Association of Fish Consumption and Mercury Exposure During Pregnancy With Metabolic Health and Inflammatory Biomarkers in Children.

Importance: The balance of mercury risk and nutritional benefit from fish intake during pregnancy for the metabolic health of offspring to date is unknown. Objective: To assess the associations of fish intake and mercury exposure during pregnancy with metabolic syndrome in children and alterations in biomarkers of inflammation in children. Design, Setting, and Participants: This population-based prospective birth cohort study used data from studies performed in 5 European countries (France, Greece, Norway, Spain, and the UK) between April 1, 2003, and February 26, 2016, as part of the Human Early Life Exposome (HELIX) project. Mothers and their singleton offspring were followed up until the children were aged 6 to 12 years. Data were analyzed between March 1 and August 2, 2019. Exposures: Maternal fish intake during pregnancy (measured in times per week) was assessed using validated food frequency questionnaires, and maternal mercury concentration (measured in micrograms per liter) was assessed using maternal whole blood and cord blood samples. Main Outcomes and Measures: An aggregate metabolic syndrome score for children was calculated using the z scores of waist circumference, systolic and diastolic blood pressures, and levels of triglyceride, high-density lipoprotein cholesterol, and insulin. A higher metabolic syndrome score (score range, -4.9 to 7.5) indicated a poorer metabolic profile. Three protein panels were used to measure several cytokines and adipokines in the plasma of children. Results: The study included 805 mothers and their singleton children. Among mothers, the mean (SD) age at cohort inclusion or delivery of their infant was 31.3 (4.6) years. A total of 400 women (49.7%) had a high educational level, and 432 women (53.7%) were multiparous. Among children, the mean (SD) age was 8.4 (1.5) years (age range, 6-12 years). A total of 453 children (56.3%) were boys, and 734 children (91.2%) were of white race/ethnicity. Fish intake consistent with health recommendations (1 to 3 times per week) during pregnancy was associated with a 1-U decrease in metabolic syndrome score in children (ß = -0.96; 95% CI, -1.49 to -0.42) compared with low fish consumption (<1 time per week) after adjusting for maternal mercury levels and other covariates. No further benefit was observed with fish intake of more than 3 times per week. A higher maternal mercury concentration was independently associated with an increase in the metabolic syndrome score of their offspring (ß per 2-fold increase in mercury concentration = 0.18; 95% CI, 0.01-0.34). Compared with low fish intake, moderate and high fish intake during pregnancy were associated with reduced levels of proinflammatory cytokines and adipokines in children. An integrated analysis identified a cluster of children with increased susceptibility to metabolic disease, which was characterized by low fish consumption during pregnancy, high maternal mercury levels, decreased levels of adiponectin in children, and increased levels of leptin, tumor necrosis factor α, and the cytokines interleukin 6 and interleukin 1ß in children. Conclusions and Relevance: Results of this study suggest that moderate fish intake consistent with current health recommendations during pregnancy was associated with improvements in the metabolic health of children, while high maternal mercury exposure was associated with an unfavorable metabolic profile in children.

The Nuclear Protein HOXB13 Enhances Methylmercury Toxicity by Inducing Oncostatin M and Promoting Its Binding to TNFR3 in Cultured Cells.

Homeobox protein B13 (HOXB13), a transcription factor, is related to methylmercury toxicity; however, the downstream factors involved in enhancing methylmercury toxicity remain unknown. We performed microarray analysis to search for downstream factors whose expression is induced by methylmercury via HOXB13 in human embryonic kidney cells (HEK293), which are useful model cells for analyzing molecular mechanisms. Methylmercury induced the expression of oncostatin M (OSM), a cytokine of the interleukin-6 family, and this was markedly suppressed by HOXB13 knockdown. OSM knockdown also conferred resistance to methylmercury in HEK293 cells, and no added methylmercury resistance was observed when both HOXB13 and OSM were knocked down. Binding of HOXB13 to the OSM gene promoter was increased by methylmercury, indicating the involvement of HOXB13 in the enhancement of its toxicity. Because addition of recombinant OSM to the medium enhanced methylmercury toxicity in OSM-knockdown cells, extracellularly released OSM was believed to enhance methylmercury toxicity via membrane receptors. We discovered tumor necrosis factor receptor (TNF) receptor 3 (TNFR3) to be a potential candidate involved in the enhancement of methylmercury toxicity by OSM. This toxicity mechanism was also confirmed in mouse neuronal stem cells. We report, for the first time, that HOXB13 is involved in enhancement of methylmercury toxicity via OSM-expression induction and that the synthesized OSM causes cell death by binding to TNFR3 extracellularly.

