pfas exposure alters brain genes neurotoxicity risks

PFAS Exposure Alters Brain Genes, Reveals Neurotoxicity Risks-University at Buffalo Study

Introduction to PFAS and their Risks

Per-and polyfluorinated alkyl substances (PFAS), commonly referred to as 'forever chemicals,' are recognized for their resilience in water, soil and human brain tissue. This capacity to bypass the blood-brain barrier and deposit in brain cells heightens their profile, necessitating deeper exploration into their neurotoxic effects.

Study Overview: Identifying Key Genes Affected by PFAS

A recent study conducted by researchers at the University at Buffalo has pinpointed 11 genes that could elucidate the brain's response to these ubiquitous chemicals found in everyday products. The findings are detailed in ACS Chemical Neuroscience.

Gene Expression Changes Due to PFAS Exposure

These genes, many of which play crucial roles in maintaining neuronal health, were consistently impacted by PFAS exposure, either upregulated or downregulated, irrespective of the specific PFAS compounds tested.

• Reduced Expression: One gene essential for neuronal cell survival was downregulated.
• Increased Expression: A gene associated with neuronal cell death was upregulated.

Insights from the Study's Lead Authors

According to G. Ekin Atilla-Gokcumen, Ph.D., lead co-corresponding author and Dr. Marjorie E. Winkler Distinguished Professor in the Department of Chemistry at UB, "Our findings suggest that these genes could serve as markers for detecting and monitoring PFAS-induced neurotoxicity in the future."

Additional Findings on Gene Expression Variability

However, the study revealed that hundreds of additional genes exhibited changes in expression, with variations depending on the compound tested. Furthermore, no correlation was found between the levels of PFAS accumulation in a cell and the degree of differential expression.

Impact of Molecular Structures on Gene Expression

Collectively, these findings indicate that the unique molecular structure of each PFAS type influence changes in gene expression.

"Although PFAS share some common chemical traits, their varying shapes and sizes result in differences in their biological effects. Understanding how our biology responds to the diverse types of PFAS is therefore of significant biomedical importance," states Diana Aga, Ph.D., the study's co-corresponding author, SUNY Distinguished Professor, Henry M. Woodburn Chair in the Department of Chemistry, and director of the UB RENEW Institute."

Investigating the Effects of PFAS on Cellular Processes

The Importance of Studying Lipids and Gene Expression

Atilla-Gokcumen further emphasizes, "Depending on the chain length or headgroup, PFAS can have significantly different effects on cells. We should not treat them as a single class of compounds, but rather as distinct compounds that warrant individual investigation."

Also contributing to the study are Omer Gokcumen, Ph.D., a professor in the Department of Biological Sciences.

Changes in Gene Expression Patterns in Neuronal Cells

PFAS do not exhibit immediate toxicity. We encounter them regularly, such as in drinking water and food packaging, often without awareness.

Atilla-Gokcumen emphasizes that researchers must identify earlier points of assessment in the cellular process, beyond simply determining whether a cell survives or dies.

Detailed Impact of PFAS on Lipids and Genes

Observations from PFAS Exposure in Neuronal-like Cells

The research team chose to investigate the impact of PFAS on the gene expression of neuronal-like cells and on lipids, molecules crucial for the cell membrane and other key functions. After 24-hour exposure to various PFAS, they observed moderate yet distinct alternations in lipid composition, along with differential expression in over 700 genes.

PFOA: The Most Impactful Compound

Among the six PFAS compounds tested, perfluorooctanoic acid (PFOA), which was previously used in nonstick cookware and recently classified as hazardous by the EPA, had the most profound impact. Despite minimal uptake, PFOA altered nearly 600 genes, far surpassing any other compound, which affected no more than 147 genes. Notably, PFOA reduced the expression of genes related to synaptic growth and neural function.

Broader Impact on Biological Pathways

Collectively, the six compounds led to alteration in biological pathways related to hypoxia signaling, oxidative stress, protein synthesis, and amino acid metabolism—key processes for neuronal function and development.

