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Epidemiological studies to determine the impact of low level toxic exposure on child development are important in guiding clinical and public health action. However, carrying out such studies and interpreting their findings presents a number of significant challenges to the investigators. First, they must find a cohort with suitable exposure, select a biomarker that will accurately determine the level of exposure and determine the endpoints that are most likely to detect subtle differences in neurodevelopment. Following that, the logistics of the study must be organised and collaboration established with the local population and health authorities. To accurately interpret the data, they must also accurately determine covariates that impact child development. After the data are collected, interpreting the findings presents a further challenge. Throughout this process, the study must adhere to fundamental epidemiological principles and clearly defined statistical approaches. This paper discusses those principles and uses the Seychelles Child Development Study to show how one epidemiological study addressed them.

Developmental methylmercury (MeHg) exposure can have lasting consequences on neural development and motor function across the lifespan. Recent evidence for MeHg targeting of myogenic pathways has drawn attention to the possibility that developing skeletal muscle plays a role in the motor deficits stemming from early life MeHg exposure. In this study we examined a potential role for muscle in influencing MeHg developmental toxicity in offspring of female mice exposed to MeHg via drinking water. Dams had access to 0, 0.5 or 5.0 ppm MeHg chloride in drinking water from two weeks prior to mating through weaning. Blood, brain and muscle tissue was harvested from dams at weaning and pups at postnatal days (PND) 6, 21 and 60 for analysis of total Hg. Muscle tissue sections were examined with histological stains. Behavioral testing of offspring was conducted at PND 60 and included locomotor activity, inverted screen, grip strength and rotarod tests to assess motor function. Total Hg (tHg) levels in dam muscles at weaning were 1.7–3-fold higher than Hg levels in blood or brain. In PND6 male and female pups, muscle and brain tHg levels were 2 to 4-fold higher than blood tHg. Brain tHg levels decreased more rapidly than muscle tHg levels between PND 6 and 21. Premised on modeling of growth dilution, brain tissue demonstrated an elimination of tHg while muscle tissue exhibited a net uptake of tHg between PND 6 and 21. Despite overall elevated Hg levels in developing muscle, no gross morphological or cytological phenotypes were observed in muscle at PND 60. At the higher MeHg dose, grip strength was reduced in both females and males at PND 60, whereas only male specific deficits were observed in locomotor activity and inverted screen tests with marginally significant deficits on rotarod. These findings highlight a potential role for developing skeletal muscle in mediating the neuromuscular insult of early life MeHg exposure.

Methyl mercury (MeHg) poisoning or Minamata disease (MD) from fish consumption is a public health concern throughout the world because all fish contain small amounts. The lowest exposure level needed to impair children's development is controversial. Actual poisoning with MeHg from fish consumption has been reliably reported only two times. It occurred in Minamata, Japan in the 1950s and then in Niigata, Japan in the 1960s. On each occasion, massive industrial pollution led to local fish having mercury levels as high as 40 ppm. In Niigata the pollution was on the Agano River and there were over 2000 commercial fishermen active at that time. We studied adult subjects who had been exposed perinatally to MeHg from fish consumption during the Niigata poisoning to determine the long-term impact of exposure. We identified mothers with elevated levels of exposure during the epidemic and those diagnosed with MeHg poisoning. The subjects of the study were their adult children, born during the epidemic. The evaluation consisted of a questionnaire (administered by interview) focusing on development, symptoms, and current function and a standard medical and neurological examination. The subjects were divided into four groups based upon prenatal levels of mercury in maternal hair or the presence of MD. For Group A the hair mercury levels were 50 ppm or more, for Group B the mercury levels were 25-49 ppm, and for Group C 10-24 ppm. The subjects in Group D were born to mothers diagnosed with MD, but their mercury levels were not measured. Exposure was predominantly prenatal, but some mothers also breast fed their infants. Group A included 13 subjects among whom two were diagnosed with congenital MeHg poisoning and in two others it was suspected. Group B included 10 subjects, of whom three had symptoms compatible with MeHg poisoning. Group C had nine subjects including one with intellectual deficit and another with hearing loss. Group D had eight subjects of whom four had symptoms compatible with MeHg exposure, but only one had abnormal neurological findings. Among the subjects thought to have congenital or childhood MeHg poisoning, intelligence did not appear to have declined over time. More children were affected by prenatal and postnatal MeHg exposure at Niigata than was previously reported.

Mercury and methyl mercury are poisonous to human body. In the recent times, exposure to mercury has been anthropogenic in nature. Within the past several decades, many incidences of mercury poisoning have been documented in several countries including Pakistan. Mercury has been ingested where it has been used to preserve crops, through the point and non-point source discharge into the surface water, and consequently entering the food chain. We conducted this scoping review of mercury and its health effects in Pakistan in order to raise the flag to a silent ongoing Minamata disease in the country. We conducted a systematic search of the available literature in Google Scholar, PubMed, and grey literature of unpublished theses and reports of various universities across the country. We found that in the northern Pakistan, suspended sediments were the major pathway of the riverine mercury transport. Sediments of Hunza and Gilgit River were found high in mercury concentrations. Gold mining leads to an increase in mercury concentration in soil and river waters flowing in this region. High concentrations up to 108 ng/L were found in Shimsal River. It is suspected that that high level of mercury transport may be leading to accumulation of mercury in major water bodies and lakes downstream. Occupational exposure to mercury and other heavy metals is common in an unregulated private sector of the country. Goldsmiths burn the amalgamated gold without personal protective measures. Direct exposure to the fumes of mercury leads to respiratory, dermatological, systemic and neurological ailments specific to mercury poisoning. We found good evidence of bioaccumulation of mercury in fish and fish products in Pakistan. The untreated waste water discharge is responsible to not only afflicted the fish but also the birds which feed on this fish. Further, the same untreated waste water from factories and agriculture runoffs affect vegetables grown in it. Studies looking at the biomarkers for mercury in humans have shown increased and even toxic levels of mercury among the most vulnerable populations of the country. Other sources of mercury exposure included mercury in traditional medicines and cigarette products. Though no evidence was found for its presence in drinking water, its existence in the food chain and occupational exposure pose great threat to the humans as well as animals.