Selenium protection against mercury neurotoxicity: Modulation of apoptosis and autophagy in the anterior pituitary.

AIMS: The aim of the present study is to shed light on the modulating action of selenium on two of the most crucial cellular pathways; apoptosis and autophagy and the possible interplay between them in determining the pituitary fate in the context of mercury intoxication through demonstration of the molecular, histopathological, immunohistochemical, and ultrastructural features of selenium mercury-treated adenohypophysis. METHODS: Thirty adult Sprague Dawley male albino rats were assigned into control group, mercury-treated group and mercury­selenium concomitantly-treated group. The adenohypophysis was subjected to structural, molecular and protein expression assessment of autophagy and apoptotic markers and western blotted analysis of Beclin 1 as a key cross-regulator of autophagy and apoptosis. KEY FINDINGS: Selenium treatment ameliorated the mercury-induced apoptosis detected by improvement in PCR and immunohistochemical expression of the apoptotic markers Bax, Bcl-2 and Caspase-3. Selenium also improved mercury-induced autophagic dysfunction with statistically significant improvement in western blotted levels of the autophagy markers LC3I, LC3II and Beclin1. The histopathological and ultrastructural studies strongly confirmed those findings. SIGNIFICANCE: The crosstalk between the apoptotic Bcl-2 family of proteins and the autophagic Beclin-1LC3 pathway in the context of mercury intoxication paves the way for developing novel effective treatment strategies for several mercury-induced pituitary diseases.

Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh.

Background: Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine. Objective: This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine. Design: In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 µg per day), 3 g creatine per day, 400 µg FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12-24, half of the participants receiving FA received placebo. Results: Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P < 0.05). In the creatine group, the mean decrease in %MMAs exceeded that of the placebo group at wk 6 and 12 (P < 0.05); creatine supplementation did not affect change in %InAs or %DMAs. The decrease in %MMAs at wk 6 and 12 was larger in the 800 µg FA than in the 400 µg FA group (P = 0.034). There were no differences in treatment effects between the 400 µg FA and creatine + FA groups. Data suggest a rebound in As metabolite proportions after FA cessation; at wk 24, log(%InAs) and %DMAs were not significantly different than baseline levels among participants who discontinued FA supplementation. Conclusions: The results of this study confirm that FA supplementation rapidly and significantly increases methylation of InAs to DMAs. Further research is needed to understand the strong cross-sectional associations between urinary creatinine and As methylation in previous studies. This trial was registered at https://clinicaltrials.gov as NCT01050556.

Continuous Exposure to Inorganic Mercury Affects Neurobehavioral and Physiological Parameters in Mice.

Contamination with mercury is a real health issue for humans with physiological consequences. The main objective of the present study was to assess the neurotoxicological effect of inorganic mercury: HgCl2. For this, adult mice were exposed prenatally, postnatally, and during the adult period to a low level of the metal, and their behavior and antioxidant status were analyzed. First, we showed that mercury concentrations in brain tissue of treated animals showed significant bioaccumulation, which resulted in behavioral deficits in adult mice. Thus, the treated mice developed an anxiogenic state, as evidenced by open field and elevated plus maze tests. This anxiety-like behavior was accompanied by a decrease in social behavior. Furthermore, an impairment of memory in these treated mice was detected in the object recognition and Y-maze tests. The enzymatic activity of the antioxidant system was assessed in eight brain structures, including the cerebral cortex, olfactory bulb, hippocampus, hypothalamus, mesencephalon, pons, cerebellum, and medulla oblongata. The results show that chronic exposure to HgCl2 caused alterations in the activity of catalase, thioredoxin reductase, glutathione peroxidase, superoxide dismutase, and glutathione S-transferase, accompanied by peroxidation of membrane lipids, indicating a disturbance in intracellular redox homeostasis with subsequent increased intracellular oxidative stress. These changes in oxidative stress were concomitant with a redistribution of essential heavy metals, i.e., iron, copper, zinc, and magnesium, in the brain as a possible response to homeostatic dysfunction following chronic exposure. The alterations observed in overall oxidative stress could constitute the basis of the anxiety-like state and the neurocognitive disorders observed.

