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Neurotoxicology Jul 2023Methylmercury (MeHg) is neurotoxic at high levels and particularly affects the developing brain. One proposed mechanism of MeHg neurotoxicity is alteration of the... (Review)
Review
PURPOSE OF REVIEW
Methylmercury (MeHg) is neurotoxic at high levels and particularly affects the developing brain. One proposed mechanism of MeHg neurotoxicity is alteration of the epigenetic programming. In this review, we summarise the experimental and epidemiological literature on MeHg-associated epigenetic changes.
RECENT FINDINGS
Experimental and epidemiological studies have identified changes in DNA methylation following in utero exposure to MeHg, and some of the changes appear to be persistent. A few studies have evaluated associations between MeHg-related changes in DNA methylation and neurodevelopmental outcomes. Experimental studies reveal changes in histone modifications after MeHg exposure, but we lack epidemiological studies supporting such changes in humans. Experimental and epidemiological studies have identified microRNA-related changes associated with MeHg; however, more research is needed to conclude if these changes lead to persistent and toxic effects.
SUMMARY
MeHg appears to interfere with epigenetic processes, potentially leading to persistent changes. However, observed associations of mercury with epigenetic changes are as of yet of unknown relevance to neurodevelopmental outcomes.
Topics: Humans; Methylmercury Compounds; DNA Methylation; Brain; Neurotoxicity Syndromes; Epigenesis, Genetic
PubMed: 37164037
DOI: 10.1016/j.neuro.2023.05.004 -
Archives of Toxicology May 2020Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into... (Review)
Review
Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into the same category as toxic metals (lead, methylmercury, arsenic) and polychlorinated biphenyls. If true, this assessment would be highly relevant considering the widespread fluoridation of drinking water and the worldwide use of fluoride in oral hygiene products such as toothpaste. To gain a deeper understanding of these assertions, we reviewed the levels of human exposure, as well as results from animal experiments, particularly focusing on developmental toxicity, and the molecular mechanisms by which fluoride can cause adverse effects. Moreover, in vitro studies investigating fluoride in neuronal cells and precursor/stem cells were analyzed, and 23 epidemiological studies published since 2012 were considered. The results show that the margin of exposure (MoE) between no observed adverse effect levels (NOAELs) in animal studies and the current adequate intake (AI) of fluoride (50 µg/kg b.w./day) in humans ranges between 50 and 210, depending on the specific animal experiment used as reference. Even for unusually high fluoride exposure levels, an MoE of at least ten was obtained. Furthermore, concentrations of fluoride in human plasma are much lower than fluoride concentrations, causing effects in cell cultures. In contrast, 21 of 23 recent epidemiological studies report an association between high fluoride exposure and reduced intelligence. The discrepancy between experimental and epidemiological evidence may be reconciled with deficiencies inherent in most of these epidemiological studies on a putative association between fluoride and intelligence, especially with respect to adequate consideration of potential confounding factors, e.g., socioeconomic status, residence, breast feeding, low birth weight, maternal intelligence, and exposure to other neurotoxic chemicals. In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe.
Topics: Animal Experimentation; Animals; Arsenic; Child; Drinking Water; Environmental Exposure; Epidemiologic Studies; Europe; Female; Fluorides; Humans; Methylmercury Compounds; Neurotoxicity Syndromes; No-Observed-Adverse-Effect Level
PubMed: 32382957
DOI: 10.1007/s00204-020-02725-2 -
The Science of the Total Environment Dec 2022Anthropogenic mercury (Hg) undergoes long-range transport to the Arctic where some of it is transformed into methylmercury (MeHg), potentially leading to high exposure...