Background Studies with children exposed to methylmercury (MeHg) through fish consumption in the Brazilian Amazon region report that the high levels of hair Hg are associated with significant decreases in intelligence, memory, attention, and visuospatial processing. Objective To investigate the relationship between mercury exposure and neuropsychological functions in riverside communities of the Brazilian Amazon. Method 263 participants aged 6 to 14 years old were assessed, from resettlement regions, near the Madeira river, Rondonia, Brazil. To assess the neuropsychological functions we used the following instruments: intelligence (WASI), working memory (Corsi Block-Tapping Task and Digit Span), verbal fluency (Word Generation - NEPSY II), inhibitory control (Inhibition Errors - NEPSY II), shifting (Trail Making Test) and manual motor dexterity (Grooved PegBoard Test). Socioeconomic status was obtained through household surveys. Total Hg levels were quantified hair samples (Total HgH) collected from the occipital region of the scalp and analyzed by Cold Vapor Atomic Absorption Spectrometry. Results The group in the upper quartile of Total HgH levels presented lower scores on the tasks that assessed estimated IQ, visuospatial working memory, semantic knowledge and phonological verbal fluency, when compared to the group in the lower quartile level. A regression analysis controlled for age, sex, and maternal education showed that for each increase of 10 μg/g of Total HgH, there was a decrease around half standard deviation in Verbal IQ, estimated IQ scores, semantic knowledge, phonological verbal fluency and for verbal and visuospatial working memory. Conclusions High concentrations of Total Hg in hair were associated with a lower performance in neuropsychological functions tests. The results show that environmental exposure to Hg is associated to children and adolescents’ lower neuropsychological performance in the riverine and resettled areas of the Brazilian Amazon region.

Photographers and filmmakers have made important contributions to the international mental health community through documentation and social commentary, leveraging the power of visual imagery. To illustrate, this article uses the example of W. Eugene Smith who photographed the catastrophic effects of methylmercury poisoning from industrial pollution in the region around Minamata Bay, Japan. Although many art forms have been comfortably integrated into mainstream psychiatry and neuropsychiatry, photography has been underappreciated and underutilized.

Industrial release of mercury into the local Minamata environment with consequent poisoning of local communities through contaminated fish and shellfish consumption is considered the classic case of environmental mercury poisoning. However, the mercury species in the factory effluent has proved controversial, originally suggested as inorganic, and more recently as methylmercury species. We used newly available methods to re-examine the cerebellum of historic Cat 717, which was fed factory effluent mixed with food to confirm the source. Synchrotron high-energy-resolution fluorescence detection-X-ray absorption spectroscopy revealed sulfur-bound organometallic mercury with a minor β-HgS phase. Density functional theory indicated energetic preference for α-mercuri-acetaldehyde as a waste product of aldehyde production. The consequences of this alternative species in the "classic" mercury poisoning should be re-evaluated.

Mercury is a severe environmental pollutant with neurotoxic effects, especially when exposed for long periods. Although there are several evidences regarding mercury toxicity, little is known about inorganic mercury (IHg) species and cerebellum, one of the main targets of mercury associated with the neurological symptomatology of mercurial poisoning. Besides that, the global proteomic profile assessment is a valuable tool to screen possible biomarkers and elucidate molecular targets of mercury neurotoxicity; however, the literature is still scarce. Thus, this study aimed to investigate the effects of long-term exposure to IHg in adult rats’ cerebellum and explore the modulation of the cerebellar proteome associated with biochemical and functional outcomes, providing evidence, in a translational perspective, of new mercury toxicity targets and possible biomarkers. Fifty-four adult rats were exposed to 0.375 mg/kg of HgCl2 or distilled water for 45 days using intragastric gavage. Then, the motor functions were evaluated by rotarod and inclined plane. The cerebellum was collected to quantify mercury levels, to assess the antioxidant activity against peroxyl radicals (ACAPs), the lipid peroxidation (LPO), the proteomic profile, the cell death nature by cytotoxicity and apoptosis, and the Purkinje cells density. The IHg exposure increased mercury levels in the cerebellum, reducing ACAP and increasing LPO. The proteomic approach revealed a total 419 proteins with different statuses of regulation, associated with different biological processes, such as synaptic signaling, energy metabolism and nervous system development, e.g., all these molecular changes are associated with increased cytotoxicity and apoptosis, with a neurodegenerative pattern on Purkinje cells layer and poor motor coordination and balance. In conclusion, all these findings feature a neurodegenerative process triggered by IHg in the cerebellum that culminated into motor functions deficits, which are associated with several molecular features and may be related to the clinical outcomes of people exposed to the toxicant.

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.

The Revisit series in this issue introduced the article by Kitamura and colleagues.1 Dr. Shoji Kitamura, born in 1915, was a medical doctor and a professor of Department of Public Health in the Medical School at Kumamoto University when Minamata disease happened. The article summarized findings from a very-early-phase epidemiological study conducted by researchers from Kumamoto University immediately after the Minamata disease incident was officially recognized on May 1, 1956. The epidemiological study was very well-conducted in a timely manner and the article was available as early as January 1957 in an academic journal published by the Medical School at Kumamoto University. This is a very influential report that demonstrated associations between fish intake and the Minamata disease after careful descriptive and analytical epidemiological studies. Although the Japanese society should have taken some actions to prevent the disease with the evidence that a research group at Kumamoto University had at that time, the pollution was not stopped until 12 years had passed since the official identification in 1956. Moreover, the struggle with Minamata disease is still in progress. This unfavorable response by the Japanese society could partly be explained by the important economic role of the causative factory at that time, when Japan had recorded a trade deficit since the end of the Second World War.2 Plastic products of the factory were key Japanese exports helping to reduce this deficit. In this commentary, after introducing the study by Kitamura and colleagues, I discuss the potentials of epidemiology, as well as consequences on public health that occurred when we did not follow the findings from the epidemiological study.

Although high or repeated exposure to different forms of Hg can have serious health consequences, the most important toxicity risk for humans is as methylmercury (MeHg) which exposure is mainly through consumption of fish. Generally, more than the 80% of Hg in hair is as MeHg, which is taken up by hair follicles as MeHg-cysteine complexes. In this context, hair samples were collected from 200 children (7 years) living in a coastal site in the North-East (A) of Italy and from 299 children (6-11 years) living in a urban area of South of Italy (B) to determine the levels of MeHg. Considering the neurotoxicity of MeHg, children were subjected to cognitive and neuropsychological tests. The hair values of Hg in the children population groups were comparable with data reported in other international surveys. On the other hand, combining results of the neurological tests with Hg levels, a possible relationship between Hg and an increase of the errors average reported in some neurological tests has been noted. Although the Hg levels were not elevated, a possible neurological influence in children, a population more susceptible than adults, might not be excluded, but the influence on neurological performances of the children could be also due to the family environment (socio economic status, educational level, etc.).

