Month: October 2024

Categories : Environmental Effects NeurologyTags :

PFAS Influence the Development and Function of the Brain

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Photo by Ryan Zazueta on Unsplash

Some per- and polyfluoroalkyl substances (PFAS) are poorly degradable and are also known as “forever chemicals”. They adversely affect health and can lead to liver damage, obesity, hormonal disorders, and cancer. A research team from the Helmholtz Centre for Environmental Research (UFZ) has investigated the effects of PFAS on the brain.

Using a combination of modern molecular biology methods and the zebrafish model, the researchers revealed the mechanism of action and identified the genes involved, which are also present in humans. The test procedure developed at the UFZ could be used for the risk assessment of other neurotoxic chemicals. The study was recently published in Environmental Health Perspectives. 

Because of their special properties – heat resistance, water and grease repellence, and high durability – PFAS are used in many everyday products (eg, cosmetics, outdoor clothing, and coated cookware). But it is precisely these properties that make them so problematic. “Because some PFAS are chemically stable, they accumulate in the environment and enter our bodies via air, drinking water, and food”, says UFZ toxicologist Prof Dr Tamara Tal. Even with careful consumption, it is nearly impossible to avoid this group of substances, which has been produced since the 1950s and now includes thousands of different compounds. “There is a great need for research, especially when it comes to developing fast, reliable, and cost-effective test systems for assessing the risks of PFAS exposure”, says Tal. So far, the environmental and health consequences have been difficult to assess.

In their current study, the researchers investigated how PFAS exposure affects brain development. To do this, they used the zebrafish model, which is frequently used in toxicology research. One advantage of this model is that around 70% of the genes found in zebrafish (Danio rerio) are also found in humans. The findings from the zebrafish model can therefore likely be transferred to humans. In their experiments, the researchers exposed zebrafish to two substances from the PFAS group (PFOS and PFHxS), which have a similar structure. The researchers then used molecular biological and bioinformatic methods to investigate which genes in the brains of the fish larvae exposed to PFAS were disrupted compared to the control fish, which were not exposed. “In the zebrafish exposed to PFAS, the peroxisome proliferator-activated receptor (ppar) gene group, which is also present in a slightly modified form in humans, was particularly active”, says Sebastian Gutsfeld, PhD student at the UFZ and first author of the study. “Toxicity studies have shown this to be the case as a result of exposure to PFAS – albeit in the liver. We have now also been able to demonstrate this for the brain”.

But what consequences does an altered activity of the ppar genes triggered by PFAS exposure have for brain development and behaviour of zebrafish larvae? The researchers investigated this in further studies using the zebrafish model. Using CRISPR/Cas9 ‘gene scissors’ the researchers were able to “selectively cut individual or several ppar genes and prevent them from functioning normally”, explains Gutsfeld. “We wanted to find out which ppar genes are directly linked to a change in larval behaviour triggered by PFAS exposure”. Proof of the underlying mechanism was directly provided. In contrast to genetically unaltered zebrafish, the knockdown fish in which the gene scissors were used should not show any behavioural changes after exposure to PFAS.

The two behavioural endpoints

In one series of experiments, the researchers continuously exposed zebrafish to PFOS or PFHxS during their early developmental phase between day one and day four and in another series of experiments only on day five. On the fifth day, the researchers then observed swimming behaviour. They used two different behavioural endpoints for this purpose. In one endpoint, swimming activity was measured during a prolonged dark phase. PFAS-exposed fish swam more than fish not exposed to PFAS, whether continuously exposed to PFAS during brain development or shortly before the behaviour test. Interestingly, hyperactivity was only present when the chemical was around. When the researchers removed PFOS or PFHxS, hyperactivity subsided. In the second endpoint, the startle response after a dark stimulus was measured. “In zebrafish exposed to PFOS for four days, we observed hyperactive swimming behaviour in response to the stimulus”, says Gutsfeld. In contrast, zebrafish only exposed to PFOS or PFHxS on the fifth day did not have a hyperactive startle response.

Based on these responses, the researchers conclude that PFOS exposure is associated with abnormal consequences – particularly during sensitive developmental phases of the brain. Using knockdown zebrafish, the researchers identified two genes from the ppar group that mediate the behaviour triggered by PFOS. 