Anthropogenic mercury (Hg) undergoes long-range transport to the Arctic where some of it is transformed into methylmercury (MeHg), potentially leading to high exposure in some Arctic inhabitants and wildlife. The environmental exposure of Hg is determined not just by the amount of Hg entering the Arctic, but also by biogeochemical and ecological processes occurring in the Arctic. These processes affect MeHg uptake in biota by regulating the bioavailability, methylation and demethylation, bioaccumulation and biomagnification of MeHg in Arctic ecosystems. Here, we present a new budget for pools and fluxes of MeHg in the Arctic and review the scientific advances made in the last decade on processes leading to environmental exposure to Hg. Methylation and demethylation are key processes controlling the pool of MeHg available for bioaccumulation. Methylation of Hg occurs in diverse Arctic environments including permafrost, sediments and the ocean water column, and is primarily a process carried out by microorganisms. While microorganisms carrying the hgcAB gene pair (responsible for Hg methylation) have been identified in Arctic soils and thawing permafrost, the formation pathway of MeHg in oxic marine waters remains less clear. Hotspots for methylation of Hg in terrestrial environments include thermokarst wetlands, ponds and lakes. The shallow sub-surface enrichment of MeHg in the Arctic Ocean, in comparison to other marine systems, is a possible explanation for high MeHg concentrations in some Arctic biota. Bioconcentration of aqueous MeHg in bacteria and algae is a critical step in the transfer of Hg to top predators, which may be dampened or enhanced by the presence of organic matter. Variable trophic position has an important influence on MeHg concentrations among populations of top predator species such as ringed seal and polar bears distributed across the circumpolar Arctic. These scientific advances highlight key processes that affect the fate of anthropogenic Hg deposited to Arctic environments.
Topics: Arctic Regions; Ecosystem; Environmental Monitoring; Mercury; Methylmercury Compounds; Soil; Water; Water Pollutants, Chemical
PubMed: 35882324
DOI: 10.1016/j.scitotenv.2022.157445 -
International Journal of Molecular... Jun 2022Methylmercury (MeHg) is a widely known environmental pollutant that causes severe neurotoxicity. MeHg-induced neurotoxicity depends on various cellular conditions,... (Review)
Review
Methylmercury (MeHg) is a widely known environmental pollutant that causes severe neurotoxicity. MeHg-induced neurotoxicity depends on various cellular conditions, including differences in the characteristics of tissues and cells, exposure age (fetal, childhood, or adulthood), and exposure levels. Research has highlighted the importance of oxidative stress in the pathogenesis of MeHg-induced toxicity and the site- and cell-specific nature of MeHg-induced neurotoxicity. The cerebellar granule cells and deeper layer cerebrocortical neurons are vulnerable to MeHg. In contrast, the hippocampal neurons are resistant to MeHg, even at high mercury accumulation levels. This review summarizes the mechanisms underlying MeHg-mediated intracellular events that lead to site-specific neurotoxicity. Specifically, we discuss the mechanisms associated with the redox ability, neural outgrowth and synapse formation, cellular signaling pathways, epigenetics, and the inflammatory conditions of microglia.
Topics: Adult; Child; Humans; Mercury; Methylmercury Compounds; Neurons; Neurotoxicity Syndromes; Oxidative Stress
PubMed: 35806222
DOI: 10.3390/ijms23137218 -
Biological & Pharmaceutical Bulletin 2023Methylmercury (MeHg) is the causal substrate of Minamata disease and a major environmental toxicant. MeHg is widely distributed, mainly in the ocean, meaning its... (Review)
Review
Methylmercury (MeHg) is the causal substrate of Minamata disease and a major environmental toxicant. MeHg is widely distributed, mainly in the ocean, meaning its bioaccumulation in seafood is a considerable problem for human health. MeHg has been intensively investigated and is known to induce inflammatory responses and neurodegeneration. However, the relationship between MeHg-induced inflammatory responses and neurodegeneration is not understood. In the present review, we first describe recent findings showing an association between inflammatory responses and certain MeHg-unrelated neurological diseases caused by neurodegeneration. In addition, cell-specific MeHg-induced inflammatory responses are summarized for the central nervous system including those of microglia, astrocytes, and neurons. We also describe MeHg-induced inflammatory responses in peripheral cells and tissue, such as macrophages and blood. These findings provide a concept of the relationship between MeHg-induced inflammatory responses and neurodegeneration, as well as direction for future research of MeHg-induced neurotoxicity.
