Categories: Health

The Genetic Impact of Forever Chemicals on Brain Function

Summary: Researchers have found that per- and polyfluorinated alkyl substances (PFAS) alter the expression of specific genes in brain cells, potentially contributing to neurotoxicity. Of the six compounds tested, perfluorooctanoic acid (PFOA) caused the most significant changes, down-regulating genes crucial for neuron survival and up-regulating those linked to cell death.

Despite common chemical characteristics, the biological effects of PFAS vary widely, making it essential to study each compound individually. These findings can help identify genetic markers of PFAS exposure and prioritize safer alternatives to phase out harmful compounds.

Key facts:

  • Impact of gene expression: Exposure to PFAS changes more than 700 genes, affecting neuronal function.
  • Most harmful compound: PFOA has a significant impact on genes related to synaptic growth and neuron survival.
  • Identified marker genes: Eleven genes consistently responded to all six PFAS tested, suggesting their use as exposure markers.

Source: University at Buffalo

Per- and polyfluoroalkyl substances (PFAS) earn their nickname “forever chemicals” by persisting in water, soil, and even the human brain.

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

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

To that end, a new study led by researchers at the University at Buffalo has identified 11 genes that could be key to understanding the brain’s response to these ubiquitous chemicals commonly found in everyday objects.

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 the December 18 issue of ACS chemical neuroscience, found 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.

Of the six types of PFAS tested, perfluorooctanoic 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 fighting fires 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 potential unknown health effects that require further investigation.”

“More 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.”

About this research news in genetics and neuroscience

Author: Tom Dinki
Source: University at Buffalo
Contact: Tom Dinki – University at Buffalo
Picture: Image is credited to Neuroscience News

Original research: Free access.
“Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells Using Transcriptomic and Lipidomic Analysis” by Marjorie E. Winkler et al. ACS chemical neuroscience


Abstract

Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells Using Transcriptomic and Lipidomic Analysis

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants that bioaccumulate in tissues and pose risks to human health. Growing evidence links PFAS to neurodegenerative and behavioral disorders, but the underlying mechanisms of their effects on neuronal function remain largely unexplored.

In this study, we used SH-SY5Y neuroblastoma cells, differentiated into neuronal-like cells, to study 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.

After exposure to 30 μM for 24 h, PFAS accumulation ranged between 40 and 6,500 ng/mg protein. Transcriptomic analysis revealed 721 differentially expressed genes (DEGs) across treatments (padj

PFOA-treated cells showed downregulation of genes involved in synaptic growth and neuronal function, while exposures to PFOS, PFDS, FTS 8:2, and FTOH 8:2 resulted in upregulation genes related to the response to hypoxia and amino acid metabolism.

Lipid profiling further demonstrated a significant increase in fatty acid levels with PFDA, PFDS, and 8:2 FTS treatments and depletion of triacylglycerols with 8:2 FTOH treatments.

These results suggest that the neurotoxic effects of PFAS are structurally dependent, providing insight into the molecular processes that may lead to PFAS-induced neuronal dysfunction.

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