“Because these genes are also present in humans, it is possible that PFAS also have corresponding effects in humans”, concludes Tal. The scientists working with Tal want to investigate the neuroactive effects of other PFAS in future research projects and expand the method so that it can ultimately be used to assess the risk of chemicals in the environment, including PFAS.

Source: Helmholtz Centre for Environmental Research – UFZ

Categories : Allergies Emergency MedicineTags :

Can Adrenaline Auto-injectors Prevent Fatal Anaphylaxis?

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Photo by Mat Napo o Unsplash

Individuals at risk of anaphylaxis are often prescribed adrenaline (epinephrine) autoinjectors such as EpiPens. A recent review published in Clinical & Experimental Allergy finds that these autoinjectors, which people use to self-administer adrenaline into the muscle, can deliver high doses of adrenaline into the blood, but these levels are short-lived and may not be sufficient to save lives in cases of fatal anaphylaxis.

Anaphylaxis is an acute systemic hypersensitivity reaction to an allergen or trigger, typically associated with skin reactions, nausea/vomiting, difficulty breathing, and shock.

Investigators noted that data from animal and human studies suggest that intravenous adrenaline infusions delivered directly into the blood can prevent fatal anaphylaxis, but adrenaline autoinjectors may have little impact in such deadly cases.

“For effective management of the most severe allergic reactions, adrenaline given by continuous intravenous infusion, with appropriate fluid resuscitation, is likely to be required—how this is safely achieved in the pre-hospital setting remains to be determined,” the authors wrote. This challenge stems from the fact that fatal anaphylaxis is unpredictable and fast. Fortunately, fatality is rare, with a population incidence of 0.03–0.51 per million per year.

Source: Wiley

Categories : AgeingTags :

Metformin Found to Slow Ageing in Primate Trial

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Photo by Andre Mouton on Unsplash

An exhaustive four year-long study has shown that metformin reduces the effect of ageing. Using a wide array of ageing indicators, the researchers found that metformin resulted in about six year regression in brain ageing. They reported their findings in Cell.

Prior research and anectodal evidence suggested that metformin had an anti-ageing effect. Given to flies, worms and rodents, the drug showed evidence of rejuvenation. People taking metformin also reported feeling younger the longer they took it for.

In a rigorous 40-month study, the researchers gave metformin to 12 elderly male cynomolgus macaques and 18 other cynomolgus monkeys the drug daily. They were aged 13–16 years, equivalent to 40–50 in human years. A control group was used, as well as middle-aged and younger controls to account for ageing effects.

The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin’s influence on delaying age-related phenotypes at the organismal level.

Tissue samples were taken at regular intervals, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin’s effects on ageing.

The results highlighted a significant slowing of aging indicators. A number of organs that seemed to benefit included the kidneys, lungs and the skin. The greatest effect was seen in the brain, however. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. In this case, treated monkeys had brain activity comparable to those six years younger.

The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. The researchers say that this work pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.

The researchers have also started a much larger phase 2 human trial, with 120 participants.

Categories : NeurologyTags :

Cannabis Use in Adolescence has Visible Effects on Brain Structure

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Photo by Anna Shvets

Cannabis use may lead to thinning of the cerebral cortex in adolescents according to a recent study.  The study demonstrates that THC – or tetrahydrocannabinol, an active substance in cannabis – causes shrinkage of the dendritic arborisation, neurons’ “network of antennae” whose role is critical for communication between neurons. This results in the atrophy of certain regions of the cerebral cortex – bad news at an age when the brain is maturing.  

The study, led by Graciela Pineyro and Tomas Paus, involved researchers at CHU Sainte-Justine and professors at the Université de Montréal Faculty of Medicine, was published in The Journal of Neuroscience.

“If we take the analogy of the brain as a computer, the neurons would be the central processor, receiving all information via the synapses through the dendritic network,” explains Tomas Paus, who is also a professor of psychiatry and neuroscience at Université de Montréal. “So a decrease in the data input to the central processor by dendrites makes it harder for the brain to learn new things, interact with people, cope with new situations, etc. In other words, it makes the brain more vulnerable to everything that can happen in a young person’s life.”

