-
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 -
Ecotoxicology (London, England) Oct 2023Mercury contamination is a widespread phenomenon that impacts ecosystems worldwide. Artisanal Small Scale Gold Mining (ASGM) activities are responsible for more than a... (Review)
Review
Mercury contamination is a widespread phenomenon that impacts ecosystems worldwide. Artisanal Small Scale Gold Mining (ASGM) activities are responsible for more than a third of atmospheric Hg emission. Due to Hg toxicity and its broad and elevated prevalence in the environment resulting from ASGM activities in the tropics, its biomonitoring is essential to better understand the availability of its methylmercury (MeHg) form in the environment. The Minamata Convention was ratified with the objective to "protect human health and the environment from anthropogenic emissions and releases of mercury compounds". Biomagnification of MeHg occurs through the trophic food web, where it biomagnifies and bioaccumulates in top predators. To monitor environmental MeHg contamination, studies have evaluated the use of living organisms; however, reptiles are among the least documented vertebrates regarding MeHg exposure. In this review we evaluate the use of crocodylians for Hg biomonitoring in tropical ecosystems. We found that out of the 28 crocodiles species, only 10 have been evaluated regarding Hg contamination. The remaining challenges when using this taxon for Hg biomonitoring are inconsistencies in the applied methodology (e.g., wet versus dry weight, tissues used, quantification method). However, due to their life history traits, crocodylians are particularly relevant for monitoring MeHg contamination in regions where ASGM activities occur. In conclusion and given their ecological and socio-economic importance, crocodylians are at great risk of MeHg contamination and are excellent bioindicators for tropical ecosystems.
Topics: Animals; Humans; Mercury; Ecosystem; Environmental Monitoring; Methylmercury Compounds; Vertebrates; Gold; Fishes
PubMed: 37815690
DOI: 10.1007/s10646-023-02703-1 -
Yakugaku Zasshi : Journal of the... 2024Methylmercury is a ubiquitous neurotoxic substance present in the environment, and health concerns, especially through the consumption of seafood, remain. Glutathione... (Review)
Review
Methylmercury is a ubiquitous neurotoxic substance present in the environment, and health concerns, especially through the consumption of seafood, remain. Glutathione (GSH)-mediated detoxification and the excretion of methylmercury are known metabolic detoxification pathways. We have also discovered a mechanism by which endogenous super-sulfides convert methylmercury to nontoxic metabolites such as bis-methylmercury sulfide. However, these metabolites are present in very small quantities, and the significance of the detoxification of methylmercury by super-sulfides is not well understood. Methylmercury binds to thiol groups in vivo but can also react with highly reactive selenols (selenocysteine residues). Such covalent bonds (S-mercuration and Se-mercuration) are broken by nucleophilic substitution reactions with other thiol and selenols, however, the contribution of super-sulfides to this substitution reaction is not well understood. Interestingly, a recent study suggested that selenoprotein P, the major selenium transport protein in plasma, binds to methylmercury, however, Se-mercuration was not determined. In this review, we introduce these series of reactions and discuss their involvement with super-sulfides in methylmercury toxicity.
Topics: Methylmercury Compounds; Selenium; Glutathione; Sulfhydryl Compounds; Sulfides
PubMed: 38171793
DOI: 10.1248/yakushi.23-00162-1 -
Inorganic Chemistry Nov 2023In this study, the stability, directionality, and physical nature of Spodium bonds (SpBs, an attractive noncovalent force involving elements from group 12 and Lewis...
In this study, the stability, directionality, and physical nature of Spodium bonds (SpBs, an attractive noncovalent force involving elements from group 12 and Lewis bases) between methylmercury (MeHg) and ethylmercury (EtHg) and amino acids (AAs) have been analyzed from both a structural (X-ray analysis) and theoretical (RI-MP2/def2-TZVP level of theory) point of view. More in detail, an inspection of the Protein Data Bank (PDB) reported evidence of noncovalent contacts between MeHg and EtHg molecules and electron-rich atoms (e.g., O atoms belonging to the protein backbone and S atoms from MET residues or the π-systems of aromatic AAs such as TYR or TRP). These results were rationalized through a computational study using MeHg coordinated to a thiolate group as a theoretical model and several neutral and charged electron-rich molecules (e.g., benzene, formamide, or chloride). The physical nature of the interaction was analyzed from electrostatics and orbital perspectives by performing molecular electrostatic potential (MEP) and natural bonding orbital (NBO) analyses. Lastly, the noncovalent interactions plot (NCIplot) technique was used to provide a qualitative view of the strength of the Hg SpBs and compare them to other ancillary interactions present in these systems as well as to shed light on the extension of the interaction in real space. We believe that the results derived from our study will be useful to those scientists devoted to protein engineering and bioinorganic chemistry as well as to expanding the current knowledge of SpBs among the chemical biology community.
