake of PFAS into cells and the extent of expression of the genetic changes they cause, highlights how each of these compounds is unique.

“If we understand why some PFAS are more harmful than others, we can prioritize phasing out the worst offenders while pursuing safer substitutes.” For example, alternatives such as short-chain PFAS are being explored because they tend to persist less in the environment and accumulate less in biological systems. However, their reduced persistence may come at the expense of effectiveness in some applications, and concerns exist about unknown potential health effects that require further research. Further research is needed to ensure that these substitutes are truly safer and effective for specific applications,” says Atilla-Gokcumen. “This research represents a major step toward achieving this goal.”

Reference: “Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells Using Transcriptomic and Lipidomic Analysis” by Logan Running, Judith R. Cristobal, Charikleia Karageorgiou, Michelle Camdzic, John Michael N. Aguilar, Omer Gokcumen, Diana S. Aga and G. Ekin Atilla-Gokcumen, November 27, 2024, ACS Chemical Neuroscience.
DOI: 10.1021/acschemneuro.4c00652

The study was funded by the Environmental Protection Agency.