Activation of ornithine decarboxylase protects against methylmercury toxicity by increasing putrescine.

We previously reported significantly increased level of putrescine, a polyamine, in the brains of mice administered methylmercury. Moreover, addition of putrescine to culture medium reduced methylmercury toxicity in C17.2 mouse neural stem cells. In this study, the role of ornithine decarboxylase (ODC), an enzyme involved in putrescine synthesis, in response to methylmercury toxicity was investigated. Methylmercury increased ODC activity in mouse cerebrum and cerebellum, but this increase was hardly observed in the kidney and liver, where methylmercury accumulated at a high concentration. In the cerebrum and cerebellum, increased putrescine was observed with methylmercury administration. Methylmercury increased ODC activity in C17.2 cells, but this was almost completely abolished in the presence of an ODC inhibitor. Methylmercury also increased the level of ODC protein in mouse brain and C17.2 cells. In addition, C17.2 cells pretreated with ODC inhibitor showed higher methylmercury sensitivity than control cells. These results suggest that the increased ODC activity by methylmercury is involved in the increase in putrescine level, and ODC plays an important role in the reduction of methylmercury toxicity. This is the first study to provide evidence that increased ODC activity may be a protective response against methylmercury-induced neurotoxicity.

Mercury-induced Oxidative Stress May Adversely Affect Pregnancy Outcome among Dental Staff: A Cohort Study.

BACKGROUND: Dental staff may be at increased risk of adverse pregnancy outcome secondary to their chronic exposure to mercury. OBJECTIVE: To investigate obstetric outcome among dental staff and explore the oxidative stress induced by mercury exposure. METHODS: A cohort of 64 pregnant dental staff (exposed group) and 60 pregnant employees (non-exposed group) were studied. Urinary mercury level and blood antioxidant activity were measured. Participants were followed to assess their obstetric outcome. RESULTS: The exposed group had a higher mean urinary mercury level and a lower blood antioxidant activity during the three trimesters compared to non-exposed group (p<0.001). Women in the exposed group were experienced more frequently spontaneous abortion and pre-eclampsia (p<0.05). Babies born to the women in the exposed group tended to be smaller for gestational age compared to those of non-exposed group (p<0.001). CONCLUSION: Pregnant dental staff suffered higher odds of developing spontaneous abortion and pre-eclampsia and giving birth to babies smaller for gestational age. This may be linked to oxidative stress induced by exposure to mercury.

Rethinking mercury: the role of selenium in the pathophysiology of mercury toxicity.