A multi-level approach to better understand the effect on humans

This project is notable for the complementary, multi-level nature of the methods used. “By analysing magnetic resonance imaging (MRI) scans of the brains of a cohort of teenagers, we had already shown that young people who used cannabis before the age of 16 had a thinner cerebral cortex,” explains Tomas Paus. “However, this research method doesn’t allow us to draw any conclusions about causality, or to really understand THC’s effect on the brain cells.”  

Given the limitations of MRI, the introduction of the mouse model by Graciela Pineyro’s team was key. “The model made it possible to demonstrate that THC modifies the expression of certain genes affecting the structure and function of synapses and dendrites,” explains Graciela Pineyro, who is also a professor in the Department of Pharmacology and Physiology at Université de Montréal. “The result is atrophy of the dendritic arborescence that could contribute to the thinning observed in certain regions of the cortex.”  

Interestingly, these genes were also found in humans, particularly in the thinner cortical regions of the cohort adolescents who experimented with cannabis. By combining their distinct research methods, the two teams were thus able to determine with a high degree of certainty that the genes targeted by THC in the mouse model were also associated to the cortical thinning observed in adolescents. 

With cannabis use on the rise among North American youth, and commercial cannabis products containing increasing concentrations of THC, it’s imperative that we improve our understanding of how this substance affects brain maturation and cognition. This successful collaborative study, involving cutting-edge techniques in cellular and molecular biology, imaging and bioinformatics analysis, is a step in the right direction for the development of effective public health measures.

Source: University of Montreal

Categories : Environmental Effects Substance UseTags :

Pharmaceutical and Illicit Drugs Contaminating New York’s Rivers

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Photo by Bill Oxford on Unsplash

In research published in Environmental Toxicology & Chemistry, investigators sampled water from 19 locations across the Hudson and East Rivers in 2021 and 2022 to identify and quantify the prescribed pharmaceuticals and drugs of abuse that are making their way into New York City’s rivers and to determine the source of these pollutants.

Metoprolol and atenolol (blood pressure medications), benzoylecgonine (the main metabolite of cocaine), methamphetamine (a stimulant), and methadone (an opioid) were the most prevalent drugs, present in more than 60% of water samples.

More drugs and higher concentrations were detected in water contaminated by Enterococci (bacteria that live in the intestinal tract) and after rainfall, indicating an impact from sewer overflow. However, the presence of drugs in clean water and during periods of dry weather indicated that wastewater treatment plant discharge may also contribute to the presence of drugs in rivers.

“This study shows how pharmaceuticals and drugs of abuse enter the New York City aquatic environment, highlighting the necessity of improving the current water management system,” said corresponding author Marta Concheiro-Guisan, PharmD, PhD, of the John Jay College of Criminal Justice.

Source: Wiley

Categories : Neurology UncategorizedTags :

Can Space Radiation Affect Astronauts’ Long-term Cognition?

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Photo: Pixabay CC0

During missions into outer space, galactic cosmic radiation (GCR) will penetrate current spacecraft shielding and thus pose a significant risk to human health. Previous studies have shown that GCR can cause short-term cognitive deficits in male rodents. Now a study published in the Journal of Neurochemistry reveals that GCR exposure can also cause long-lasting learning deficits in female rodents.

The impact of GCR on cognition was lessened when mice were fed an antioxidant and anti-inflammatory compound called CDDO-EA.

Beyond its immediate implications for space exploration, the findings contribute to a broader understanding of radiation’s long-term impact on cognitive health.

“Our study lays the groundwork for future causal delineation of how the brain responds to complex GCR exposure and how these brain adaptations result in altered behaviours,” said co-corresponding author Sanghee Yun, PhD, of the Children’s Hospital of Philadelphia Research Institute and the University of Pennsylvania Perelman School of Medicine.

Source: Wiley

Categories : NeurologyTags :

Insights into How the Brain Regenerates Lost Myelin

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Myelin sheath damage. Credit: Scientific Animations CC4.0

The neurons of the brain are protected by an insulating layer called myelin. In certain diseases like multiple sclerosis, the protective myelin layer around neurons is damaged and lost, leading to death of neurons and disability. New research published in The FEBS Journal reveals the importance of a protein called C1QL1 for promoting the replacement of the specialised cells that produce myelin. The findings could have important implications for the ongoing effort to develop new and improved therapies for the treatment of demyelinating diseases.

