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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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2021. Published by Elsevier B.V.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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, Rondônia, 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (© 2018 John Wiley & Sons, Ltd.)

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.)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The methylmercury contamination of Minamata Bay during the WWII postwar period resulted in thousands of Japanese citizens suffering horrific neurological injury. Fear and miscommunication destroyed and changed family and social structure. In addition, the Minamata poisoning caused momentous changes in the civic discourse in Japan and was an instrumental event in the democratization of the country. This manuscript describes the effects that the environmental contamination and human poising had in the transition of Japan from a feudal society to a democratic one.

Methylmercury (MeHg) induces site-specific neurotoxicity in the adult brain. In this study, we investigated the site-specific expression of the signaling cascade related to neural activity in a mouse model of MeHg intoxication showing neurodegeneration only in the deep layer of the cerebral cortex, especially layer IV. We performed time course studies of c-fos and brain-derived neurotrophic factor (BDNF) expression levels which are proper markers of neural activity. We showed that upregulation of both markers preceded the neuronal degeneration in the cerebral cortex. Immunohistochemical analysis revealed the site-specific upregulation of c-fos in the deep layer of the cerebral cortex. Western blot analysis showed that c-fos and BDNF expression was associated with CREB phosphorylation, which was triggered by the activation of the p44/42 MAPK, p38 MAPK and PKA pathways. However, we did not detect any changes in the expression levels of c-fos and BDNF proteins and no signs of neuronal degeneration in the hippocampus and cerebellum, despite the fact that we could detect accumulation of MeHg in these two brain regions. These results suggested an intriguing possibility that MeHg-induced neuronal degeneration was caused by site-specific neural hyperactivity triggered by the activation of MAPK and PKA/CREB pathways followed by c-fos and BDNF upregulation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Methylmercury (MeHg) is a highly neurotoxic environmental pollutant. Even though molecular mechanisms mediating MeHg toxicity are not completely understood, several lines of evidence indicate that the neurotoxic effects resultant from MeHg exposure represent a consequence of its pro-oxidative properties. In this regard, MeHg is a soft electrophile that preferentially interacts with (and oxidize) nucleophilic groups (mainly thiols and selenols) from biomolecules, including proteins and low-molecular-weight molecules. Such interaction contributes to the occurrence of oxidative stress and impaired function of several molecules [proteins (receptors, transporters, enzymes, structural proteins), lipids (i.e., membrane constituents and intracellular messengers), and nucleic acids (i.e., DNA)], culminating in neurotoxicity.In this chapter, an initial background on the general aspects regarding the neurotoxicology of MeHg, with a particular focus on its pro-oxidative properties and its interaction with nucleophilic thiol- and selenol-containing molecules, is provided. Even though experimental evidence indicates that symptoms (i.e., motor impairment) resultant from MeHg exposure are linked to its pro-oxidative properties, as well as to their molecular consequences (lipid peroxidation, disruption of glutamate and/or calcium homeostasis, etc.), data concerning the relationship between molecular parameters and behavioral impairment others that those related to the motor function (i.e., visual impairment, cognitive skills, etc.) are scarce. Thus, even though scientific research has provided a significant amount of knowledge concerning the mechanisms mediating MeHg-induced neurotoxicity in the last decades, the whole scenario is far from being completely understood, and further research in this area is well warranted.

Metals are the oldest toxins known to humans. Metals differ from other toxic substances in that they are neither created nor destroyed by humans (Casarett and Doull's, Toxicology: the basic science of poisons, 8th edn. McGraw-Hill, London, 2013). Metals are of great importance in our daily life and their frequent use makes their omnipresence and a constant source of human exposure. Metals such as arsenic [As], lead [Pb], mercury [Hg], aluminum [Al] and cadmium [Cd] do not have any specific role in an organism and can be toxic even at low levels. The Substance Priority List of Agency for Toxic Substances and Disease Registry (ATSDR) ranked substances based on a combination of their frequency, toxicity, and potential for human exposure. In this list, As, Pb, Hg, and Cd occupy the first, second, third, and seventh positions, respectively (ATSDR, Priority list of hazardous substances. U.S. Department of Health and Human Services, Public Health Service, Atlanta, 2016). Besides existing individually, these metals are also (or mainly) found as mixtures in various parts of the ecosystem (Cobbina SJ, Chen Y, Zhou Z, Wub X, Feng W, Wang W, Mao G, Xu H, Zhang Z, Wua X, Yang L, Chemosphere 132:79-86, 2015). Interactions among components of a mixture may change toxicokinetics and toxicodynamics (Spurgeon DJ, Jones OAH, Dorne J-L, Svendsen C, Swain S, Stürzenbaum SR, Sci Total Environ 408:3725-3734, 2010) and may result in greater (synergistic) toxicity (Lister LJ, Svendsen C, Wright J, Hooper HL, Spurgeon DJ, Environ Int 37:663-670, 2011). This is particularly worrisome when the components of the mixture individually attack the same organs. On the other hand, metals such as manganese [Mn], iron [Fe], copper [Cu], and zinc [Zn] are essential metals, and their presence in the body below or above homeostatic levels can also lead to disease states (Annangi B, Bonassi S, Marcos R, Hernández A, Mutat Res 770(Pt A):140-161, 2016). Pb, As, Cd, and Hg can induce Fe, Cu, and Zn dyshomeostasis, potentially triggering neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, changes in heme synthesis have been associated with neurodegeneration, supported by evidence that a decline in heme levels might explain the age-associated loss of Fe homeostasis (Atamna H, Killile DK, Killile NB, Ames BN, Proc Natl Acad Sci U S A 99(23):14807-14812, 2002).The sources, disposition, transport to the brain, mechanisms of toxicity, and effects in the central nervous system (CNS) and in the hematopoietic system of each one of these metals will be described. More detailed information on Pb, Mn, Al, Hg, Cu, and Zn is available in other chapters. A major focus of the chapter will be on Pb toxicity and its interaction with other metals.

