Methylmercury induces neuronal cell death by inducing TNF-α expression through the ASK1/p38 signaling pathway in microglia.

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.

A scoping review of sources of mercury and its health effects among Pakistan's most vulnerable population.

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 We conducted a systematic search of the available literature in Google Scholar, PubMed, and grey literature of unpublished theses and reports of various universities across the country.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.

Oxidative Damage in Human Periodontal Ligament Fibroblast (hPLF) after Methylmercury Exposure.

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 µM) causing 100% of cell death at 7 µM MeHg exposure. The general metabolism status was firstly affected by 2 µM MeHg exposure (43.8 ± 1.7%), while a significant decrease of cell viability has arisen significantly only at 3 µM 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 µM) were chosen based on LC50 value (4.2 µM). 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 µM MeHg when compared to control. Finally, no alteration in the DNA integrity was observed at 0.3 µM MeHg exposure, but 3 µM 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 µM MeHg through the increase of total GSH level and DNA damage, the lower concentration of MeHg used (0.3 µM) requires attention since the intracellular mercury accumulation may be toxic at chronic exposures.

Hormesis of mercuric chloride-human serum albumin adduct on N9 microglial cells via the ERK/MAPKs and JAK/STAT3 signaling pathways.

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-1ß 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-1ß. 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.

Determination of mercury in hair of children.

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.).

Methylmercury promotes prostacyclin release from cultured human brain microvascular endothelial cells via induction of cyclooxygenase-2 through activation of the EGFR-p38 MAPK pathway by inhibiting protein tyrosine phosphatase 1B activity.

Methylmercury is an environmental pollutant that exhibits neurotoxicity when ingested, primarily in the form of neuropathological lesions that localize along deep sulci and fissures, in addition to edematous and inflammatory changes in patient cerebrums. These conditions been known to give rise to a variety of ailments that have come to be collectively termed Minamata disease. Since prostaglandins I2 and E2 (PGI2 and PGE2) increase vascular permeability and contribute to the progression of inflammatory changes, we hypothesize that methylmercury induces the synthesis of these prostaglandins in brain microvascular endothelial cells and pericytes. To test this theory, human brain microvascular endothelial cells and pericytes were cultured and treated with methylmercury, after which the PGI2 and PGE2 released from endothelial cells and/or pericytes were quantified by enzyme-linked immunosorbent assay while protein and mRNA expressions in endothelial cells were analyzed by western blot analysis and real-time reverse transcription polymerase chain reaction, respectively. Experimental results indicate that methylmercury inhibits the activity of protein tyrosine phosphatase 1B, which in turn activates the epidermal growth factor receptor-p38 mitogen-activated protein kinase pathway that induces cyclooxygenase-2 expression. It was also found that the cyclic adenosine 3',5'-monophosphate pathway, which can be activated by PGI2 and PGE2, is involved in methylmercury-induced cyclooxygenase-2 expression. Since it appears that protein tyrosine phosphatase 1 B serves as a sensor protein for methylmercury in these mechanisms, it is our belief that the results of the present study may provide additional insights into the molecular mechanisms responsible for edematous and inflammatory changes in the cerebrum of patients with Minamata disease.

Methylmercury exposure and health effects.

Methylmercury is a hazardous substance that is of interest with regard to environmental health, as inorganic mercury circulating in the general environment is dissolved into freshwater and seawater, condensed through the food chain, ingested by humans, and consequently affects human health. Recently, there has been much interest and discussion regarding the toxicity of methylmercury, the correlation with fish and shellfish intake, and methods of long-term management of the human health effects of methylmercury. What effects chronic exposure to a low concentration of methylmercury has on human health remains controversial. Although the possibility of methylmercury poisoning the heart and blood vessel system, the reproductive system, and the immune system is continuously raised and discussed, and the carcinogenicity of methylmercury is also under discussion, a clear conclusion regarding the human health effects according to exposure level has not yet been drawn. The Joint FAO/WHO Expert Committee on Food Additives proposed to prepare additional fish and shellfish intake recommendations for consumers based on the quantified evaluation of the hazardousness of methylmercury contained in fish and shellfish, methylmercury management in the Korea has not yet caught up with this international trend. Currently, the methylmercury exposure level of Koreans is known to be very high. The starting point of methylmercury exposure management is inorganic mercury in the general environment, but food intake through methylation is the main exposure source. Along with efforts to reduce mercury in the general environment, food intake management should be undertaken to reduce the human exposure to methylmercury in Korea.