In experiments conducted in mice, deleting the gene that codes for C1QL1 caused a delay in the rate at which oligodendrocytes (the cells that make myelin) mature, leading to reduced myelination of neurons.

After mice were fed a drug that destroys myelin, recovery of oligodendrocytes and myelination were delayed in mice lacking the C1QL1 protein. Causing mice to express more C1QL1, however, led to increased numbers of oligodendrocytes and more myelination upon drug withdrawal, suggesting that C1QL1 helps to restore the damaged myelin layer.  Thus, investigational therapies that boost C1QL1 may hold promise against demyelinating diseases.

“Our basic research on C1QL1 is nascent, but there is potential that it is relevant for a novel treatment for multiple sclerosis,” said corresponding author David C. Martinelli, PhD, of the University of Connecticut Health Center. “New drug treatment options for patients with multiple sclerosis could have a large impact on their quality of life.”

Source: Wiley

Categories : Cardiovascular Disease Environmental EffectsTags :

Risk of Cardiovascular Disease Linked to Arsenic in Water

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Long term exposure to arsenic in water may increase cardiovascular disease and especially heart disease risk even at exposure levels below the US regulatory limit (10µg/L) according to a new study in Environmental Health Perspectives. This is the first study to describe exposure-response relationships at concentrations below the current regulatory limit and substantiates that prolonged exposure to arsenic in water contributes to the development of ischaemic heart disease.

The researchers, from Columbia University Mailman School of Public Health, compared various time windows of exposure, finding that the previous decade of water arsenic exposure up to the time of a cardiovascular disease event contributed the greatest risk.

“Our findings shed light on critical time windows of arsenic exposure that contribute to heart disease and inform the ongoing arsenic risk assessment by the EPA. It further reinforces the importance of considering non-cancer outcomes, and specifically cardiovascular disease, which is the number one cause of death in the US and globally,” said Danielle Medgyesi, a doctoral Fellow in the Department of Environmental Health Sciences at Columbia Mailman School. “This study offers resounding proof of the need for regulatory standards in protecting health and provides evidence in support of reducing the current limit to further eliminate significant risk.”

According to the American Heart Association and other leading health agencies, there is substantial evidence that arsenic exposure increases the risk of cardiovascular disease. This includes evidence of risk at high arsenic levels (> 100µg/L) in drinking water. The U.S. Environmental Protection Agency reduced the maximum contaminant level (MCL) for arsenic in community water supplies (CWS) from 50µg/L to 10µg/L beginning in 2006. Even so, drinking water remains an important source of arsenic exposure among CWS users. The natural occurrence of arsenic in groundwater is commonly observed in regions of New England, the upper Midwest, and the West, including California.

To evaluate the relationship between long-term arsenic exposure from CWS and cardiovascular disease, the researchers used statewide healthcare administrative and mortality records collected for the California Teachers Study cohort from enrollment through follow-up (1995-2018), identifying fatal and nonfatal cases of ischemic heart disease and cardiovascular disease. Working closely with collaborators at the California Office of Environmental Health Hazard Assessment (OEHHA), the team gathered water arsenic data from CWS for three decades (1990-2020).

The analysis included 98 250 participants, 6119 ischaemic heart disease cases and 9,936 CVD cases. Excluded were those 85 years of age or older and those with a history of CVD at enrolment. Similar to the proportion of California’s population that relies on CWS (over 90%), most participants resided in areas served by a CWS (92%). Leveraging the extensive years of arsenic data available, the team compared time windows of relatively short-term (3-years) to long-term (10-years to cumulative) average arsenic exposure. The study found decade-long arsenic exposure up to the time of a cardiovascular disease event was associated with the greatest risk, consistent with a study in Chile finding peak mortality of acute myocardial infarction around a decade after a period of very high arsenic exposure. This provides new insights into relevant exposure windows that are critical to the development of ischemic heart disease.

Nearly half (48%) of participants were exposed to an average arsenic concentration below California’s non-cancer public health goal < 1 µg/L. In comparison to this low-exposure group, those exposed to 1 to < 5 µg/L had modestly higher risk of ischaemic heart disease, with increases of 5 to 6%. Risk jumped to 20% among those in the exposure ranges of 5 to < 10 µg/L (or one-half to below the current regulatory limit), and more than doubled to 42% for those exposed to levels at and above the current EPA limit ≥ 10µg/L. The relationship was consistently stronger for ischemic heart disease compared to cardiovascular disease, and no evidence of risk for stroke was found, largely consistent with previous research and the conclusions of the current EPA risk assessment.