We recently found that tumor necrosis factor-α (TNF-α) may be involved in neuronal cell death induced by methylmercury in the mouse brain. Here, we examined the cells involved in the induction of TNF-α expression by methylmercury in the mouse brain by in situ hybridization. TNF-α-expressing cells were found throughout the brain and were identified as microglia by immunostaining for ionized calcium binding adaptor molecule 1 (Iba1). Methylmercury induced TNF-α expression in mouse primary microglia and mouse microglial cell line BV2. Knockdown of apoptosis signal-regulating kinase 1 (ASK1), an inflammatory cytokine up-regulator that is responsible for reactive oxygen species (ROS), decreased methylmercury-induced TNF-α expression through decreased phosphorylation of p38 MAP kinase in BV2 cells. Suppression of methylmercury-induced reactive oxygen species (ROS) by antioxidant treatment largely abolished the induction of TNF-α expression and phosphorylation of p38 by methylmercury in BV2 cells. Finally, in mouse brain slices, the TNF-α antagonist (WP9QY) inhibited neuronal cell death induced by methylmercury, as did the p38 inhibitor SB203580 and liposomal clodronate (a microglia-depleting agent). These results indicate that methylmercury induces mitochondrial ROS that are involved in activation of the ASK1/p38 pathway in microglia and that this is associated with induction of TNF-α expression and neuronal cell death.

Human exposure to mercury is a major public health concern, causing neurological outcomes such as motor and visual impairment and learning disabilities. Currently, human exposure in the Amazon is among the highest in the world. A recent systematic review (doi:10.1016/j.jtemb.2018.12.001), however, highlighted the lack of high-quality studies on mercury-associated neurotoxicity. There is, therefore, a need to improve research and much to still learn about how exposure correlates with disease. In this review, we discuss studies evaluating the associations between neurological disturbances and mercury body burden in Amazonian populations, to generate recommendations for future studies. A systematic search was performed during July 2020, in Pubmed/Medline, SCOPUS and SCIELO databases with the terms (mercury*) and (Amazon*). Four inclusion criteria were used: original article (1), with Amazonian populations (2), quantifying exposure (mercury levels) (3), and evaluating neurological outcomes (4). The extracted data included characteristics (as year or origin of authorship) and details of the research (as locations and type of participants or mercury levels and neurological assessments). Thirty-four studies, most concentrated within three main river basins (Tapajos, Tocantins, and Madeira) and related to environmental exposure, were found. Mercury body burden was two to ten times higher than recommended and main neurological findings were cognitive, vision, motor, somatosensory and emotional deficits. Important insights are described that support novel approaches to researching mercury exposure and intoxication, as well as prevention and intervention strategies. As a signatory country to the Minamata Convention, Brazil has the opportunity to play a central role in improving human health and leading the research on mercury intoxication.

Mercuric chloride (HgCl

Author(s): Myers, Gary; van Wijngaarden, Edwin; Lasley, Stephen M; Cranmer, Joan M; Lein, Pamela J; Westerink, Remco HS

We report a rare case of fatal intoxication in a 40-year-old man caused by injection of a fluid containing organic mercury, allegedly in an attack with a syringe fixed to the tip of an umbrella. The man suffered from severe neurological symptoms and progressive multiorgan failure and died 10 months later in refractory status epilepticus. Autopsy revealed severe brain atrophy and non-specific kidney damage. Neuropathological examination showed neuronal loss especially in the occipital lobe, distinct granule cell necrosis in the cerebellum and Wallerian degeneration in the brainstem. Postmortem toxicological analysis revealed extremely increased levels of mercury in liver and kidney tissue as well as methylmercury levels in peripheral blood.

β-HgS, differing from environmental mercury pollutants (MeHgCl and HgCl

Methylmercury (MeHg) is the causative substance of Minamata disease, which is associated with various neurological disorders such as sensory disturbance and ataxia. It has been suggested low-level dietary intake of MeHg from MeHg-containing fish during gestation adversely affects the fetus. In our study, we investigated the toxicological effects of MeHg exposure on neuronal differentiation focusing on epigenetics. We used human fetal brain-derived immortalized cells (LUHMES cells) as a human neuronal differentiation model. Cell viability, neuronal, and catecholamine markers in LUHMES cells were assessed after exposure to MeHg (0–1000 nM) for 6 days (from day 2 to day 8 of neuronal differentiation). Cell viability on day 8 was not affected by exposure to 1 nM MeHg for 6 days. mRNA levels of AADC, DBH, TUJ1, and SYN1 also were unaffected by MeHg exposure. In contrast, levels of TH, the rate-limiting enzyme for dopamine synthesis, were significantly decreased after MeHg exposure. Acetylated histone H3, acetylated histone H3 lysine 9, and tri-methyl histone H3 lysine 9 levels at the TH gene promoter were not altered by MeHg exposure. However, tri-methylation of histone H3 lysine 27 levels, related to transcriptional repression, were significantly increased at the TH gene promotor after MeHg exposure. In summary, MeHg exposure during neuronal differentiation led to epigenetic changes that repressed TH gene expression. This study provides useful insights into the toxicological mechanisms underlying the effects of developmental MeHg exposure during neuronal differentiation.

Mercury (Hg), a divalent metal, produces adverse effects predominantly in the renal and central nervous systems. The aim of this study was to determine the effectiveness of copper (Cu) in prevention of mercuric mercury (HgMT: metallothioneins; PBG-synthase: porphobilinogen synthase.

Severe methylmercury poisoning occurred in Minamata and neighboring communities in Japan during the 1950s and 1960s, causing what is known as Minamata disease. Although an increase in stillbirths and a reduced male proportion at birth (i.e., reduced sex ratio) have been reported, no studies have evaluated the impact of exposure on an entire set of infant and birth outcomes. We therefore evaluated the temporal trends of these outcomes in the Minamata area from 1950 to 1974. We focused on the spontaneous/artificial stillbirth rate, crude fertility rate, male proportion at birth, male proportion among stillbirths, and infant mortality. We obtained the number of stillbirths, live births, and infant deaths in Minamata City and Kumamoto Prefecture (as a reference) from 1950 to 1974. After plotting annual figures for each outcome, we divided the study period into five intervals and compared them between Minamata City and Kumamoto Prefecture using the chi-squared test. We observed a slightly increased spontaneous stillbirth rate and decreased artificial stillbirth rate in Minamata City, followed by a reduced crude fertility rate. The crude fertility rates in Minamata City during the period 1955-1965 were significantly lower compared with those in Kumamoto Prefecture (p

This article reviews the clinical use of the metal chelators sodium 2,3-dimercapto-1-propanesulfonate (DMPS), meso-2,3-dimercaptosuccinic acid (DMSA), and calcium disodium edetate (CaEDTA, calcium EDTA) in overexposure and poisonings with salts of lead (Pb), mercury (Hg), and arsenic (As). DMSA has considerably lower toxicity than the classic heavy metal antagonist BAL (2,3-dimercaptopropanol) and is also less toxic than DMPS. Because of its adverse effects, CaEDTA should be replaced by DMSA as the antidote of choice in treating moderate Pb poisoning. Combination therapy with BAL and CaEDTA was previously recommended in cases of severe acute Pb poisoning with encephalopathy. We suggest that BAL in such cases acted as a shuttling Pb transporter from the intra- to the extracellular space. The present paper discusses if a combination of the extracellularly distributed DMSA with the ionophore, Monensin may provide a less toxic combination for Pb mobilization by increasing both the efflux of intracellularly deposited Pb and the urinary Pb excretion. Anyhow, oral therapy with DMSA should be continued with several intermittent courses. DMPS and DMSA are also promising antidotes in Hg poisoning, whereas DMPS seems to be a more efficient agent against As poisoning. However, new insight indicates that a combination of low-dosed BAL plus DMPS could be a preferred antidotal therapy to obtain mobilization of the intracerebral deposits into the circulation for subsequent rapid urinary excretion.