INTRODUCTION: There is increasing evidence that the pathophysiological target of mercury is in fact selenium, rather than the covalent binding of mercury to sulfur in the body's ubiquitous sulfhydryl groups. The role of selenium in mercury poisoning is multifaceted, bidirectional, and central to understanding the target organ toxicity of mercury. METHODS: An initial search was performed using Medline/PubMed, Toxline, Google Scholar, and Google for published work on mercury and selenium. These searches yielded 2018 citations. Publications that did not evaluate selenium status or evaluated environmental status (e.g., lake or ocean sediment) were excluded, leaving approximately 500 citations. This initial selection was scrutinized carefully and 117 of the most relevant and representative references were selected for use in this review. Binding of mercury to thiol/sulfhydryl groups: Mercury has a lower affinity for thiol groups and higher affinity for selenium containing groups by several orders of magnitude, allowing for binding in a multifaceted way. The established binding of mercury to thiol moieties appears to primarily involve the transport across membranes, tissue distribution, and enhanced excretion, but does not explain the oxidative stress, calcium dyshomeostasis, or specific organ injury seen with mercury. Effects of mercury on selenium and the role this plays in the pathophysiology of mercury toxicity: Mercury impairs control of intracellular redox homeostasis with subsequent increased intracellular oxidative stress. Recent work has provided convincing evidence that the primary cellular targets are the selenoproteins of the thioredoxin system (thioredoxin reductase 1 and thioredoxin reductase 2) and the glutathione-glutaredoxin system (glutathione peroxidase). Mercury binds to the selenium site on these proteins and permanently inhibits their function, disrupting the intracellular redox environment. A number of other important possible target selenoproteins have been identified, including selenoprotein P, K, and T. Impairment of the thioredoxin and glutaredoxin systems allows for proliferation intracellular reactive oxygen species which leads to glutamate excitosis, calcium dyshomeostasis, mitochondrial injury/loss, lipid peroxidation, impairment of protein repair, and apoptosis. Methylmercury is a more potent inhibitor of the thioredoxin system, partially explaining its increased neurotoxicity. A second important mechanism is due to the high affinity of mercury for selenium and the subsequent depletion of selenium stores needed for insertion into de novo generation of replacement selenoproteins. This mercury-induced selenium deficiency state inhibits regeneration of the selenoproteins to restore the cellular redox environment. The effects of selenium on mercury and the role this plays in biological response to mercury: Early research suggested selenium may provide a protective role in mercury poisoning, and with limitations this is true. The roles selenium plays in this reduction of mercury toxicity partially depends on the form of mercury and may be multifaceted including: 1) facilitating demethylation of organic mercury to inorganic mercury; 2) redistribution of mercury to less sensitive target organs; 3) binding to inorganic mercury and forming an insoluble, stable and inert Hg:Se complex; 4) reduction of mercury absorption from the GI tract; 5) repletion of selenium stores (reverse selenium deficiency); and 6) restoration of target selenoprotein activity and restoring the intracellular redox environment. There is conflicting evidence as to whether selenium increases or hinders mercury elimination, but increased mercury elimination does not appear to be a major role of selenium. Selenium supplementation has been shown to restore selenoprotein function and reduce the toxicity of mercury, with several significant limitations including: the form of mercury (methylmercury toxicity is less responsive to amelioration) and mercury dose. CONCLUSIONS: The interaction with selenium is a central feature in mercury toxicity. This interaction is complex depending on a number of features such as the form of mercury, the form of selenium, the organ and dose. The previously suggested "protective effect" of selenium against mercury toxicity may in fact be backwards. The effect of mercury is to produce a selenium deficiency state and a direct inhibition of selenium's role in controlling the intracellular redox environment in organisms. Selenium supplementation, with limitations, may have a beneficial role in restoring adequate selenium status from the deficiency state and mitigating the toxicity of mercury.

Chemical Speciation of Selenium and Mercury as Determinant of Their Neurotoxicity.

The antagonism of mercury toxicity by selenium has been well documented. Mercury is a toxic metal, widespread in the environment. The main target organs (kidneys, lungs, or brain) of mercury vary depending on its chemical forms (inorganic or organic). Selenium is a semimetal essential to mammalian life as part of the amino acid selenocysteine, which is required to the synthesis of the selenoproteins. This chapter has the aim of disclosing the role of selenide or hydrogen selenide (Se-2 or HSe-) as central metabolite of selenium and as an important antidote of the electrophilic mercury forms (particularly, Hg2+ and MeHg). Emphasis will be centered on the neurotoxicity of electrophile forms of mercury and selenium. The controversial participation of electrophile mercury and selenium forms in the development of some neurodegenerative disease will be briefly presented. The potential pharmacological use of organoseleno compounds (Ebselen and diphenyl diselenide) in the treatment of mercury poisoning will be considered. The central role of thiol (-SH) and selenol (-SeH) groups as the generic targets of electrophile mercury forms and the need of new in silico tools to guide the future biological researches will be commented.

Impaired cross-talk between the thioredoxin and glutathione systems is related to ASK-1 mediated apoptosis in neuronal cells exposed to mercury.

Mercury (Hg) compounds target both cysteine (Cys) and selenocysteine (Sec) residues in peptides and proteins. Thus, the components of the two major cellular antioxidant systems - glutathione (GSH) and thioredoxin (Trx) systems - are likely targets for mercurials. Hg exposure results in GSH depletion and Trx and thioredoxin reductase (TrxR) are prime targets for mercury. These systems have a wide-range of common functions and interaction between their components has been reported. However, toxic effects over both systems are normally treated as isolated events. To study how the interaction between the glutathione and thioredoxin systems is affected by Hg, human neuroblastoma (SH-SY5Y) cells were exposed to 1 and 5µM of inorganic mercury (Hg2+), methylmercury (MeHg) or ethylmercury (EtHg) and examined for TrxR, GSH and Grx levels and activities, as well as for Trx redox state. Phosphorylation of apoptosis signalling kinase 1 (ASK1), caspase-3 activity and the number of apoptotic cells were evaluated to investigate the induction of Trx-mediated apoptotic cell death. Additionally, primary cerebellar neurons from mice depleted of mitochondrial Grx2 (mGrx2D) were used to examine the link between Grx activity and Trx function. Results showed that Trx was affected at higher exposure levels than TrxR, especially for EtHg. GSH levels were only significantly affected by exposure to a high concentration of EtHg. Depletion of GSH with buthionine sulfoximine (BSO) severely increased Trx oxidation by Hg. Notably, EtHg-induced oxidation of Trx was significantly enhanced in primary neurons of mGrx2D mice. Our results suggest that GSH/Grx acts as backups for TrxR in neuronal cells to maintain Trx turnover during Hg exposure, thus linking different mechanisms of molecular and cellular toxicity. Finally, Trx oxidation by Hg compounds was associated to apoptotic hallmarks, including increased ASK-1 phosphorylation, caspase-3 activation and increased number of apoptotic cells.