Topics: Methylmercury Compounds; X-Rays; Amino Acids; Mercury; Electrons
PubMed: 37902775
DOI: 10.1021/acs.inorgchem.3c02716 -
Environmental Science & Technology Nov 2023Mercury (Hg) is a toxic contaminant that has been mobilized and distributed worldwide and is a threat to many wildlife species. Amphibians are facing unprecedented...
Mercury (Hg) is a toxic contaminant that has been mobilized and distributed worldwide and is a threat to many wildlife species. Amphibians are facing unprecedented global declines due to many threats including contaminants. While the biphasic life history of many amphibians creates a potential nexus for methylmercury (MeHg) exposure in aquatic habitats and subsequent health effects, the broad-scale distribution of MeHg exposure in amphibians remains unknown. We used nonlethal sampling to assess MeHg bioaccumulation in 3,241 juvenile and adult amphibians during 2017-2021. We sampled 26 populations (14 species) across 11 states in the United States, including several imperiled species that could not have been sampled by traditional lethal methods. We examined whether life history traits of species and whether the concentration of total mercury in sediment or dragonflies could be used as indicators of MeHg bioaccumulation in amphibians. Methylmercury contamination was widespread, with a 33-fold difference in concentrations across sites. Variation among years and clustered subsites was less than variation across sites. Life history characteristics such as size, sex, and whether the amphibian was a frog, toad, newt, or other salamander were the factors most strongly associated with bioaccumulation. Total Hg in dragonflies was a reliable indicator of bioaccumulation of MeHg in amphibians (R ≥ 0.67), whereas total Hg in sediment was not (R ≤ 0.04). Our study, the largest broad-scale assessment of MeHg bioaccumulation in amphibians, highlights methodological advances that allow for nonlethal sampling of rare species and reveals immense variation among species, life histories, and sites. Our findings can help identify sensitive populations and provide environmentally relevant concentrations for future studies to better quantify the potential threats of MeHg to amphibians.
Topics: Animals; Methylmercury Compounds; Odonata; Water Pollutants, Chemical; Mercury; Amphibians; Environmental Monitoring
PubMed: 37902062
DOI: 10.1021/acs.est.3c05549 -
Ecotoxicology and Environmental Safety Nov 2023Methylmercury is a neurotoxic compound that can enter rice fields through rainfall or irrigation with contaminated wastewater, and then contaminate the human food chain...
Methylmercury is a neurotoxic compound that can enter rice fields through rainfall or irrigation with contaminated wastewater, and then contaminate the human food chain through the consumption of rice. Flooded paddy soil has a porous structure that facilitates air exchange with the atmosphere, but the presence of trace amounts of oxygen in flooded rice field soil and its impact on microbial-mediated formation of methylmercury is still unclear. We compared the microbial communities and their functions in oxygen-depleted and oxygen-limited paddy soil. We discovered that oxygen-limited paddy soil had higher methylmercury concentration, which was strongly correlated with soil properties and methylation potential. Compared with oxygen-depleted soil, oxygen-limited soil altered the microbial composition based on 16 S rRNA sequences, but not based on hgcA sequences. Moreover, oxygen-limited soil enhanced microbial activity significantly, increasing the abundance of more than half of the KEGG pathways, especially the metabolic pathways that might be involved in methylation. Our study unveils how microbial communities influence methylmercury formation in oxygen-limited paddy soil. ENVIRONMENTAL IMPLICATIONS: This study examined how low oxygen input affects microbial-induced MeHg formation in anaerobic paddy soil. We found that oxygen-limited soil produced more MeHg than oxygen-depleted soil. Oxygen input altered the microbial community structure of 16 S rRNA sequencing in anaerobic paddy soil, but had little impact on the hgcA sequencing community structure. Microbial activity and metabolic functions related to MeHg formation were also higher in oxygen-limited paddy soil. We suggest that oxygen may not be a limiting factor for Hg methylators, and that insufficient oxygen input in flooded paddy soil increases the risk of human exposure to MeHg from rice consumption.