In the present study, to investigate the prevention mechanism of proanthocyanidins from lotus seedpod (LSPCs) on methyl mercuric chloride (MMC) induced neurotoxicity, neuron/astrocyte cells were co-cultured to simulate the microenvironment in vivo to the greatest extent. The results showed that, compared with MMC group, pretreatment with LSPCs not only improved cell survival rate, decreased the release of lactate dehydrogenase (LDH), decreased the intracellular reactive oxygen species (ROS) level, and prevented the increase of intracellular [Ca2+]i, but also significantly increased the total anti-oxidation capacity (T-AOC) (p＜0.05), the levels of glutathione peroxidase (GSH-Px) (p＜0.05), glutathione (GSH) (p＜0.05), and mitochondrial membrane potential (MMP) (p＜0.01). Besides, LSPCs up-regulated the expression of transcriptional factor Nrf2/HO-1 in a concentration-dependent manner. Moreover, LSPCs reduced the expression of Bax protein, significantly increased the expression of Bcl-xl, Bcl-2, β-Ⅲ-Tubulin, SYN, and Arc proteins. The expression of these proteins is mainly regulated by genes and reflects the changes of genes functions. Taken together, these results suggested that LSPCs could enhance cellular antioxidant defense capacity through regulating the activation of Nrf2/HO-1, and involving the inhibition of mitochondria-mediated apoptotic signaling pathway.

Guillain-Barré syndrome is an entity of diverse etiology, characterized by acute, symmetric, ascending and progressive muscle weakness, being one of the most frequent acquired polyneuropathies in childhood. Neuropathies produced by heavy metals, mercury and lead, and metalloids, such as arsenic, organophosphorus pesticides and carbon tetrachloride, should be considered among the differential diagnoses. We present a 14-year-old patient with a presumptive diagnosis of Guillain-Barré syndrome without response to conventional treatment with gamma globulin. Considering other etiologies, heavy metal neuropathy was suspected, and mercury poisoning was confirmed. The aim of this presentation is to make pediatricians aware about the impact of environmental toxic agents on children's health in order to make an early diagnosis by researching key data through the environmental clinical history.El síndrome de Guillain-Barré constituye una entidad de etiología diversa, que se caracteriza por debilidad muscular aguda, simétrica, ascendente y progresiva, y es una de las polineuropatías adquiridas más frecuentes en la infancia. Entre los diagnósticos diferenciales, deben considerarse las neuropatías producidas por metales pesados, mercurio y plomo, y metaloides, como el arsénico, plaguicidas organofosforados y el tetracloruro de carbono. Se presenta a un paciente de 14 años con diagnóstico de síndrome de Guillain-Barré sin respuesta al tratamiento convencional con gammaglobulina. Considerando otras etiologías, se sospechó neuropatía producida por metales pesados, y se confirmó intoxicación por mercurio. El objetivo de esta presentación es concientizar a los pediatras acerca del impacto de los tóxicos ambientales en la salud infantil para realizar un diagnóstico precoz pesquisando datos clave a través de la historia clínica ambiental.

This study was financed in part by the Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior-Brasil (CAPES)-Finance Code 001. Lygia S. Nogueira was supported by Programa Nacional de P?s-Gradua??o (PNPD/CAPES). Universidade Federal do Par?. Laborat?rio de Biologia Estrutural e Funcional. Bel?m, PA, Brazil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Citogen?tica e Cultura de Tecidos. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Citogen?tica e Cultura de Tecidos. Ananindeua, PA, Brasil. Universidade Federal do Par?. Laborat?rio de Cultura Celular. Bel?m, PA, Brazil. Universidade Federal do Par?. Laborat?rio de Cultura Celular. Bel?m, PA, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Toxicologia. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Citogen?tica e Cultura de Tecidos. Ananindeua, PA, Brasil / Universidade Federal do Par?. Instituto de Ci?ncias Exatas e Naturais. Bel?m, PA, Brazil. Universidade Federal do Par?. Laborat?rio de Biologia Estrutural e Funcional. Bel?m, PA, Brazil. Human exposure to mercury (Hg) is primary associated with its organic form, methylmercury (MeHg), through the ingestion of contaminated seafood. However, Hg contamination is also positively correlated with the number of dental restorations, total surface of amalgam, and organic mercury concentration in the saliva. Among the cells existing in the oral cavity, human periodontal ligament fibroblast (hPLF) cells are important cells responsible for the production of matrix and extracellular collagen, besides sustentation, renewal, repair, and tissue regeneration. In this way, the present study is aimed at investigating the potential oxidative effects caused by MeHg on hPLF. Firstly, we analyzed the cytotoxic effects of MeHg (general metabolism status, cell viability, and mercury accumulation) followed by the parameters related to oxidative stress (total antioxidant capacity, GSH levels, and DNA damage). Our results demonstrated that MeHg toxicity increased in accordance with the rise of MeHg concentration in the exposure solutions (1-7 ?M) causing 100% of cell death at 7 ?M MeHg exposure. The general metabolism status was firstly affected by 2 ?M MeHg exposure (43:8?1:7%), while a significant decrease of cell viability has arisen significantly only at 3 ?M MeHg exposure (68:7?1:4%). The ratio among these two analyses (named fold change) demonstrated viable hPLF with compromised cellular machinery along with the range of MeHg exposure. Subsequently, two distinct MeHg concentrations (0.3 and 3 ?M) were chosen based on LC50 value (4.2 ?M). hPLF exposed to these two MeHg concentrations showed an intracellular Hg accumulation as a linear-type saturation curve indicating that metal accumulated diffusively in the cells, typical for metal organic forms such as methyl. The levels of total GSH decreased 50% at exposure to 3 ?M MeHg when compared to control. Finally, no alteration in the DNA integrity was observed at 0.3 ?M MeHg exposure, but 3 ?M MeHg caused significant damage. In conclusion, it was observed that MeHg exposure affected the general metabolism status of hPLF with no necessary decrease on the cell death. Additionally, although the oxidative imbalance in the hPLF was confirmed only at 3 ?M MeHg through the increase of total GSH level and DNA damage, the lower concentration of MeHg used (0.3 ?M) requires attention since the intracellular mercury accumulation may be toxic at chronic exposures.