Effect of morin-5'-sulfonic acid sodium salt on the expression of apoptosis related proteins caspase 3, Bax and Bcl 2 due to the mercury induced oxidative stress in albino rats.

Many environmental contaminants have been reported to disturb the pro-oxidant or antioxidant balance of the cells by inducing oxidative stress. Oxidative stress mediated by the HgCl2 induces DNA, protein and lipid oxidation resulted in necrosis or apoptosis, or both. Currently flavonoids are being emerging topic and reported to have antiviral, anti-inflammatory, anti- tumor and antioxidant activities. Morin is one of the flavonoid protects the cells from oxygen free radical damage and scavenges the free radicals and metals and also heals the injured cells commercially. Morin hydrate is sparingly soluble in water. Hence, the water soluble morin -5'- sulfonic acid sodium salt (NaMSA) was selected and synthesized. Aim of the present study was to analyze the effect of morin-5'-sulfonic acid sodium salt on the expression of apoptosis related proteins caspase 3, Bax and Bcl 2 due to the mercury induced oxidative stress in albino rats.. The experimental rats were exposed to sub lethal concentration of mercuric chloride (1.25mg/kg) and the ameliorating effect of NaMSA was studied by using apoptotic protein markers Bax and caspase-3 and Bcl-2. The obtained results were analyzed using one way analysis of variance by the Duncan's Multiple comparison test to determine the level of significance (p) and p<0.05 was considered as statistically significant. Administration of mercuric chloride (1.25mg/kg) in the experimental rats increased the expression of Bax and caspase-3 and a decreased expression was noted in the Bcl-2 level compared with control bands significantly (p<0.05). On the other hand NaMSA (50mg/kg) and HgCl2 (1.25mg/kg) simultaneous administration did not bring any change in the protein expression of Bax, Caspase-3 and Bcl-2 levels compared with control rats. Hence, the membrane damage was protected, stopped the cell death and apoptosis. This could be due to the morin-5'-sulfonic acid sodium salt effective chelation action on the HgCl2 generated free radicals.

Mechanisms involved in the transport of mercuric ions in target tissues.

Mercury exists in the environment in various forms, all of which pose a risk to human health. Despite guidelines regulating the industrial release of mercury into the environment, humans continue to be exposed regularly to various forms of this metal via inhalation or ingestion. Following exposure, mercuric ions are taken up by and accumulate in numerous organs, including brain, intestine, kidney, liver, and placenta. In order to understand the toxicological effects of exposure to mercury, a thorough understanding of the mechanisms that facilitate entry of mercuric ions into target cells must first be obtained. A number of mechanisms for the transport of mercuric ions into target cells and organs have been proposed in recent years. However, the ability of these mechanisms to transport mercuric ions and the regulatory features of these carriers have not been characterized completely. The purpose of this review is to summarize the current findings related to the mechanisms that may be involved in the transport of inorganic and organic forms of mercury in target tissues and organs. This review will describe mechanisms known to be involved in the transport of mercury and will also propose additional mechanisms that may potentially be involved in the transport of mercuric ions into target cells.

[Molecular genetic aspects of endothelial dysfunction in individuals exposed to mercury].

The article deals with frequency data on polymorphism of candidate genes participating in endothelial dysfunction (EDN1 Lys198Asn, NOS3 T786C, AGT Thrl74Met and AGT Met23SThr) in totality with concentrations of their active substances in individuals exposed to mercury. Findings are changes in levels of nitrogen oxide, endothelin-1, angiotensin II metabolites in examinees including those without cardiovascular diseases. The genetic conditionality is connected with unfavorable genotypes of polymorphic variants - Met235Thr of AGT gene and Lys198Asn of EDNI gene. Changes in levels of biochemical markers of endothelial dysfunction in individuals exposed to mercury indicate serious endothelial function disorders and are not genetically determined processes.