Consistent Gene Regulation Across PFAS Compounds

Uniform Gene Expression Patterns

Eleven gene consistently exhibited similar expression patterns—either upregulated or downregulated—across all six compounds. One of the genes consistently downregulated was mesencephalic astrocyte-derived neurotrophic factor, which is critical for neuronal cell survival and has been shown to alleviate symptoms of neurodegenerative diseases in rat models. Conversely, thioredoxin-interacting protein, consistently upregulated, has been associated with neuronal cell death.

"All 11 genes displayed consistent regulation across the PFAS compounds tested. This uniformity in response points to their potential as reliable markers for PFAS exposure assessment, though further research is required to explore how these genes react to different types of PFAS," says Atilla-Gokcumen.

The Challenge of Identifying Safer Alternatives

The Need for Effective Alternatives

Despite the significant harm posed by PFAS, effective alternatives have not yet been identified.

Long-Term Need for PFAS in Critical Applications

While alternatives may be found for uses such as food packaging, their role in critical sectors like firefighting and semiconductor manufacturing may remain indispensable in the foreseeable future.

Evaluating the Harmful PFAS Compounds

As Atilla-Gokcumen points out, studies like are essential. The diverse gene reactions to different compounds, combined with the absence of a direct link between PFAS uptake and gene expression changes, highlights the distinct nature of each compound.

Prioritizing Harmful PFAS and Exploring Safer Substitutes

"By identifying the most harmful PFAS compounds, we can focus on eliminating the worst offenders and pursuing safer altrnatives, short-chain PFAS, which are less persistent in the environment and accumulate less in organisms, are being considered as potential substitutes," Atilla-Gokcumen explains.

"While short-chain PFAS exhibit lower environmental persistence, their effectiveness in certain applications may be compromised, and concerns about potential unforeseen health risks remain. Additional studies are essential to confirm the safety and efficacy of these substitutes for specific uses. This research represent a crucial advancement toward that goal."

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Stay Informed About the Latest on PFAS and Environmental Health!

Understanding the impact of PFAS on human health and the environment is more crucial than ever. With new research revealing the potential neurotoxicity and other harmful effects of these chemicals, staying up-to-date on the latest findings is essential.

For more insights into PFAS research and environmental health issues, explore our other blogs:

• Human Health Issues Blog: Dive Deeper into the complex relationship between chemicals and health in our Human Health Issues Blog.
• FSNews365: Stay informed about emerging scientific breakthroughs and their real-world implications on health and the environment. Visit FSNews365 for more articles.
• Earth Day Harsh Reality: Learn about the environmental impact of chemicals like PFAS and discover solutions to create a sustainable future, Explore Earth Day Harsh Reality.

Join the conversation and help drive awareness for a healthier planet and population.

viking genetic lineages in Faroe islands

Distinct Viking Lineages Found in Faroe Islands and Iceland, Study Shows

Introduction to Viking Colonization of the Faroe Islands and Iceland

Geneticists have analyzed the Y-chromosome haplogroup distribution in the Faroe Islands, colonized by Vikings circa 900 CE, and compared it to modern Scandinavian populations.

Their analysis revealed that the haplotype distribution in the Faroe Islands most closely resembled Norway and Denmark, with weaker resemblance to Sweden, and diverged from Iceland. This supports the conclusion that Viking settlers in the Faroe Islands originated across Scandinavia, differing geographically and genetically from those who settled in Iceland.

Viking Origins and Settlement Patterns

Viking's Maritime Ambitions and North Atlantic Expansion

During the late eighth to eleventh centuries, Vikings demonstrated extraordinary maritime ambition, journeying across the Atlantic to North America and Greenland, and charting paths through the Mediterranean and Eurasia.

Early Habitation in the Faroe Islands

The Faroe Islands, a North Atlantic archipelago of 18 islands, are among the places the Vikings are known to have settled. However, archaeological evidence Suggests earlier habitation dating back to around 300 CE, possibly by Celtic monks or other groups from the British Isles. According to the Faereyinga Saga, written around 1200, Viking chief Grimur Kamban established a settlement there between 872 and 930 CE.