Topics: Humans; Methylmercury Compounds; Soil; Oxygen; Soil Pollutants; Mercury; Microbiota; Oryza
PubMed: 37856980
DOI: 10.1016/j.ecoenv.2023.115585 -
Neurotoxicology Jul 2023Current guidelines for developmental neurotoxicity (DNT) evaluation are based on animal models. These have limitations so more relevant, efficient and robust approaches...
Current guidelines for developmental neurotoxicity (DNT) evaluation are based on animal models. These have limitations so more relevant, efficient and robust approaches for DNT assessment are needed. We have used the human SH-SY5Y neuroblastoma cell model to evaluate a panel of 93 mRNA markers that are frequent in Neuronal diseases and functional annotations and also differentially expressed during retinoic acid-induced differentiation in the cell model. Rotenone, valproic acid (VPA), acrylamide (ACR) and methylmercury chloride (MeHg) were used as DNT positive compounds. Tolbutamide, D-mannitol and clofibrate were used as DNT negative compounds. To determine concentrations for exposure for gene expression analysis, we developed a pipeline for neurite outgrowth assessment by live-cell imaging. In addition, cell viability was measured by the resazurin assay. Gene expression was analyzed by RT-qPCR after 6 days of exposure during differentiation to concentrations of the DNT positive compounds that affected neurite outgrowth, but with no or minimal effect on cell viability. Methylmercury affected cell viability at lower concentrations than neurite outgrowth, hence the cells were exposed with the highest non-cytotoxic concentration. Rotenone (7.3 nM) induced 32 differentially expressed genes (DEGs), ACR (70 µM) 8 DEGs, and VPA (75 µM) 16 DEGs. No individual genes were significantly dysregulated by all 3 DNT positive compounds (p < 0.05), but 9 genes were differentially expressed by 2 of them. Methylmercury (0.8 nM) was used to validate the 9 DEGs. The expression of SEMA5A (encoding semaphorin 5A) and CHRNA7 (encoding nicotinic acetylcholine receptor subunit α7) was downregulated by all 4 DNT positive compounds. None of the DNT negative compounds dysregulated any of the 9 DEGs in common for the DNT positive compounds. We suggest that SEMA5A or CHRNA7 should be further evaluated as biomarkers for DNT studies in vitro since they also are involved in neurodevelopmental adverse outcomes in humans.
Topics: Animals; Humans; Methylmercury Compounds; Rotenone; RNA, Messenger; Neuroblastoma; Neurons; Neurotoxicity Syndromes; Cell Differentiation
PubMed: 37210002
DOI: 10.1016/j.neuro.2023.05.011 -
Journal of Lipid Research Nov 2023Although pregnant women's fish consumption is beneficial for the brain development of the fetus due to the DHA in fish, seafood also contains methylmercury (MeHg), which...
Although pregnant women's fish consumption is beneficial for the brain development of the fetus due to the DHA in fish, seafood also contains methylmercury (MeHg), which adversely affects fetal brain development. Epidemiological studies suggest that high DHA levels in pregnant women's sera may protect the fetal brain from MeHg-induced neurotoxicity, but the underlying mechanism is unknown. Our earlier study revealed that DHA and its metabolite 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) produced by cytochrome P450s (P450s) and soluble epoxide hydrolase (sEH) can suppress MeHg-induced cytotoxicity in mouse primary neuronal cells. In the present study, DHA supplementation to pregnant mice suppressed MeHg-induced impairments of pups' body weight, grip strength, motor function, and short-term memory. DHA supplementation also suppressed MeHg-induced oxidative stress and the decrease in the number of subplate neurons in the cerebral cortex of the pups. DHA supplementation to dams significantly increased the DHA metabolites 19,20-epoxydocosapentaenoic acid (19,20-EDP) and 19,20-DHDP as well as DHA itself in the fetal and infant brains, although the expression levels of P450s and sEH were low in the fetal brain and liver. DHA metabolites were detected in the mouse breast milk and in human umbilical cord blood, indicating the active transfer of DHA metabolites from dams to pups. These results demonstrate that DHA supplementation increased DHA and its metabolites in the mouse pup brain and alleviated the effects of MeHg on fetal brain development. Pregnant women's intake of fish containing high levels of DHA (or DHA supplementation) may help prevent MeHg-induced neurotoxicity in the fetus.