These results highlight the serious health consequences not only when community water systems do not meet the current EPA standard but also at levels below the current standard. The study found a substantial 20% risk at arsenic exposures ranging from 5 to < 10 µg/L which affected about 3.2% of participants, suggesting that stronger regulations would provide significant benefits to the population. In line with prior research, the study also found higher arsenic concentrations, including concentrations above the current standard, disproportionally affect Hispanic and Latina populations and residents of lower socioeconomic status neighbourhoods.

“Our results are novel and encourage a renewed discussion of current policy and regulatory standards,” said Tiffany Sanchez, senior author. “However, this also implies that much more research is needed to understand the risks associated with arsenic levels that CWS users currently experience. We believe that the data and methods developed in this study can be used to bolster and inform future studies and can be extended to evaluate other drinking water exposures and health outcomes.”

Source: Columbia University’s Mailman School of Public Health

Categories : Injury & Trauma Metabolic DisordersTags :

Key Molecule in Wound Healing Identified

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A new study from Karolinska Institutet and the Chinese Academy of Medical Sciences has identified an RNA molecule that is important for skin wound healing. The research, published in Nature Communications, may have implications for the treatment of hard-to-heal wounds.

The study focuses on the molecular processes in wound healing that regulate the transition from inflammation to a proliferative phase, where new cells form to repair damaged tissue. Researchers have now mapped lncRNA (long non-coding RNA molecules) in human skin wounds in tissue samples from Karolinska University Hospital, identifying a key regulator in wound healing.

“Our study reveals that the lncRNA molecule SNHG26 plays a pivotal role in guiding skin cells through the stages of wound healing, from an inflammatory stage to a healing phase,” explains Ning Xu Landén, docent at the Department of Medicine, Solna, Karolinska Institutet.

The researchers also used mouse models to uncover how this molecule interacts with genes involved in inflammation and tissue regeneration. In mice lacking SNHG26, wound healing was delayed, emphasising the molecule’s importance in the balance between inflammation and tissue repair. The discovery paves the way for new therapeutic approaches for acute and chronic wounds.

“By targeting SNHG26, we may be able to accelerate healing and reduce complications, particularly in chronic wounds where prolonged inflammation is a major problem,” says Ning Xu Landén.

Source: Karolinska Institutet

Categories : Mental HealthTags :

Sex Differences in Rates of Psychiatric Disorders over the Lifespan

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In a recently published study, researchers at the Institute for Environmental Medicine (IMM), Karolinska Institutet show that there are pronounced sex differences in the incidence rates of psychiatric disorders over the lifespan, which varied depending on age, type of psychiatric disorders, calendar period, and socioeconomic status.

Psychiatric disorders are among the most pressing global public health concerns. The sex difference in psychiatric disorders is among the most robust finding in psychiatry. For example, males have a higher risk of neurodevelopmental disorders, while females are more prone to depression and anxiety disorders. However, most of the evidence were based on prevalence studies, without differentiating new-onset (incident) cases from prevalent and recurrent cases, which may not inform optimal time windows for screening and interventions to reduce sex differences. There is research gap on sex differences in incident psychiatric disorders over the lifespan.

By using the nationwide Swedish register data and adopting a life-course approach, the researchers at IMM and collaborators from MEB, Uppsala University, Oslo University Hospital, and University of Iceland, have been able to depict a comprehensive atlas of sex differences in the incidence rates of clinically diagnosed psychiatric disorders over the lifespan, with an emphasis on analyzing sex differences by various types of psychiatric disorders, socioeconomic status and calendar period.

Their findings that sex differences in psychiatric disorders exist almost across the whole life supports the need of gendered mental health prevention strategies. The variation in these differences by age and socioeconomic status suggests that the current knowledge can be enhanced by integrating data on age and socioeconomic status. This study also provides evidence for screening and intervention strategies that focus on specific age groups and socially disadvantaged populations, where pronounced sex disparity in psychiatric disorders were observed.

Source: Karolinska Institutet