From which region of Scandinavia did Grimur and his followers originate?

Study Methodology and Genetic Analysis

Research Team and Objectives

According to Dr. Christopher Tillquist, associate professor at the University of Louisville and lead author of a study in Frontiers in Genetics, "Our findings provide strong evidence that the Faroe Islands were colonized by male settlers from different Scandinavian populations.

Dr. Allison Mann from the University of Wyoming and Dr. Eyðfinn Magnussen from the University of the Faroe Islands collaborated with Tillquist as co-authors.

Genetic Analysis of Faroese Men

The researchers analyzed the genotypes of 139 men from the Faroese islands of Borðoy, Streymoy, and Suðuroy, focusing on 12 "short tandem repeat" (STR) loci on the Y-chromosome. Each individual was assigned to the most probable haplogroup, which reflects varying distributions across modern Europe.

Comparison with Modern Scandinavian Populations

The researchers compared the genotype distributions of the Faroese sample to those of 412 men from Norway, Sweden, Denmark, Iceland, and Ireland, enabling the reconstruction of the Viking founder's source population.

Key Findings of the Study

Distinct Viking Lineages in the Faroe Islands and Iceland

The analysis revealed that the haplotype distribution in the Faroe Islands most closely resembled Norway and Denmark, with weaker resemblance to Sweden. It diverged significantly from Iceland, suggesting that Viking settlers in the Faroe Islands came from across Scandinavia, differing geographically and genetically from those who settled in Iceland.

Innovative Genetic Methodology: "Mutational Distance from Modal Haplotype"

The authors introduced an innovative genetic method, termed "Mutational Distance from Model Haplotype," to analyze variation in SNPs within the STRs, uncovering a "founder effect" in the genetic makeup of modern Faroese and Icelandic male populations, a result of historical colonization by a limited number of individuals.

Implications of the Findings

Distinct Genetic Signatures in the Faroe Islands and Iceland

"While it has long been assumed that the Faroe Islands and Iceland were settled by similar Norse populations, our innovative analysis reveals that the founders of these islands came from distinct gene pools within Scandinavia," stated Tillquist.

"A group with diverse Scandinavian origins settled in the Faroe Islands, while a genetically distinct group of Vikings colonized Iceland, leaving behind separate genetic signatures that endure today."

"Despite the geographic closeness, there appears to have been no subsequent interbreeding between these two  populations. Our findings indicate that the Viking expansion into the North Atlantic was more intricate than previously understood."

The Genetic Legacy of Viking Exploration

"Every longship that embarked on the journey to these remote islands carried not just Vikings, but the unique genetic legacies of their homelands. Through tracing these distinct routes of settlement and conquest, we can now tell a more multifaceted story of Viking exploration than what history has previously conveyed," stated Tillquist.

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Want to learn more about Viking history and genetics? Explore our comprehensive articles on Viking expansion, DNA studies, and ancient maritime journeys.

innovative-crispr-gene-silencing-without-dna-cuts

Innovative CRISPR System Silences Genes Without DNA Cuts

Researchers at Vilnius University's Life Sciences Center (LSC), under the leadership of Prof. Patrick Pausch, have uncovered a novel mechanism for silencing specific genes without the need for DNS cutting. Published in Nature Communications, this breakthrough allows cells to 'pause' certain genetic instructions, offering a fresh approach to gene regulation.

Research Team and Collaboration

The research group, comprising doctoral student Rimvydė Čepaite, Dr. Aistė Skorupskaitė, undergraduate Gintarė Žvejyte, and Prof. Pausch from Vilnius University, in collaboration with international partners, has uncovered how cells employ a targeted system to identify and silence unwanted DNA. This discovery holds potential for developing safer gene modification techniques, paving the way for repairing disease-causing genes.