Inherited effects of low-dose exposure to methylmercury in neural stem cells.

Methylmercury (MeHg) is an environmental contaminant with recognized neurotoxic effects, particularly to the developing nervous system. In the present study, we show that nanomolar concentrations of MeHg can induce long-lasting effects in neural stem cells (NSCs). We investigated short-term direct and long-term inherited effects of exposure to MeHg (2.5 or 5.0 nM) using primary cultures of rat embryonic cortical NSCs. We found that MeHg had no adverse effect on cell viability but reduced NSC proliferation and altered the expression of cell cycle regulators (p16 and p21) and senescence-associated markers. In addition, we demonstrated a decrease in global DNA methylation in the exposed cells, indicating that epigenetic changes may be involved in the mechanisms underlying the MeHg-induced effects. These changes were observed in cells directly exposed to MeHg (parent cells) and in their daughter cells cultured under MeHg-free conditions. In agreement with our in vitro data, a trend was found for decreased cell proliferation in the subgranular zone in the hippocampi of adult mice exposed to low doses of MeHg during the perinatal period. Interestingly, this impaired proliferation had a measurable impact on the total number of neurons in the hippocampal dentate gyrus. Importantly, this effect could be reversed by chronic antidepressant treatment. Our study provides novel evidence for programming effects induced by MeHg in NSCs and supports the idea that developmental exposure to low levels of MeHg may result in long-term consequences predisposing to neurodevelopmental disorders and/or neurodegeneration.

Glutathione-mediated neuroprotection against methylmercury neurotoxicity in cortical culture is dependent on MRP1.

Methylmercury (MeHg) exposure at high concentrations poses significant neurotoxic threat to humans worldwide. The present study investigated the mechanisms of glutathione-mediated attenuation of MeHg neurotoxicity in primary cortical culture. MeHg (5 µM) caused depletion of mono- and disulfide glutathione in neuronal, glial and mixed cultures. Supplementation with exogenous glutathione, specifically glutathione monoethyl ester (GSHME) protected against the MeHg induced neuronal death. MeHg caused increased reactive oxygen species (ROS) formation measured by dichlorodihydrofluorescein (DCF) fluorescence with an early increase at 30 min and a late increase at 6h. This oxidative stress was prevented by the presence of either GSHME or the free radical scavenger, trolox. While trolox was capable of quenching the ROS, it showed no neuroprotection. Exposure to MeHg at subtoxic concentrations (3 µM) caused an increase in system x(c)(-) mediated (14)C-cystine uptake that was blocked by the protein synthesis inhibitor, cycloheximide (CHX). Interestingly, blockade of the early ROS burst prevented the functional upregulation of system x(c)(-). Inhibition of multidrug resistance protein-1 (MRP1) potentiated MeHg neurotoxicity and increased cellular MeHg. Taken together, these data suggest glutathione offers neuroprotection against MeHg toxicity in a manner dependent on MRP1-mediated efflux.

The in vitro effects of Trolox on methylmercury-induced neurotoxicity.

