Scientists identify 11 genes affected by PFAS, shedding light on neurotoxicity

Perfluorinated and polyfluorinated alkyl substances (PFAS) persist in water, soil, and even human brains, earning them the nickname “forever chemicals.” This unique ability to cross the blood-brain barrier and accumulate in brain tissue makes PFASs of particular concern, but the mechanisms underlying their neurotoxicity need to be further studied.

To this end, a new study by University of 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 products. Identified. The paper will be published in the journal ACS Chemical Neuroscience.

These genes, some of which are involved in processes essential to nerve cell health, were found to be consistently affected by PFAS exposure, with more or less expression, regardless of the type of PFAS compound tested. I did. For example, all of the compounds decreased the expression of a gene important for neuronal survival and increased the expression of another gene associated with neuronal cell death.

“Our findings indicate that these genes may serve as future markers for detecting and monitoring PFAS-induced neurotoxicity,” said first co-corresponding author G. Ekin. said Atilla-Gokcumen, Dr. Marjorie E. Winkler. Department of Chemistry within the UB College of Arts and Sciences.

Still, the study found more than hundreds of genes whose expression changed in different directions based on the compounds tested. Furthermore, there was no correlation between the level at which PFAS accumulated within cells and the extent to which PFAS caused differential gene expression.

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

“Despite sharing certain chemical characteristics, PFAS differ in shape and size, leading to variation in their biological effects. “Knowledge of how people react to PFAS is of biomedical importance,” said other researchers in the study. Co-corresponding author Dr. Diana Agha, Distinguished Professor, State University of New York, Henry M. Woodburn Professor, Department of Chemistry, Director, UB RENEW Institute;

“Depending on chain length and headgroup, PFAS can have very different effects on cells,” Atilla-Gokcumen adds. “We shouldn’t look at them as one big class of compounds, but rather as compounds that actually need to be investigated individually.”

Other authors include Dr. Omar Gokmen, professor in the School of Biological Sciences;

The ups and downs of gene expression

PFAS are not immediately toxic. We are exposed to them almost every day through things like drinking water and food packaging, and we don’t even realize it.

“Researchers therefore need to look beyond just whether a cell lives or dies, to find endpoints further upstream in cellular processes,” Atila-Gokumen says.

The research team is investigating how PFAS affects gene expression in neuron-like cells and how they affect lipids, molecules that help make up cell membranes, among other important functions. I decided to focus on it. Exposure to different PFAS for 24 hours resulted in modest but distinct changes in lipids, with more than 700 genes differentially expressed.

Of the six PFAS tested, perfluorooctanoic acid (PFOA), once commonly used in nonstick pans and recently deemed hazardous by the EPA, has the highest impact. The power was great. Despite its low uptake, PFOA altered the expression of nearly 600 genes, while no other compound altered more than 147. Specifically, PFOA decreased the expression of genes involved in synaptic growth and neuronal function.

In total, the six compounds induced changes in biological pathways involved in hypoxic signaling, oxidative stress, protein synthesis, and amino acid metabolism that are important for neuronal function and development.

Eleven of the genes were found to be more or less similarly expressed for all six compounds. One gene that was consistently downregulated was midbrain astrocyte-derived neurotrophic factor. This is important for neuronal survival and has been shown to reverse symptoms of neurodegenerative diseases in rats. One gene that is consistently upregulated is thioredoxin-interacting protein, which is thought to be associated with neuronal cell death.

“Each of these 11 genes showed consistent regulation across all PFASs we tested. This uniform response suggests they may serve as promising markers for assessing PFAS exposure. However, further research is needed to understand how these genes respond to other types of PFAS.”

Identify the worst option

PFAS can be harmful, but the reality is that no good replacement has yet been found.

The compound could potentially be substituted in applications such as food packaging, but its effectiveness in firefighting and semiconductor manufacturing, for example, may need to continue in the long term.

That’s why research like this is important, Atila-Gokumen says. The fact that most genes respond differently to different compounds, and the lack of correlation between the uptake of PFAS into cells and the degree of genetic changes they cause, explains how unique each of these compounds is. It highlights what it is.

“If we can understand why some PFAS are more harmful than others, we can prioritize phasing out the most harmful PFAS while seeking safer alternatives. For example: “Alternatives like short-chain PFAS are being considered because they have low persistence in the environment and tend to accumulate,” Atila-Gokumen explains.

“However, efficacy may be sacrificed due to reduced persistence in certain applications, and there are concerns about potential unknown health effects, which warrant further investigation. Further research is needed to confirm that it is truly safe and effective. This study is a major step toward achieving this goal.”