The relationship between mercury and autism: A comprehensive review and discussion.

The brain pathology in autism spectrum disorders (ASD) indicates marked and ongoing inflammatory reactivity with concomitant neuronal damage. These findings are suggestive of neuronal insult as a result of external factors, rather than some type of developmental mishap. Various xenobiotics have been suggested as possible causes of this pathology. In a recent review, the top ten environmental compounds suspected of causing autism and learning disabilities were listed and they included: lead, methyl-mercury, polychorinated biphenyls, organophosphate pesticides, organochlorine pesticides, endocrine disruptors, automotive exhaust, polycyclic aromatic hydrocarbons, polybrominated diphenyl ethers, and perfluorinated compounds. This current review, however, will focus specifically on mercury exposure and ASD by conducting a comprehensive literature search of original studies in humans that examine the potential relationship between mercury and ASD, categorizing, summarizing, and discussing the published research that addresses this topic. This review found 91 studies that examine the potential relationship between mercury and ASD from 1999 to February 2016. Of these studies, the vast majority (74%) suggest that mercury is a risk factor for ASD, revealing both direct and indirect effects. The preponderance of the evidence indicates that mercury exposure is causal and/or contributory in ASD.

Mercury induced haemocyte alterations in the terrestrial snail Cantareus apertus as novel biomarker.

The aim of the present work was to study the response of a suite of cellular and biochemical markers in the terrestrial snail Cantareus apertus exposed to mercury in view of future use as sensitive tool suitable for mercury polluted soil monitoring and assessment. Besides standardized biomarkers (metallothionein, acetylcholinesterase, and lysosomal membrane stability) novel cellular biomarkers on haemolymph cells were analyzed, including changes in the spread cells/round cells ratio and haemocyte morphometric alterations. The animals were exposed for 14 days to Lactuca sativa soaked for 1h in HgCl2 solutions (0.5 e 1 µM). The temporal dynamics of the responses were assessed by measurements at 3, 7 and 14 days. Following exposure to HgCl2 a significant alteration in the relative frequencies of round cells and spread cells was evident, with a time and dose-dependent increase of the frequencies of round cells with respect to spread cells. These changes were accompanied by cellular morphometric alterations. Concomitantly, a high correspondence between these cellular responses and metallothionein tissutal concentration, lysosomal membrane stability and inhibition of AChE was evident. The study highlights the usefulness of the terrestrial snail C. apertus as bioindicator organism for mercury pollution biomonitoring and, in particular, the use of haemocyte alterations as a suitable biomarker of pollutant effect to be included in a multibiomarker strategy.

Mercuric chloride induced hepatotoxic and hematologic changes in rats: The protective effects of sodium selenite and vitamin E.

This study focuses on investigating the possible protective effect of sodium selenite (Na2SeO3) and/or vitamin E against mercuric chloride (HgCl2)-induced hepatotoxicity in rat. Male rats were given HgCl2 (1 mg/kg body weight (bw)) and HgCl2 plus Na2SeO3 (0.25 mg/kg bw) and/or vitamin E (100 mg/kg bw) daily via gavage for 4 weeks. HgCl2-treated groups had significantly higher white blood cell and thrombocyte counts than the control group. Serum activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl-transferase, and lactate dehydrogenase significantly increased and serum levels of total protein, albumin, triglyceride, total cholesterol, and low-density lipoprotein cholesterol significantly decreased in the HgCl2-treated groups compared with control group. Malondialdehyde level significantly increased and superoxide dismutase, catalase, and glutathione peroxidase activities decreased in liver tissue of HgCl2-treated rats. Also, HgCl2 exposure resulted in histopathological changes. Supplementation of Na2SeO3 and/or vitamin E provided partial protection in hematological and biochemical parameters that were altered by HgCl2 As a result, Na2SeO3 and/or vitamin E significantly reduced HgCl2-induced hepatotoxicity, but not protected completely.

Selenium as an antidote in the treatment of mercury intoxication.