Exposure to mercury, lead and polychlorinated biphenyls (PCBs) have been associated with emotional dysregulation, but their neuronal correlates have yet to be examined. Inuit from Nunavik (Northern Quebec, Canada) face internalizing problems and are among the most exposed individuals to these environmental contaminants in the world. The aim of this study was to examine the link between pre- and postnatal exposure to these contaminants and brain fear-circuitry in Inuit adolescents. Facial expression stimuli were presented to participants (mean age = 18.3 years) in a magnetic resonance imaging (MRI) scanner. Fear conditioning and extinction tasks included neutral faces as the conditioned threat and safety cues and a fearful face paired with a shrieking scream as the unconditioned stimulus. Functional MRI data were gathered at the conditioning phase (n = 71) and at the extinction phase (n = 62). Mercury, lead and PCB 153 concentrations were measured in blood samples at birth (cord blood) and at the time of the adolescent testing to estimate pre- and postnatal exposure, respectively. For each time point, exposures were categorized in tertiles (low, moderate and high exposed groups). Mixed analyses of variance were conducted for each contaminant of interest controlling for sex, age, socioeconomic status, drug/alcohol use, food insecurity and contaminant co-exposure. Results revealed greater differential activation during the conditioning phase in the right orbitofrontal cortex in participants with moderate and high concentrations of cord blood PCB 153 compared to those in the low exposure group. During the extinction phase, the high prenatal mercury exposed group showed a lower differential activation in the right and left anterior cingulate cortex compared to those in the low-exposed group; whereas there was a higher differential activation in right dorsolateral prefrontal cortex in the high postnatal lead exposed group compared to the moderate- and low-exposed groups. Our study is the first to show alterations in the prefrontal brain areas in fear conditioning and extinction tasks in relation to environmental contaminant exposures. The observed brain correlates may advance our understanding of the emotional problems associated with environmental chemical toxicity.

Mercury an important therapeutic substance in Tibetan Medicine undergoes complex “detoxification” prior to inclusion in multi-ingredient formulas. In an initial cross-sectional study, patients taking Tibetan Medicine for various conditions were evaluated for mercury toxicity. Two groups were identified: Group 1, patients taking “ Tsothel” the most important detoxified mercury preparation and Group 2, patients taking other mercury preparations or mercury free Tibetan Medicine. Atomic fluorescence spectrometry of Tibetan Medicine showed mercury consumption 130 µg/kg/day (Group 1) and 30 µg/kg/day (Group 2) ( P ≤ 0.001), levels above EPA (RfDs) suggested threshold (0.3 µg/kg /day) for oral chronic exposure. Mean duration of Tibetan Medicine treatment was 9 ± 17 months (range 3–116) (Group 1) and 5 ± 1.96 months (range 1–114) (Group 2) (NS) with cumulative days of mercury containing Tibetan Medicine, 764 days ± 1214 (range 135–7330) vs. 103 days ± 111 (range 0–426), respectively ( P ≤ 0.001). Comparison of treatment groups with healthy referents (Group 3) not taking Tibetan Medicine showed no significant differences in prevalence of 23 non-specific symptoms of mercury toxicity, abnormal neurological, cardiovascular and dental findings and no correlation with mercury exposure variables; consumption, cumulative treatment days, blood/ urine Hg. Liver and renal function tests in treatment groups were not significantly increased compared to referents, with mean urine Beta2 Microglobulin within the normal range and not significantly associated with Hg exposure variables after correcting for confounding variables. Neurocognitive testing showed no significant intergroup differences for Wechsler Memory Scale, Grooved Pegboard, Visual Retention, but Group1 scores were better for Mini-Mental, Brief Word Learning, Verbal Fluency after correcting for confounding variables. These results suggest mercury containing Tibetan Medicine does not have appreciable adverse effects and may exert a possible beneficial effect on neurocognitive function. Since evidence of mercury as a toxic heavy metal, however, is well known, further analysis of literature on mercury use in other Asian traditional systems is highly suggested prior to further studies.

Saint Ioannis Lampadistis is a Cypriot saint of the Greek Orthodox Church, widely venerated in his island of origin. He lived during the 11th century and was blinded by ingesting contaminated fish in the mountainous area of Galata, withdrew from civil life when he was 18, and died at the age of 22. The reason for his blindness remains unknown, though it is widely attributed to an unknown poison related to the copper mines of the region. As fish is the end reservoir of organic mercury, it is quite possible that his blindness was the result of heavy metal toxicity. Organic mercury is associated with CNS atrophy and hypoplasia, and blindness is a frequent presenting symptom. While not much is known about the saint’s clinical symptoms (as his ecclestiastical biography focuses on his example and miracles), organic mercury poisoning could explain his sudden loss of vision, thus possibly making him the first-recorded case of organic mercury poisoning in history.

Occupational exposure to elemental mercury vapor usually occurs through inhalation during its utilizations. This leads to a variety of adverse health effects. In some Islamic cities, this type of poisoning may occur during gilding of shrines using elemental mercury with gold. Herein, we report on three male patients aged 20–53 years, who were diagnosed with occupational metallic mercury poisoning due to gilding of a shrine. All patients presented with neuro-psychiatric disorders such as anxiety, loss of memory and concentration, and sleep disorders with high urinary mercury concentrations of 326–760 μg/L upon referring, 3–10 days after cessation of elemental mercury exposure. Following chelating therapy, the patients recovered clinically and their mercury concentrations declined to non-toxic level (

Aims: The aim of this study is to assess the neuropsychological manifestations of mercury exposure in dentists. Methods: A cross-sectional study was carried out including 64 dentists matched to a control group according to age and gender. This study protocol included a neurological evaluation, a questionnaire assessing the study groups’ general characteristics and personal factors that may affect mercury urinary excretion in both groups. EUROQUEST questionnaire and Hospital Anxiety and Depression scale (HADS) were used to evaluate the neuropsychological symptoms reported during the last 12 months. In both groups, mercury impregnation was assessed by monitoring urinary mercury. Results: In the exposed group, scores of neurological symptoms, memory disturbances and anxiety were found to be significantly higher than those in controls (p < 0.01). Mean scores of HAD Depression’s scale were higher in the exposed group than in controls. Most of the neurotoxic manifestations were correlated to the levels of urinary mercury excretion in the exposed group. Mean levels of urinary mercury were significantly higher in the dentists group than in controls, with respective values of 21.1 ± 19.6µg/g of creatinine and 0.05 ± 0.9µg/g of creatinine. In nine dentists having urinary mercury levels higher than 35µg/g of creatinine, neurological examination showed a bilateral and symmetric intentional tremor in both upper limbs. In the exposed group, the neuropsychological manifestations and levels of urinary mercury were found to be significantly correlated. Conclusion: Increased levels of urinary mercury observed in dentists suggest that exposure to mercury vapour emissions adversely affects dental professionals, therefore prevention measures should be strengthened, with a special medical supervision program of dentists exposed to mercury vapours should be implemented. We have also outlined some relevant patents in this article.