Methylmercury (MeHg), an environmental toxicant primarily found in fish and seafood poses a dilemma to both consumers and regulatory authorities given the nutritional benefits of fish consumption vs. possible adverse neurological damage caused by MeHg. The present study addresses whether supplementation with 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), alters the neuro-oxidative effects of MeHg in C6-glioma and B35-neuronal cell lines. As indicators of cytotoxicity, reduced glutathione (GSH), reactive oxygen species (ROS) and mitochondrial activity (MTT) were measured. The cellular mercury (Hg) content was measured with high resolution-inductively coupled plasma mass spectrometry (HR-ICPMS). The amount of MeHg-induced ROS was significantly reduced (p<0.05) after treatment with 50muM Trolox in C6 glial cell line. However, treatment with Trolox did not induce any significant increase in GSH levels or MTT activity in either of the cell lines. In addition, treatment with Trolox did not induce any significant changes in intracellular MeHg levels. The MeHg and Trolox treated C6 glial cell line differed significantly (p<0.05) from the B35 cell line for MTT, ROS and GSH activity. These findings provide experimental evidence that preincubation with Trolox prevents MeHg-induced ROS generation in C6 glial cell line by quenching of free radicals and not by changes in intracellular GSH or MeHg content.

Methylmercury speciation influences brain gene expression and behavior in gestationally-exposed mice pups.

The greatest source of human exposure to methylmercury (MeHg) is the diet, in particular the consumption of seafood. To investigate the importance of dietary MeHg speciation on neurotoxicity, balb/c mice dams were exposed to MeHgCys (the naturally-occurring salt) and MeHgCl (the laboratory salt), at concentrations up to 4.5 mg/kg, for 11 weeks (inclusive of 3 weeks gestational and 2 weeks post-partum exposure). Impacts of developmental exposure were assessed in their offspring by monitoring transcriptomic (brain gene expression via microarray and quantitative PCR), tissue mercury (Hg) accumulation, and neurobehavioral endpoints. There were no differences in tissue Hg accumulation between the two forms of MeHg presented, but differences in pup behavior and gene expression endpoints were noted. For example, MeHgCl, but not MeHgCys, impaired pup activity in an open field assessment. Similar impacts of MeHgCl were noted in adults. A total of 131 genes were differentially-regulated in pup brains following maternal exposure to MeHg, 50 of which were specific to MeHgCys and 35 specific to MeHgCl. Regulated genes were significantly enriched for several annotation categories including metal/zinc-binding and transcription regulation. In contrast few antioxidant genes were differentially regulated. This analysis provided insight into mechanisms by which MeHg may impair cellular processes in addition to behavioral impairments such as those associated with learning and memory. The results show differences between the toxic impacts of MeHg species, and also highlight the potential utility of an integrated approach incorporating gene expression with behavioral endpoints.

The food and drug administration agrees to classify mercury fillings.

In the United States Court of Appeals of the District of Columbia Circuit, the Appellants Mom's Against Mercury, Connecticut Coalition for Environmental Justice, Oregonians for Life, California Citizens for Health Freedom, Kevin J. Biggers, Karen Johnson, Linda Brocato, R. Andrew Landerman, and Antia Vazquez Tibaul filed a petition for review of Regulatory Inaction by the Food and Drug Administration (FDA). On Monday June 2, 2008, the lawsuit was settled with the FDA after it agreed to classify mercury fillings. During its negotiation session with the Appellants, the FDA indicated that it would change its website on mercury fillings. The FDA no longer claims that no science exists about the safety of mercury amalgam or that other countries have acted for environmental reasons only. On its website, the FDA now states the following: "Dental amalgams contain mercury, which may have neurotoxic effects on the nervous systems of developing children and fetus." The FDA also states that "Pregnant women and persons who may have a health condition that makes them more sensitive to mercury exposure, including individuals with existing high levels of mercury bioburden, should not avoid seeking dental care, but should discuss options with their health practitioner." The FDA decision to classify mercury fillings is a reflection of the legislations enacted in Europe and Canada that highlight the neurotoxic effects of mercury fillings.