In the 1950s, large-scale food poisoning caused by methylmercury was identified in Minamata, Japan. Although severe intrauterine exposure cases (ie, congenital Minamata disease patients) are well known, possible impacts of methylmercury exposure in utero among residents, which is likely at lower levels than in congenital Minamata disease patients, are rarely explored. In 2014, the authors examined neurological and neurocognitive functions among 18 exposed participants in Minamata, focusing on fine motor, visuospatial construction, and executive functions. More than half of the participants had some fine motor and coordination difficulties. In addition, several participants had lower performance for neurocognitive function tests (the Rey-Osterrieth Complex Figure test and Keio version of the Wisconsin card sorting test). These deficits imply diffuse brain damage. This study suggests possible neurological and neurocognitive impacts of prenatal exposure to methylmercury among exposed residents of Minamata.

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.

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.

Objective: To identify features of cognitive impairment in patients with toxic (mercury or alcohol) encephalopathy., Material and Methods: The study involved 36 patients with chronic mercury intoxication and 30 people with chronic alcoholism. A control group included 30 age-matched healthy men who were not exposed to toxic substances and alcohol abuse. All patients underwent neuropsychological examination, which involved a set of neuropsychological Luria rated memory status, praxis, gnosis and speeches. MMSE and FAB were used for the diagnosis of moderate cognitive impairment. Computer electroencephalography and cognitive evoked potentials method were used as well., Results and Conclusion: The diffuse brain injury in toxic encephalopathy (alcohol and mercury) on EEG, and according to the results of neuropsychological testing was identified. Changes in analytical and synthetic thinking, audio-verbal, long-term, visual memory, reciprocal coordination, finger gnosis, impressive speech were observed in mercury encephalopathy. Functional failure of the frontal lobe and the premotor area of the left hemisphere were revealed in alcoholic encephalopathy.

The aims of this study were to evaluate whether chronic intoxication with mercury chloride (HgCl2), in a low concentration over a long time, can be deposited in the central nervous tissue and to determine if this exposure induces motor and cognitive impairments. Twenty animals were intoxicated for 45 days at a dose of 0.375 mg/kg/day. After this period, the animals underwent a battery of behavioral tests, in a sequence of open field, social recognition, elevated T maze and rotarod tests. They were then sacrificed, their brains collected and the motor cortex and hippocampus dissected for quantification of mercury deposited. This study demonstrates that long-term chronic HgCl2 intoxication in rats promotes functional damage. Exposure to HgCl2 induced anxiety-related responses, short- and long-term memory impairments and motor deficits. Additionally, HgCl2 accumulated in both the hippocampus and cortex of the brain with a higher affinity for the cortex.

To assess severity of cognitive disorders in chronic mercury intoxication, the authors performed claster and discrimination analysis of neuropsychologic and neurophysiologic research data from workers exposed to mercury during long length of service, from patients with early and marked stages of chronic mercurial intoxication. Cognitive disorders in chronic mercurial intoxication have three severity degrees, in the light degree disorders patients demonstrate lower amplitude of cognitive evoked potentials, poor long-term memory and associative thinking. Moderate cognitive disorders are characterized by decreased visual, long-term memory, concentration of attention, poor optic and spatial gnosis. Marked cognitive disorders with chronic mercurial intoxication present with more decreased long-term, short-term, picturesque memory, poor intellect, optic and spatial gnosis and associative thinking.