About forty certified patients aged around 50 years old existed as living witnesses to fetal-type Minamata disease (methylmercury poisoning due to in utero exposure) in Minamata, Japan in 2006. Computerized hand tremor and postural sway tests with spectral analysis were conducted for 24 of them and in matched control subjects to examine the pathophysiological feature of neuromotor function. The tremor intensities of the patients with fetal-type Minamata disease were significantly larger than those of the 67 controls at every frequency band for both hands. In the patients, proportions for intensity at 1-6 Hz of both hands were larger, but those of the intensity at 6-10 Hz were smaller compared with the controls. The center frequency of a tremor was significantly lower in the patients than in the controls. Only eight males of the 24 patients were examined to evaluate postural sway because of extremely low scores in activities of daily living in the remaining. Most of the postural sway parameters obtained with eyes open and closed were significantly larger in the patients than in the male controls. Likewise, Romberg quotients of postural sway in anterior-posterior direction were significantly higher in the patients. In conclusion, the patients with fetal-type Minamata disease of our study showed a larger tremor of low frequency at less than 6 Hz and postural instability. Spectral analyses of computerized hand tremor and postural sway are suggested to be useful for assessing the pathophysiological change, related to a lesion of the cerebellum, resulting from prenatal methylmercury exposure.

Minamata disease in Japan and the large-scale poisoning by methylmercury (MeHg) in Iraq caused wide public concerns about the risk emanating from mercury for human health. Nowadays, it is widely known that all forms of mercury induce toxic effects in mammals, and increasing evidence supports the concern that environmentally relevant levels of MeHg could impact normal biological functions in wildlife. The information of mechanism involved in mercurial toxicity is growing but knowledge gaps still exist between the adverse effects and mechanisms of action, especially at the molecular level. A body of data obtained from experimental studies on mechanisms of mercurial toxicity in vivo and in vitro points to that disruption of the antioxidant system may play an important role in the mercurial toxic effects. Moreover, the accumulating evidence indicates that signaling transduction, protein or/and enzyme activity, and gene regulation are involving in mediating toxic and adaptive response to mercury exposure. We conducted here a comprehensive review of mercurial toxic effects on wildlife and human, in particular synthesized key findings of molecular pathways involved in mercurial toxicity from the cells to human. We discuss the molecular evidence related mercurial toxicity to the adverse effects, with particular emphasis on the gene regulation. The further studies relying on Omic analysis connected to adverse effects and modes of action of mercury will aid in the evaluation and validation of causative relationship between health outcomes and gene expression.

The authors revealed mercury role in pathologic changes of central mechanisms underlying cerebral circulation in metabolic circle, associated with changes in central afferent pathways in thalamic region. Relationship was established between intensity of the diagnosed affect and changes in levels of antibodies to proteins S-100, general myeline protein, myeline-associated glycoprotein - that can indicate general neurodegeneration process. Antibodies level can serve as a marker of demyelination intensity in central pathways under exposure to neurotoxicants.

Mercury and its compounds are classified into three main groups: metallic mercury (Hg0), inorganic mercury (Hg2+), and organic mercury (methyl mercury: CH3Hg+, etc.). Metallic mercury is the only metal that is liquid at ambient temperature and normal pressure, which readily forms an amalgam with other metals. Therefore, mercury has long been used for refining various metals, and mercury amalgam has been used for dental treatment. Mercury has also been used in measuring instruments such as thermometers, barometers and blood pressure monitors, as well as electric appliances such as lighting equipment and dry batteries. Large amounts of metallic mercury are still used in other countries as a catalyst in the production of caustic soda by electrolysis. In addition, mercury compounds have been used in various chemicals such as mercurochrome, agricultural chemicals, and mildew-proofing agents. However, the use of mercury has also caused health problems for people. Minamata disease in Japan is a typical example. Also, since mercury is highly volatile, it is discharged as a product of industrial activities or derived from volcanoes, and it has been concluded on the basis of the findings of the United Nations Environment Program (UNEP) that it is circulating globally. Therefore, with the aim of establishing an internationally legally binding treaty for the regulation of mercury use to reduce risk, an intergovernmental negotiating committee was established in 2009. Japan actively contributed to this negotiation owing to its experience with Minamata disease, which led to the Convention on the regulation of mercury use being discharged as the "Minamata Convention on Mercury" and the treaty came into force on August 16, 2017. In this review, we introduce 1) the Global Mercury Assessment by UNEP; 2) mercury kinetics, exposure assessment and toxicity of different chemical forms; 3) large-scale epidemics of methylmercury poisoning; 4) methylmercury exposure assessment and health survey in whale-eating populations; 5) elemental mercury exposure assessment and health survey of mercury mine workers in China.

The authors present a review of literature on the involvement of perinatal and postnatal mercury exposure in the pathogenesis of autistic spectrum disorders (ASD). A number of studies have shown a reliable association between perinatal and postnatal exposure to mercury and ASD development aa well as clinical and laboratory markers of the severity of these disorders. However the association was not confirmed in other studies. Such contradictions may be explained by differences in the composition of study groups, including geographical characteristics, and the influence of the factors related to mercury neurotoxicity.Представлен обзор данных научной литературы о роли перинатального и постнатального действия ртути в патогенезе расстройств аутистического спектра (РАС). Обращено внимание на связь между уровнем ртути в биологических субстратах организма детей с РАС и некоторыми клиническими показателями тяжести этих расстройств. Наряду с исследованиями, подтверждающими этот факт, приведены данные, указывающие на отсутствие значимой связи между воздействием ртути и развитием РАС. Наличие подобных противоречий авторы рассматривают в аспекте различий в подходах к формированию обследованных групп и географических особенностей мест проживания больных, а также влияния факторов, определяющих нейротоксичность ртути.

Chronic exposure to heavy metals such as Pb, As, and MeHg can be associated with an increased risk of developing neurodegenerative diseases. Our in vitro bioassays results showed the potency of heavy metals in the order of Pb SIGNIFICANCE: The proteomics techniques have been claimed to be more sensitive than the conventional toxicological assays, facilitating the measurement of responses to heavy metals (Pb, As, and MeHg) exposure before obvious harm has occurred demonstrating their predictive value. Also, proteomics allows for the comparison of responses between Pb, As, and MeHg metals, permitting the evaluation of potency differences hippocampal cells of the brain. Hereby, the molecular information provided by pathway and gene functional analysis can be used to develop a more thorough understanding of each metal mechanism at the protein level for different neurological adverse outcomes (e.g. Parkinson's disease, Alzheimer's diseases). Efforts are put into developing proteomics based toxicity testing methods using in vitro models for improving human risk assessment. Some of the key proteins identified can also potentially be used as biomarkers in epidemiologic studies. These heavy metal response patterns shed new light on the mechanisms of mRNA splicing, ubiquitin pathway role in neurodegeneration, and can be useful for the development of molecular biomarkers of heavy metals exposure.