Topics: Infant; Animals; Humans; Pregnancy; Female; Mice; Methylmercury Compounds; Docosahexaenoic Acids; Brain; Oxidative Stress; Fetus
PubMed: 37838304
DOI: 10.1016/j.jlr.2023.100458 -
Archives of Toxicology Sep 2023The risk of methylmercury (MeHg) toxicity following ingestion of contaminated foodstuffs (e.g., fish) is directly related to the kinetics of MeHg elimination among...
The risk of methylmercury (MeHg) toxicity following ingestion of contaminated foodstuffs (e.g., fish) is directly related to the kinetics of MeHg elimination among individuals. Yet, the factors driving the wide range of inter-individual variability in MeHg elimination within a population are poorly understood. Here, we investigated the relationship between MeHg elimination, gut microbiome demethylation activity, and gut microbiome composition using a coordinated human clinical trial and gnotobiotic mouse modeling approach together with metagenomic sequence analysis. We first observed MeHg elimination half-lives (t) ranging from 28 to 90 days across 27 volunteers. Subsequently, we found that ingestion of a prebiotic induced changes in the gut microbiome and mixed effects (increased, decrease, and no effect) on elimination in these same individuals. Nonetheless, elimination rates were found to correlate with MeHg demethylation activity in cultured stool samples. In mice, attempts to remove the microbiome via generation of germ-free (GF) animals or through antibiotic (Abx) treatment both diminished MeHg demethylation to a similar extent. While both conditions substantially slowed elimination, Abx treatment resulted in significantly slower elimination than the GF condition, indicating an additional role for host-derived factors in supporting elimination. Human fecal microbiomes transplanted to GF mice restored elimination rates to that seen in control mice. Metagenomic sequence analysis of human fecal DNA did not identify genes encoding proteins typically involved in demethylation (e.g., merB, organomercury lyase). However, the abundance of several anaerobic taxa, notably Alistipes onderdonkii, were positively correlated with MeHg elimination. Surprisingly, mono-colonization of GF free mice with A. onderdonkii did not restore MeHg elimination to control levels. Collectively, our findings indicate the human gut microbiome uses a non-conventional pathway of demethylation to increase MeHg elimination that relies on yet to be resolved functions encoded by the gut microbes and the hostClinical Trial NCT04060212, prospectively registered 10/1/2019.
Topics: Humans; Animals; Mice; Methylmercury Compounds; Gastrointestinal Microbiome; Microbiota; Kinetics; Demethylation
PubMed: 37392210
DOI: 10.1007/s00204-023-03548-7 -
Toxicology Mechanisms and Methods Jan 2024Mercury is a ubiquitous environmental contaminant and can be found in inorganic (Hg, Hg and Hg) and organic forms (chiefly CHHg or MeHg). The main route of human,... (Review)
Review
Mercury is a ubiquitous environmental contaminant and can be found in inorganic (Hg, Hg and Hg) and organic forms (chiefly CHHg or MeHg). The main route of human, mammals and bird exposure occurs predatory fish ingestion. Occupational exposure to Hg (and Hg) can also occur; furthermore, in gold mining areas the exposure to inorganic Hg can also be high. The toxicity of electrophilic forms of Hg (EHg) is mediated by disruption of thiol (-SH)- or selenol (-SeH)-containing proteins. The therapeutic approaches to treat methylmercury (MeHg), Hg and Hg are limited. Here we discuss the potential use of ebselen as a potential therapeutic agent to lower the body burden of Hg in man. Ebselen is a safe drug for humans and has been tested in clinical trials (for instance, brain ischemia, noise-induce hearing loss, diabetes complications, bipolar disorders) at doses varying from 400 to 3600 mg per day. Two clinical trials with ebselen in moderate and severe COVID are also approved. Ebselen can be metabolized to an intermediate with -SeH (selenol) functional group, which has a greater affinity to electrophilic Hg (EHg) forms than the available thiol-containing therapeutic agents. Accordingly, as observed and rodent models Ebselen exhibited protective effects against MeHg, indicating its potential as a therapeutic agent to treat MeHg overexposure. The combined use of ebselen with thiol-containing molecules (e.g. N-acetylcysteine and enaramide)) is also commented, because they can have synergistic protective effects against MeHg.
Topics: Animals; Humans; Mercury; Methylmercury Compounds; Azoles; Sulfhydryl Compounds; Mammals
PubMed: 37731353
DOI: 10.1080/15376516.2023.2258958