Topics: Humans; Methylmercury Compounds; Neurotoxicity Syndromes; Inflammation; Astrocytes; Central Nervous System
PubMed: 37661394
DOI: 10.1248/bpb.b23-00075 -
Biochimica Et Biophysica Acta.... Aug 2019Mercury (Hg) exposure remains a major public health concern due to its widespread distribution in the environment. Organic mercurials, such as MeHg, have been... (Review)
Review
Mercury (Hg) exposure remains a major public health concern due to its widespread distribution in the environment. Organic mercurials, such as MeHg, have been extensively investigated especially because of their congenital effects. In this context, studies on the molecular mechanism of MeHg-induced neurotoxicity are pivotal to the understanding of its toxic effects and the development of preventive measures. Post-translational modifications (PTMs) of proteins, such as phosphorylation, ubiquitination, and acetylation are essential for the proper function of proteins and play important roles in the regulation of cellular homeostasis. The rapid and transient nature of many PTMs allows efficient signal transduction in response to stress. This review summarizes the current knowledge of PTMs in MeHg-induced neurotoxicity, including the most commonly PTMs, as well as PTMs induced by oxidative stress and PTMs of antioxidant proteins. Though PTMs represent an important molecular mechanism for maintaining cellular homeostasis and are involved in the neurotoxic effects of MeHg, we are far from understanding the complete picture on their role, and further research is warranted to increase our knowledge of PTMs in MeHg-induced neurotoxicity.
Topics: Animals; Humans; Methylmercury Compounds; Mitochondria; Neurotoxicity Syndromes; Oxidative Stress; Phosphorylation; Protein Processing, Post-Translational; Proteins; Reactive Oxygen Species
PubMed: 30385410
DOI: 10.1016/j.bbadis.2018.10.024 -
International Journal of Molecular... Mar 2021Methylmercury (MeHg) toxicity is a major environmental concern. In the aquatic reservoir, MeHg bioaccumulates along the food chain until it is consumed by riverine... (Review)
Review
Methylmercury (MeHg) toxicity is a major environmental concern. In the aquatic reservoir, MeHg bioaccumulates along the food chain until it is consumed by riverine populations. There has been much interest in the neurotoxicity of MeHg due to recent environmental disasters. Studies have also addressed the implications of long-term MeHg exposure for humans. The central nervous system is particularly susceptible to the deleterious effects of MeHg, as evidenced by clinical symptoms and histopathological changes in poisoned humans. In vitro and in vivo studies have been crucial in deciphering the molecular mechanisms underlying MeHg-induced neurotoxicity. A collection of cellular and molecular alterations including cytokine release, oxidative stress, mitochondrial dysfunction, Ca and glutamate dyshomeostasis, and cell death mechanisms are important consequences of brain cells exposure to MeHg. The purpose of this review is to organize an overview of the mercury cycle and MeHg poisoning events and to summarize data from cellular, animal, and human studies focusing on MeHg effects in neurons and glial cells. This review proposes an up-to-date compendium that will serve as a starting point for further studies and a consultation reference of published studies.
Topics: Animals; Bioaccumulation; Brain; Humans; Inflammation; Methylmercury Compounds; Microbiota; Neurotoxicity Syndromes
PubMed: 33803585
DOI: 10.3390/ijms22063101 -
The Journal of Toxicological Sciences 2021Methylmercury (MeHg), the causal substrate in Minamata disease, can lead to severe and chronic neurological disorders. The main symptom of Minamata disease is sensory...
Methylmercury (MeHg), the causal substrate in Minamata disease, can lead to severe and chronic neurological disorders. The main symptom of Minamata disease is sensory impairment in the four extremities; however, the sensitivity of individual sensory modalities to MeHg has not been investigated extensively. In the present study, we performed stimulus-response behavioral experiments in MeHg-exposed rats to compare the sensitivities to pain, heat, cold, and mechanical sensations. MeHg (6.7 mg/kg/day) was orally administered to 9-week-old Wistar rats for 5 days and discontinued for 2 days, then administered daily for another 5 days. The four behavioral experiments were performed daily on each rat from the beginning of MeHg treatment for 68 days. The pain sensation decreased significantly from day 11 onwards, but recovered to control levels on day 48. Other sensory modalities were not affected by MeHg exposure. These findings suggest that the pain sensation is the sensory modality most susceptive to MeHg toxicity and that this sensitivity is reversible following discontinuation of the exposure.