Severe methylmercury poisoning occurred in Minamata and neighboring communities in Japan during the 1950s and 1960s. A considerable number of children were born with conditions resembling cerebral palsy, later known as congenital Minamata disease. Although surviving patients are now in their 50s or 60s, few assessments of functional capacities in daily living have been performed. We assessed the changes in Activities of Daily Living (ADL) status of 11 patients over a 10-year period. For assessment of ADL, we applied the Barthel Index (BI) and the Functional Independence Measure (FIM). We obtained the patients' current and previous status information by interview of their caregivers or from medical records and then compared them using the Wilcoxon signed-rank test. Both ADL measures, including the status related with cognition, had significantly declined during the 10 years. The same was true for the overall BI score (p = 0.01). Similarly, all functions of the FIM scores declined (i.e., self-care, sphincter control, mobility, locomotion, communication, and social cognition), and for FIM physical and cognition subscores as well as FIM total score, the declines were statistically significant. The present study indicates that the ADL status of congenital Minamata disease patients, now in their 50s or 60s, has substantially declined during the last 10 years; a decline that was much steeper in comparison with expectation in subjects of similar ages, but in agreement with accelerated ageing also reported in subjects with cerebral palsy, past polio infection, or epilepsy. While already incapacitated due to the prenatal methylmercury poisoning, their accelerated ageing may suggest that patients with developmental neurotoxicity have less reserve capacity to compensate for normal ageing. These patients will need continuous and increasing medical and welfare support in the community.

Mercury chloride (HgCl2), a neurotoxicant that cannot penetrate the blood-brain barrier (BBB). Although when the BBB are got damaged by neurodegenerative disorders, the absorbed HgCl2, mainly in form of Hg (II)-serum albumin adduct (Hg-HSA) in human plasma, can penetrate BBB and affect central nervous system (CNS) cells. Current study planned to evaluate the effect of Hg-HSA on the physiological function of N9 microglial cells. At low dosage (15 ng/mL) of Hg-HAS, the observed outcomes was: promoted cell propagation, Nitric Oxide (NO) and intracellular Ca2+ levels enhancement, suppressed the release of TNF-α and IL-1β and inhibited cell proliferation. At high dosage (15 μg/mL) we observed decline in NO and intracellular Ca2+ levels, and increment in the release of TNF-α and IL-1β. These biphasic effects are similar to hormesis, and the hormesis, in this case, was executed through ERK/MAPKs and JAK/STAT3 signaling pathways. Study of quantum chemistry revealed that Hg2+ could form stable coordination structures in both Asp249 and Cys34 sites of HSA. Although five-coordination structure in Asp249 site is more stable than four-coordination structure in Cys34 site but four-coordination structure is formed easily in-vivo in consideration of binding-site position in spatial structure of HSA.

Methyl mercury is a teratogenic and neurodevelopmental toxicant in the environment. MeHg affects several biological pathways critical for brain development. The present study validated the effect of Fisetin on developmental MeHg exposure induced alterations in mitochondrial apoptotic pathway and Rho GTPase mRNA expressions in hippocampus of F

Methylmercury (MeHg) is known to cause neurobehavioral impairment in human and experimental animals. We previously reported that MeHg (5 mg Hg/kg) induced severe neurobehavioral dysfunction in 4-week-old KK-Ay mice, although it is difficult to evaluate quantitatively the neurobehavioral impairment in MeHg-treated KK-Ay mice because of their obesity. The aim of this study was to evaluate MeHg-induced neurobehavioral dysfunction in KK-Ay mice using the dynamic weight-bearing test, which analyzes the animal's weight distribution between the four limbs. Male 12-week-old KK-Ay mice were treated with MeHg (5 mg Hg/kg) three times per week for 5 weeks. Body weight loss began after approximately 2 weeks of MeHg treatment, and decreased significantly at 4 weeks. Seven of the nine MeHg-treated mice exhibited overt neurological symptoms such as ataxia and gait disturbance. The weight-bearing load was lower for the forelimb than for the hindlimb at baseline and until 1 week after MeHg treatment was initiated. In weeks 2-4, the dynamic weight-bearing loads on the forelimb and hindlimb were similar. The load on the forelimb exceeded the load on the hindlimb after 5 weeks of treatment. This finding indicates that the dynamic weight-bearing test is useful for semi-quantitative evaluation of neurobehavioral impairment in MeHg-treated rodents, and is less stressful for the animals. Infiltration of CD204-positive macrophages was observed in the sciatic nerve of MeHg-treated mice, suggesting that CD204 can serve as a useful marker of tissue injury in peripheral nerves and a possible target in regenerating peripheral nerves and controlling neuropathies.

Autism spectrum disorders are neurodevelopmental dysfunctions that are characterised by deficits in social integration and communication, associated with restricted interests and stereotypic behaviour. A high percentage are related to language disorders, sensory dysfunctions, attention deficit disorder, bipolarity, intellectual disability or epilepsy, among other comorbidities. It is estimated that around 30% of children with autism, with typical early development, may present regression in the first years of life, which was already reported by Kanner in one of his original cases. The term regression refers to the loss of social, communicative or motor skills. It is essential to be alert to any symptoms of autistic regression, since it is not always an unspecific usual manifestation of the clinical spectrum of autism. Although little is known about the pathogenesis of regression, it needs to be organised hierarchically, as it can be part of different conditions with a variety of causes.The aim of this study is to analyse distinct conditions that need to be addressed in the case of a child with autistic regression, including genetic and toxic causations, autoimmune and nutritional phenomena, and epilepsies.When faced with a case of autistic regression it is essential to try to identify the possible aetiology, as this can allow specific treatment and adequate genetic counselling to be established.Regresion autista: aspectos clinicos y etiologicos.Introduccion. Los trastornos del espectro autista son disfunciones del neurodesarrollo que se caracterizan por deficits en la integracion social y la comunicacion, asociados a intereses restringidos y conductas estereotipadas. Un alto porcentaje se asocia a trastorno del lenguaje, disfunciones sensoriales, trastorno por deficit de atencion, bipolaridad, discapacidad intelectual o epilepsia, entre otras comorbilidades. Se estima que aproximadamente un 30% de los niños con autismo, con desarrollo tipico inicial, pueden presentar regresion en los primeros años de vida, lo cual ya fue comunicado por Kanner en uno de sus casos originales. Se denomina regresion a la perdida de habilidades sociales, comunicativas o motoras. Es esencial estar atentos ante cualquier cuadro de regresion autista, ya que no siempre es una manifestacion habitual inespecifica del espectro clinico de autismo. Si bien la patogenia de la regresion se comprende poco, debe ser jerarquizada, ya que puede ser parte de diferentes entidades con diversas etiologias. Objetivo. Analizar diferentes entidades que deben evocarse frente a un niño con regresion autista, incluyendo etiologias geneticas, toxicas, fenomenos autoinmunes, nutricionales y epilepsias. Conclusion. Frente a un cuadro de regresion autista es esencial intentar identificar la posible etiologia, dado que esto puede permitir un tratamiento especifico y un adecuado asesoramiento genetico.