The Novelty of the Type IV-A CRISPR System

Differences from Conventional CRISPR Gene Editing

According to Prof. Pausch, the newly examined type IV-A CRISPR system differs from the conventional CRISPR gene-editing approach, which acts like molecular 'scissors' to cut genes. This system instead uses an RNA-guided complex to direct the enzyme DinG along DNA strands, achieving gene silencing in a more nuanced manner.

Mechanism of Gene Silencing

The researcher finds it intriguing that the system can identify the exact DNA site needed for its action. "This process involves Cas8 and Cas5 proteins, which locate a short motif next to the RNA guide's target. When this motif is detected, the proteins unwind the DNA, enabling a closer look at the target sequence."

R-loops and the Role of RNA in Gene Silencing

Understanding R-loops in DNA Binding

An essential step in this process involves the creation of R-loops—open DNA configurations where RNA binds, triggering the system to begin gene silencing.

"The 'R' in R-loop denotes RNA," explains the research professor. "This structure is fundamental in DNA-binding CRISPR-Cas systems, allowing them to examine DNA and locate the precise target. A stable R-loop forms only if the DNA sequence closely aligns with the guide RNA, serving as a cue for initiating gene silencing."

The Role of the DinG Enzyme

He explains that the DinG enzyme intensifies gene suppression by separating DNA strands, allowing the system to act across an extended DNA region.

Implications for Future Gene Editing Applications

This discovery paves the way for genome editing applications that avoid DNA cuts, potentially leading to more accurate tools for research and biotechnology. "Our system's ability to traverse DNA without making cuts is particularly promising for advanced gene-editing techniques," remarks Prof. Pausch, who believes this approach could offer safer options for societal benefit through genetic modifications.

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fixing-genes-before-birth-mrna-delivery-prenatal-therapy

Fixing Genes Before Birth: Innovative mRNA Delivery for Prenatal Therapy

Overview of the Breakthrough

Recent research demonstrates a biomedical tool capable of delivering genetic material to edit faulty genes within developing fetal brain cells. Tested in mice, this technology may prevent the onset of neurodevelopmental conditions, including Angelman and Rett syndromes, before birth.

Quote: "This technology has far-reaching implications for neurodevelopmental therapy," said Aijun Wang, UC Davis professor of surgery and biomedical engineering. "We may be able to correct genetic issues fundamentally during vital brain development windows."

Collaborative Research Efforts

This study, a collaboration between the Wang Lab and UC berkeley's Murthy Lab, was published in ACS Nano. The researchers hope to refine this technology to treat genetic conditions diagnosed prenatally, enabling early intervention within the womb to reduce developmental cell harm.

Advanced mRNA Delivery Mechanism: A New Approach to Gene Editing

Role of Proteins and mRNA

Proteins play a vital role in body's functions, assembled in cells following instructions from messenger RNA (mRNA). In some genetic disorders, genes may overproduce or underproduce proteins, leading to imbalances that may require gene silencing or protein supplementation.

Insight: "Due to their large and intricate structures, proteins are difficult to deliver," Wang noted. "Effective delivery is a major challenge, and overcoming it is key to advancing disease treatment."

Lipid Nanoparticle (LNP) Technology for mRNA Delivery

Scientists identified a method to deliver mRNA to cells, enabling them to produce functional proteins directly. This involves a unique lipid nanoparticle (LNP) formulation that carries mRNA, transfecting the cells with the instructions needed for protein synthesis.

Delivering mRNA through LNP technology is advancing disease treatments, playing crucial roles in vaccine development, gene editing, and protein therapies. The Pfizer and Moderna COVID-19 vaccines have highlighted its potential and increased its use.

Enhancing mRNA Delivery with Lipid Nanoparticles (LNPs)

Increasing Efficiency with Acid-Degradable Linkers

In a recent paper published in Nature Nanotechnology, researchers Wang and Murthy outlined an innovative lipid nanoparticle (LNP) formulation that ensures safe and efficient mRNA delivery. To achieve this, LNPs must successfully reach the cells, where they undergo endocytosis. This process enables the cell to dismantle the LNP, thereby liberating the mRNA payload.