Topics: Animals; Hypesthesia; Male; Mercury Poisoning, Nervous System; Methylmercury Compounds; Pain; Rats, Wistar; Rats
PubMed: 34078837
DOI: 10.2131/jts.46.303 -
Environment International Jan 2021Mercury is among the ten most dangerous chemicals for public health, and is a priority concern for the 128 signatory countries of the Minamata Convention. Mercury... (Review)
Review
Mercury is among the ten most dangerous chemicals for public health, and is a priority concern for the 128 signatory countries of the Minamata Convention. Mercury emissions to the atmosphere increased 20% between 2010 and 2015, with South America, Sub-Saharan Africa and Southeast Asia as the main contributors. Approximately 80% of the total mercury emissions in South America is from the Amazon, where the presence of the metal is ubiquitous and highly dynamic. The presence of this metal is likely increasing, with global consequences, due to events of the last two years including extensive biomass burning and deforestation, as well as mining activities and the construction of large-scale projects, such as dams. Here we present a concise profile of this mobilization, highlighting the human exposure to this metal in areas without mining history. Mercury reaches the food chain in its most toxic form, methylmercury, intoxicating human populations through the intake of contaminated fish. Amazonian populations present levels over 6 ppm of hair mercury and, according to the 175:250:5:1 ratio for methylmercury intake : mercury hair : mercury brain : mercury blood, consume 2-6 times the internationally recognized reference doses. This exposure is alarmingly higher than that of other populations worldwide. A possible biphasic behavior of the mercury-related phenomena, with consequences that may not be observed in populations with lower levels, is hypothesized, supporting the need of improving our knowledge of this type of chronic exposure. It is urgent that we address this serious public health problem in the Amazon, especially considering that human exposure may be increasing in the near future. All actions in this region carry the potential to have global repercussions.
Topics: Animals; Environmental Exposure; Hair; Humans; Mercury; Methylmercury Compounds; Mining; South America
PubMed: 33120229
DOI: 10.1016/j.envint.2020.106223 -
International Journal of Environmental... Jan 2023Although the molecular mechanisms underlying methylmercury toxicity are not entirely understood, the observed neurotoxicity in early-life is attributed to the covalent... (Review)
Review
Although the molecular mechanisms underlying methylmercury toxicity are not entirely understood, the observed neurotoxicity in early-life is attributed to the covalent binding of methylmercury to sulfhydryl (thiol) groups of proteins and other molecules being able to affect protein post-translational modifications from numerous molecular pathways, such as glutamate signaling, heat-shock chaperones and the antioxidant glutaredoxin/glutathione system. However, for other organomercurials such as ethylmercury or thimerosal, there is not much information available. Therefore, this review critically discusses current knowledge about organomercurials neurotoxicity-both methylmercury and ethylmercury-following intrauterine and childhood exposure, as well as the prospects and future needs for research in this area. Contrasting with the amount of epidemiological evidence available for methylmercury, there are only a few in vivo studies reporting neurotoxic outcomes and mechanisms of toxicity for ethylmercury or thimerosal. There is also a lack of studies on mechanistic approaches to better investigate the pathways involved in the potential neurotoxicity caused by both organomercurials. More impactful follow-up studies, especially following intrauterine and childhood exposure to ethylmercury, are necessary. Childhood vaccination is critically important for controlling infectious diseases; however, the safety of mercury-containing thimerosal and, notably, its effectiveness as preservative in vaccines are still under debate regarding its potential dose-response effects to the central nervous system.
Topics: Humans; Thimerosal; Methylmercury Compounds; Preservatives, Pharmaceutical; Mercury; Vaccines; Neurotoxicity Syndromes; Sulfhydryl Compounds
PubMed: 36673825
DOI: 10.3390/ijerph20021070