Neurotoxicological mechanism of methylmercury induced by low-dose and long-term exposure in mice: oxidative stress and down-regulated Na+/K(+)-ATPase involved.

Methylmercury (MeHg), a potent neurotoxicant, easily passes through the blood-brain barrier (BBB), accumulates in the brain regions and causes severe irreversible damage. However, the neurotoxic effects and action mechanisms of MeHg are still unclear, especially in low-dose and long-term exposure. In this study, we attempted to explore the toxic effects of low-dose MeHg (0.05 mg/kg/day), which was the possible exposed dose by ingestion in MeHg-contaminated areas, on the time course of changes in locomotor activities and auditory brainstem response (ABR) system after administration for 7 consecutive weeks in mice. The results showed that the retention time on the rotating rod (60 rpm) was preferentially decreased after 1-week oral administration with MeHg. The locomotor activities parameters of ambulatory distances and stereotype-1 episodes were significantly increased and vertical-plane entries were progressively decreased after MeHg exposure in 3 consecutive weeks. Gradually progressive abnormality of ABR (increase in hearing thresholds, prolonged absolute and interwave latencies) was found during 4-6 weeks administration of MeHg. These impairments correlated with significant Hg accumulation and biochemical alterations in brain regions and/or other tissues, including the increase of lipid peroxidation (LPO) production, influence of Na+/K(+)-ATPase activities and nitric oxide (NO) levels were found. These findings provide evidence that the signaling of oxidative stress/Na+/K(+)-ATPase/NO plays a role in the underlying mechanisms of the neurotoxic effects induced by low-dose and long-term exposure of MeHg.

Selenium as a potential protective factor against mercury developmental neurotoxicity.

Experimental studies suggest that selenium (Se) may decrease methylmercury (MeHg) toxicity under certain exposure regimens. In epidemiological studies, the exposure to MeHg occurs from fish and seafood, which are also a source of beneficial nutrients such as selenium. However, little is known about the potential protective effects of dietary Se against MeHg neurotoxicity in humans. The possible interaction was assessed in two birth cohorts in the Faroe Islands, consisting of singleton term births from 1986 to 1987 (N=1,022), and 1994 to 1995 (N=182), respectively. Dietary habits in this fishing population included frequent consumption of seafood, including whale meat high in mercury. Both Hg and Se were measured in cord whole blood. Neurodevelopmental outcomes were evaluated at age 7 years in both cohorts, and the smaller cohort also included neurological assessment on several prior occasions. Each outcome was modeled as a function of Hg and Se interactions (with adjustments for potential risk factors) by expressing the effects of log10(Hg) within the lowest 25%, the middle 50%, and the highest 25% of the Se distribution. Surplus Se was present in cord blood, the average being a 10-fold molar excess above MeHg. Regression analyses failed to show consistent effects of Se, or statistically significant interaction terms between Se and MeHg. Overall, no evidence was found that Se was an important protective factor against MeHg neurotoxicity. Prevention, therefore, needs to address MeHg exposures rather than Se intakes. Because of the benefits associated with fish intake during pregnancy, consumers should be advised to maintain a high fish and seafood intake that is low in Hg contamination. Additional research is needed to determine the identity of the nutrients responsible for the beneficial effects.

Glutathione modulation influences methyl mercury induced neurotoxicity in primary cell cultures of neurons and astrocytes.