Selenium (Se) is an essential trace element for humans. It is found in the enzyme glutathione peroxidase. This enzyme protects the organism against certain types of damage. Some data suggest that Se plays a role in the body's metabolism of mercury (Hg). Selenium has in some studies been found to reduce the toxicity of Hg salts. Selenium and Hg bind in the body to each other. It is not totally clear what impact the amount of Se has in the human body on the metabolism and toxicity of prolonged Hg exposure.

A systems toxicology approach identifies Lyn as a key signaling phosphoprotein modulated by mercury in a B lymphocyte cell model.

Network and protein-protein interaction analyses of proteins undergoing Hg²âº-induced phosphorylation and dephosphorylation in Hg²âº-intoxicated mouse WEHI-231 B cells identified Lyn as the most interconnected node. Lyn is a Src family protein tyrosine kinase known to be intimately involved in the B cell receptor (BCR) signaling pathway. Under normal signaling conditions the tyrosine kinase activity of Lyn is controlled by phosphorylation, primarily of two well known canonical regulatory tyrosine sites, Y-397 and Y-508. However, Lyn has several tyrosine residues that have not yet been determined to play a major role under normal signaling conditions, but are potentially important sites for phosphorylation following mercury exposure. In order to determine how Hg²âº exposure modulates the phosphorylation of additional residues in Lyn, a targeted MS assay was developed. Initial mass spectrometric surveys of purified Lyn identified 7 phosphorylated tyrosine residues. A quantitative assay was developed from these results using the multiple reaction monitoring (MRM) strategy. WEHI-231 cells were treated with Hg²âº, pervanadate (a phosphatase inhibitor), or anti-Ig antibody (to stimulate the BCR). Results from these studies showed that the phosphoproteomic profile of Lyn after exposure of the WEHI-231 cells to a low concentration of Hg²âº closely resembled that of anti-Ig antibody stimulation, whereas exposure to higher concentrations of Hg²âº led to increases in the phosphorylation of Y-193/Y-194, Y-501 and Y-508 residues. These data indicate that mercury can disrupt a key regulatory signal transduction pathway in B cells and point to phospho-Lyn as a potential biomarker for mercury exposure.

The retention time of inorganic mercury in the brain--a systematic review of the evidence.

Reports from human case studies indicate a half-life for inorganic mercury in the brain in the order of years-contradicting older radioisotope studies that estimated half-lives in the order of weeks to months in duration. This study systematically reviews available evidence on the retention time of inorganic mercury in humans and primates to better understand this conflicting evidence. A broad search strategy was used to capture 16,539 abstracts on the Pubmed database. Abstracts were screened to include only study types containing relevant information. 131 studies of interest were identified. Only 1 primate study made a numeric estimate for the half-life of inorganic mercury (227-540 days). Eighteen human mercury poisoning cases were followed up long term including autopsy. Brain inorganic mercury concentrations at death were consistent with a half-life of several years or longer. 5 radionucleotide studies were found, one of which estimated head half-life (21 days). This estimate has sometimes been misinterpreted to be equivalent to brain half-life-which ignores several confounding factors including limited radioactive half-life and radioactive decay from surrounding tissues including circulating blood. No autopsy cohort study estimated a half-life for inorganic mercury, although some noted bioaccumulation of brain mercury with age. Modelling studies provided some extreme estimates (69 days vs 22 years). Estimates from modelling studies appear sensitive to model assumptions, however predications based on a long half-life (27.4 years) are consistent with autopsy findings. In summary, shorter estimates of half-life are not supported by evidence from animal studies, human case studies, or modelling studies based on appropriate assumptions. Evidence from such studies point to a half-life of inorganic mercury in human brains of several years to several decades. This finding carries important implications for pharmcokinetic modelling of mercury and potentially for the regulatory toxicology of mercury.

Public health department response to mercury poisoning: the importance of biomarkers and risks and benefits analysis for chelation therapy.

Chelation therapy is often used to treat mercury poisoning. Public health personnel are often asked about mercury toxicity and its treatment. This paper provides a public health department response to use of a mercury-containing cosmetic in Minnesota, a perspective on two unpublished cases of chelation treatment for postulated mercury toxicity, and comments on the use of a nonsystemic treatment for removal of mercury following the Iraqi seed coat poisoning incident. Physicians should evaluate sources of exposure, biomarkers, and risks and benefits before recommending chelation therapy for their patients. Potential risks to chelation therapy and its little understood subtle or latent effects are areas of public health concern.