There was executed the examination of patients with occupational chronic mercury intoxication in the post-exposure period after the exposure to metallic mercury vapor. 47 persons with an established diagnosis of chronic mercury intoxication (HMI) passed the laboratory and immunological examination in the period of exposure to metallic mercury vapor in a production environment. The average age of men accounted for 49.2±1.2 years. The experience of work in hazardous working conditions amounted of 21.65±1.61 years (1 observation). All these same cases were observed in the institute clinic again after 5 years (2 observation) and 10 years (3 observation). A control group of healthy men consisted of 47 cases included persons of representative both age and general work experience, without a professional route of contact with hazardous substances. The level of such cytokines as IL-1β, IL-2, IL-4, IL-6, TNF-a, INF-y and neurotropic IgG class antibodies directed to proteins of the nervous tissue (NF-200, GFAP, MBP, B-dependent Ca-channel, Glu-R, DA-R, R-GABA, Ser-R, R-Chol, DNA, B2GP) in serum were determined by enzyme linked immunosorbent assay. There was established the gain in the imbalance of inflammatory mediators and production ofneural antibodies in dynamics after the termination of the production in conditions of metallic mercury vapors. Revealed features of the regulatory relationship between the level of cytokines and the severity of the autoimmune process were shown to contribute to the maintenance and progression of neurodegenerative processes. There was recommended the identification of immunoregulatory markers (IL-1β, IL-4, TNF-a, NF-AT to 200, GFAP, S-100) as an additional criteria for the diagnosis of health disorders in operating and monitoring the course of the progredient professional mercury intoxication.

Methylmercury (MeHg) is a widespread environmental contaminant with established developmental neurotoxic effects. Computational models have identified glucocorticoid receptor (GR) signaling to be a key mediator behind the birth defects induced by Hg, but the mechanisms were not elucidated. Using molecular dynamics simulations, we found that MeHg can bind to the GR protein at Cys736 (located close to the ligand binding site) and distort the conformation of the ligand binging site. To assess the functional consequences of MeHg interaction with GR, we used a human cell line expressing a luciferase reporter system (HeLa AZ-GR). We found that 100 nM MeHg does not have any significant effect on GR activity alone, but the transactivation of gene expression by GR upon Dex (a synthetic GR agonist) administration was reduced in cells pre-treated with MeHg. Similar effects were found in transgenic zebrafish larvae expressing a GR reporter system (SR4G). Next we asked whether the effects of developmental exposure to MeHg are mediated by the effects on GR. Using a mutant zebrafish line carrying a loss-of-function mutation in the GR (grS357) we could show that the effects of developmental exposure to 2.5 nM MeHg are mitigated in absence of functional GR signaling. Taken together, our data indicate that inhibition of GR signaling may have a role in the developmental neurotoxic effects of MeHg.

Mercury affects the nervous system and has been implicated in altering heart rhythm and function. We sought to better define its role in modulating heart rate variability, a well-known marker of cardiac autonomic function.This is a systematic review study.We searched PubMed, Embase, TOXLINE, and DART databases without language restriction. We report findings as a qualitative systematic review because heterogeneity in study design and assessment of exposures and outcomes across studies, as well as other methodological limitations of the literature, precluded a quantitative meta-analysis.We identified 12 studies of mercury exposure and heart rate variability in human populations (ten studies involving primarily environmental methylmercury exposure and two studies involving occupational exposure to inorganic mercury) conducted in Japan, the Faroe Islands, Canada, Korea, French Polynesia, Finland, and Egypt. The association of prenatal mercury exposure with lower high-frequency band scores (thought to reflect parasympathetic activity) in several studies, in particular the inverse association of cord blood mercury levels with the coefficient of variation of the R-R intervals and with low-frequency and high-frequency bands at 14 years of age in the Faroe Islands birth cohort study, suggests that early mercury exposure could have a long-lasting effect on cardiac parasympathetic activity. Studies with later environmental exposures to mercury in children or in adults were heterogeneous and did not show consistent associations.The evidence was too limited to draw firm causal inferences. Additional research is needed to elucidate the effects of mercury on cardiac autonomic function, particularly as early-life exposures might have lasting impacts on cardiac parasympathetic function.

Monomethylmercury (MeHg(+)) is an environmental pollutant, which at sufficiently high exposures, has induced neurotoxicosis in several animal species, including humans. Adverse neurological effects due to gestational exposure are of particular concern as MeHg(+) readily crosses the blood-brain and placental barriers. The degree to which environmental concentrations in marine prey affect free-living piscivorous wildlife, however, remains largely undetermined. We examined associations of gestational exposures to mercury on neurodevelopment and survival using hair and blood concentrations of total mercury ([THg]) in a stranded population of Pacific harbor seal pups from central California. A positive association was determined for the presence of abnormal neurological symptoms and increasing [THg] in blood (P = 0.04), but not hair. Neither hair nor blood [THg] was significantly associated with survival, or the neurodevelopmental milestone 'free-feeding', which was measured from the onset of hand-assisted feeding to the time at which pups were able to consume fish independently. Both hair and blood [THg] exceeded threshold values considered potentially toxic to humans and other mammalian wildlife species. The higher [THg] in blood associated with abnormal neurological symptoms may indicate an adverse effect of this pollutant on neurodevelopment in harbor seal pups. These data have broader implications with respect to human health and public policy as harbor seals and humans consume similar fish species, and it is possible that safeguard levels established for marine mammals could also extend to human populations that regularly consume fish.

Large-scale food poisoning caused by methylmercury was identified in Minamata, Japan, in the 1950s (Minamata Disease). Although the diagnostic criteria for the disease was controversial and difficult during that time, we, the Kumamoto University Study Group, carried out a large-scale study to assess the clinical features in 1972-1973. The author tried to reassess the results of that study to appraise the diagnostic criteria established in 1977 on the basis of those results. A substantial number of residents in the exposed area exhibited neurologic signs, especially paresthesia of only the extremities, namely, the male residents of Minamata City showed a positive predictive value of 0.73 and a negative predictive value of 0.23. The relative risks of paresthesia only were 2.6 (2.0-3.3) and 1.2 (0.9-1.5), in Minamata and Goshonoura related to Ariake (control), respectively. At least until 1977, the diagnostic criteria remained valid, although it was inadequate. Nevertheless, presently, a follow-up study of the certified patients may lead to the development of efficient new diagnostic criteria.