Methyl mercury (MeHg) is highly neurotoxic and may lead to numerous neurodegenerative disorders. In this study, we investigated the role of glutathione (GSH) and reactive oxygen species (ROS) in MeHg-induced neurotoxicity, using primary cell cultures of cerebellar neurons and astrocytes. To evaluate the effect of GSH on MeHg-induced cytotoxicity, ROS and GSH were measured using the fluorescent indicators chloro methyl derivative of di-chloro di-hydro fluorescein diacetate (CMH(2)DCFDA) and monochlorobimane (MCB). Cell-associated MeHg was measured with (14)C-radiolabeled MeHg. Mitochondrial dehydrogenase activity was detected by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]. MTT timeline study was also performed to evaluate the effects of both the concentration and duration of MeHg exposure. The intracellular GSH content was modified by pretreatment with N-acetyl cysteine (NAC) or di-ethyl maleate (DEM) for 12 h. Treatment with 5 microM MeHg for 30 min led to significant (p<0.05) increase in ROS and reduction (p<0.001) in GSH content. Depletion of intracellular GSH by DEM further increased the generation of MeHg-induced ROS in both cell cultures. Conversely, NAC supplementation increased intracellular GSH and provided protection against MeHg-induced oxidative stress in both cell cultures. MTT studies also confirmed the efficacy of NAC supplementation in attenuating MeHg-induced cytotoxicity. The cell-associated MeHg was significantly (p<0.02) increased after DEM treatment. In summary, depletion of GSH increases MeHg accumulation and enhances MeHg-induced oxidative stress, and conversely, supplementation with GSH precursor protects against MeHg exposure in vitro.

Accidental intrathecal mercury application.

The authors present a case of accidental intrathecal mercury application. A 69-year-old white woman was admitted to our department with suspected meningitis following surgery for spinal stenosis at another hospital. Postoperatively, she had developed a cerebro-spinal fluid (CSF) fistula with a subcutaneous cavity. Local wound irritation had been suspected and, unfortunately, mercury-containing disinfectant was injected into the cavity. Within 24 h the patient demonstrated acute neurological deterioration due to meningitis and encephalitis and was admitted to our clinic with suspected meningitis due to postoperative CSF fistula. Lumbar puncture revealed desinfectant-stained, non-bloody CSF, while lumbar MRI demonstrated the large lumbar subcutaneous cavity. Additionally, CSF fistula was visualized on MRI. Laboratory examination revealed extremely high mercury levels in CSF, blood and urine. Treatment consisted in insertion of a lumbar drainage to wash out the mercury. The patient underwent medical detoxication using chelating agents (DMPS: RS-2,3-dimercapto-1-propansulfonacid, DMSA: meso-2,3-dimercaptosuccinatacid). Surgery was performed in order to close the cavity and the fistula. Postoperatively, the patient was admitted to the intensive care unit and remained intubated for 3 days. Within 4 weeks after surgery, she demonstrated good recovery. Eighteen months after intoxication, polyneuropathy and slight neuropsychological deficiencies were detectable.

Mercury exposure and early effects: an overview.

OBJECTIVES: This paper was given as a keynote address at the conference on The Assessment of the Effects Due to Low Doses of Inorganic Mercury following Environmental and Occupational Exposures: Human and in vitro Studies on the Specific Mechanisms of Toxicity in Gargnano, Italy, in September 2001. METHODS: The most relevant literature over the past 40 years has been reviewed, and in particular, the proceedings of the World Health Organisation conferences on the health effects of inorganic and organic mercury exposure have been considered. RESULTS: In an uncontaminated environment the general population is exposed to mercury vapour from the atmosphere and from dental amalgam, while the diet, mainly from fish, is the principal source for methyl mercury absorption. Mercury vapour release from amalgam fillings increases with chewing, with absorption and uptake by the brain and kidneys. Infants exposed to phenyl mercury from treated diapers and young children ingesting mercurous chloride in teething powders have developed acrodynia (pink disease), and Kawasaki disease and the use of mercurial skin lightening creams has been followed by the development of the nephrotic syndrome. Both mercury compounds and mercury vapour have given rise to contact dermatitis in the general population. Epidemics of mercury poisoning have followed release of mercury into the environment from industrial activity, with uptake of methyl mercury from fish eating in Minamata Bay and uptake of both inorganic and methyl mercury following release of mercury vapour and deposition into waterways from gold recovery procedures in the Amazon basin. The ingestion of wheat and barley seed treated with an alkyl mercury fungicide for sowing, by a largely illiterate population in Iraq, led to a major outbreak of poisoning with a high fatality rate. Following exposure to mercury vapour, the earliest clinically observed adverse effects at urine mercury levels of the order of 30-100 mg/g creatinine, are objectively detectable tremor, psychological disorder and impaired nerve conduction velocity in sensitive subjects, with subjective symptoms of irritability, fatigue and anorexia. At these and at lower levels, proteinuria has also been observed. Both glomerular and tubular damage may occur at exposure levels lower than those giving rise to central nervous system effects. An immunological effect has also been observed in studies on clinically asymptomatic workers with low level exposure. CONCLUSIONS: As mercury can give rise to allergic and immunotoxic reactions which may be genetically regulated, in the absence of adequate dose-response studies for immunologically sensitive individuals, it has not been possible to set a level for mercury in blood or urine below which mercury related symptoms will not occur.