An individual mRNA molecule measure approximately 100 nanometers in diameter, whereas a typical sheet of paper has a thickness of about 100,000 nanometers.

According to Niren Murthy, a bioengineering professor at the University of California, Berkeley, and co-investigator on this project, the lipid nanoparticles (LNPs) created in this study incorporate a novel acid-degradable linker that facilitates rapid degradation within cells. This innovative linker also allows for the engineering of LNPs with reduced toxicity.

Wang explained that when cells internalize the lipid nanoparticles (LNPs), the particles undergo degradation in the acidic environment of the endosome. This process facilitates a more efficient and timely release of mRNA into the cytosol—the liquid matrix within the cell where mRNA is translated into proteins. This localization is crucial for the mRNA to exert its intended effect.

The relationship between efficiency and toxicity is critical. Thus, understanding the quantity of lipid nanoparticle (LNP) carries required for a cell to uptake sufficient amounts of proteins is essential. If the uptake efficiency is inadequate, researchers may have to administer a higher number of nanoparticles, which could result in multiple doses or elevated doses that risk eliciting a toxic immune response.

Wang stated that the primary challenge in delivering mRNA to the central nervous system has been the toxicity that induces inflammation.

The study demonstrated that the lipid nanoparticle (LNP) approach enhances the efficiency of mRNA translation, thereby decreasing the requirement for potentially toxic dosages.

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Issuing the documentation necessary to develop the CAS9 enzyme for gene editing techniques

Utilizing LNPs to Deliver CAS9 Enzyme for Genetic Editing

Targeting Genetic Disorders with CAS9 mRNA

In the study, the authors descirbe how LNP technology can be leveraged for delivering CAS9 mRNA to treat genetic conditions affecting the central nervous system during fetal development. The researchers focused their tests on the gene responsible for Angelman syndrome, a rare neurodevelopmental condition.

In genetic conditions, damage can accumulate during gestation and shortly after birth. Research indicates that delivering therapies to brain cells is more effective before the blood-brain barrier is fully developed in infants. Therefore, the sooner the intervention occurs, the more beneficial it is. The goal is to halt disease progression in utero.

The research team administered the LNP containing mRNA directly into the ventricles of the fetal brain in a mouse model. The mRNA is translated into CAS9, a protein that functions as molecular scissors for gene editing. The resulting CAS9 protein will target and edit the gene associated with Angelman syndrome.

Wang described mRNA as akin to a Lego assembly guide, detailing the instructions for forming functional proteins. The cell is equipped with the components to construct CAS9; our contribution is to deliver the mRNA sequence, allowing the cell to translate it into proteins.

The research demonstrated that the LNP tool exhibited exceptional efficiency in delivering mRNA, which translated into CAS9.

Visualization and Efficacy in Neural Cells

The researchers utilized tracers to visualize all neurons that had been edited within the brain. Their findings showed that the nanoparticles were incorporated by the developing neural stem and progenitor cells, leading to genetic modifications in 30% of the brain stem cells in the mouse model.

Key Findings and Future Potential

Transfection Efficiency in Brain Cells

• "Transfecting 30% of the entire brain, particularly the stem cells, is significant. As the fetus continues to develop, these cells migrate and distribute throughout various regions of the brain," stated Wang.
• As fetal development progressed, the study demonstrated that stem cells proliferated and migrated to establish the central nervous system. Notably, more than 60% of the neurons in the hippocampus and 40% in the cortex were successfully transfected.

Future Outlook: Wang noted that this approach is highly promising for genetic disorders affecting the central nervous system. If successful, many neurons may be corrected by the time the baby is born, possibly leading to a symptom-free outcome.

Wang expects to find a significantly increased rate of transfection in cells from a mouse model affected by disease.

"Neurons affected by mutations my be eliminated due to the buildup of disease symptoms, while healthy neurons may survive and proliferate, potentially enhancing therapeutic efficacy. By understanding cellular mechanisms, we can harness this knowledge to align with the cell's natural pathways," he explained.

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