[Neuroendocrine and neurobehavioral effects associated with exposure to low doses of mercury from habitual consumption of marine fish]. / Effetti neuroendocrini e neurocomportamentali associati con esposizione a basse dosi di mercurio derivanti da consumo abituale di pesce di mare.

OBJECTIVES: To evaluate neuroendocrine and neurobehavioral effects possibly associated with increased dietary intake of organic mercury (Hg), a group of 22 subjects living on the island of Carloforte (south-west Sardinia) was examined, who were regular consumers of tuna fish with relatively high Hg content. This group, never exposed occupationally to either Hg or to other neurotoxic substances, was compared with 22 age-matched controls employed at a chemical plant in Portotorres (northern Sardinia). METHODS: Hg in urine (HgU) and serum prolactin (PRL) were measured in all cases, whereas measurements of total (HgB) and organic blood mercury were available only for 10 subjects from Carloforte and 6 controls. Data about working history and lifestyle (education, smoking habit, alcohol and sea fish consumption) were collected by an interviewer using a standardised questionnaire. Neurotoxic symptoms were evaluated by a self-administered questionnaire, whereas a test battery, including some computerised tests of the Swedish Performance Evaluation System (SPES) to assess vigilance and psychomotor performance, some tests on motor coordination (Luria-Nebraska and Branches Alternate Movement Task) and one memory test for numbers (Digit Span) was administered to assess neurobehavioral changes associated with exposure to dietary intake of organic mercury. In all cases, characteristics of hand tremor were evaluated by the CATSYS System 7.0. RESULTS: HgU values were significantly higher in the Carloforte group (median 6.5, range 1.8-21.5 micrograms/g creatinine) compared with controls (median 1.5, range 0.5-5.3 micrograms/g creatinine). Serum PRL was significantly higher among subjects from Carloforte and correlated with both urine and blood Hg levels. The scores of each item of the questionnaire investigating neurological symptoms were not statistically different in the two groups. In some tests of the SPES battery (Color Word Vigilance, Digit Symbol and Finger Tapping) the performance of the Carloforte group was significantly worse than that of controls, whereas in the other neurobehavioral tests poorer performances by the Carloforte group were not statistically significant. None of the tremor parameters was significantly different comparing the two groups. Multivariate analysis--controlling for education level and other covariates--carried out for the Symbol-Digit Reaction Time and for the Branches Alternate Movement Task (BAMT) showed that organic Hg concentration in blood was the most significant factor negatively affecting individual performance in these tests. Serum PRL was correlated with some neurobehavioral tests (Digit Symbol, Finger Tapping and BAMT). CONCLUSIONS: Some of the neurobehavioral tests were sensitive enough to discriminate groups with different Hg body burden, even in the low-dose range. However, the pattern of results suggests adverse neurobehavioral effects, especially on psycho-motor coordination, with a significant dose-effect relationship, mostly associated with long-term exposure to low levels of organic mercury due to the usual consumption of large fish with relatively high levels of Hg in the flash.