Adult-onset methylmercury (MeHg) exposure is thought to result primarily in sensory and motor deficits but effects on learning are poorly understood. One mechanism by which chronic MeHg may exert its neurotoxicity is via sustained disruption of intracellular calcium homeostasis, with a consequent increase of intracellular Ca(2+) ions in vulnerable neurons. A biochemically heterogeneous group of compounds, calcium channel blockers, have been shown in vitro to attenuate MeHg's toxicity. To evaluate the role of calcium antagonism in MeHg toxicity in vivo, adult BALB/c mice were exposed chronically to 0 or 15 ppm of Hg (as MeHg) via drinking water and to nimodipine, a dihydropryidine, L-type Ca(2+) channel blocker with action in the CNS. Nimodipine was administered orally in diets (0, 20, or 200 ppm, producing approximately 0, 2, or 20 mg/kg/day of nimodipine). An incremental repeated acquisition (IRA) of response chains procedure was used to detect MeHg-induced deficits in learning or motoric function and to evaluate possible neuroprotection by nimodipine. MeHg impaired performance on the IRA task, and this was partially or completely blocked by dietary nimodipine, depending on dose. Measures of learning co-varied with measures of motoric function as indicated by overall response rate. Nimodipine delayed or prevented the behavioral toxicity of MeHg exposure as evidenced by IRA performance; effects on learning seemed secondary to response rate decreases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The benefit of the nutritious elements in fish is insufficient for explaining the controversial finding regarding prenatal mercury (Hg) exposure and neurodevelopment; the varying frequency of susceptible genes among these populations may shed light on these observations. However, limited studies have been reported on the association between genetic susceptibility of prenatal Hg exposure and child development. Apolipoprotein E (APOE, protein; Apoe, gene) is a major protein transporter expressed in the brain. The Apoe epsilon 4 (ε4) allele is associated with poor neural repair function and is a risk factor associated with Alzheimer disease. We conducted a prospective cohort study in 2004 and 2005. In this study, 168 subjects were recruited at delivery and followed up at two years of age, and genetic polymorphisms of Apoe were included to assess genetic susceptibility and to determine the relationship between Hg concentrations in cord blood and neurodevelopment. The results showed that adverse effects on neurodevelopment were consistently associated with prenatal Hg exposure in all subtests of Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT) among ε4 carriers as assessed by both simple linear and multiple linear regression models. After controlling for confounding factors, statistical significance was found in the subtests of cognition tests (β=-8.47, 95% confidence interval (CI)=-16.10 to -0.84), social tests (β=-11.02, 95% CI=-20.85 to -1.19) and the whole test of CDIIT (β=-10.45, 95% CI=-17.36 to -3.54) in a multiple linear regression model. Additionally, the interaction effect between gene polymorphisms of Apoe and Hg levels was significant in the whole test CDIIT and subtests of cognition, language and fine motor tests. In conclusion, Apoe modifies the adverse effects of cord blood Hg on neurodevelopment at the age of two years., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Prenatal exposure to methylmercury can cause both neurobehavioral deficits and neurophysiological changes. However, evidence of neurotoxic effects within the visual nervous system is inconsistent, possibly due to incomplete statistical adjustment for beneficial nutritional factors. We evaluated the effect of prenatal methylmercury exposure on visual evoked potential (VEP) latencies in Faroese children with elevated prenatal methylmercury exposure. A cohort of 182 singleton term births was assembled in the Faroe Islands during 1994-1995. At age 7 years, VEP tracings were obtained from 139 cohort subjects after exclusion of subjects with abnormal vision conditions. We used multiple regression analysis to evaluate the association of mercury concentrations in cord blood and maternal hair at parturition with VEP latencies after adjustment for potential confounders that included the cord-serum phospholipid concentration of n-3 polyunsaturated fatty acids (PUFAs) and the duration of breastfeeding. Unadjusted correlations between mercury exposure and VEP latencies were equivocal. Multiple regression models showed that increased mercury concentrations, especially in maternal hair, were associated with delayed latencies for VEP peak N145. After covariate adjustment, a delay of 2.22 ms (p=0.02) was seen for each doubling of the mercury concentration in maternal hair. In agreement with neuropsychological findings, the present study suggests that prenatal methylmercury exposure may have an adverse effect on VEP findings despite the absence of clinical toxicity to the visual system. However, this association was apparent only after adjustment for n-3 PUFA status., (Copyright © 2013. Published by Elsevier B.V.)

Background: Dental amalgam is approximately 50% metallic mercury and releases mercury vapor into the oral cavity, where it is inhaled and absorbed. Maternal amalgams expose the developing fetus to mercury vapor. Mercury vapor can be toxic, but uncertainty remains whether prenatal amalgam exposure is associated with neurodevelopmental consequences in offspring., Objective: To determine if prenatal mercury vapor exposure from maternal dental amalgam is associated with adverse effects to cognition and development in children., Methods: We prospectively determined dental amalgam status in a cohort of 300 pregnant women recruited in 2001 in the Republic of Seychelles to study the risks and benefits of fish consumption. The primary exposure measure was maternal amalgam surfaces present during gestation. Maternal occlusal points were a secondary measure. Outcomes were the child's mental (MDI) and psychomotor (PDI) developmental indices of the Bayley Scales of Infant Development-II (BSID-II) administered at 9 and 30 months. Complete exposure, outcome, and covariate data were available on a subset of 242 mother-child pairs., Results: The number of amalgam surfaces was not significantly (p>0.05) associated with either PDI or MDI scores. Similarly, secondary analysis with occlusal points showed no effect on the PDI or MDI scores for boys and girls combined. However, secondary analysis of the 9-month MDI was suggestive of an adverse association present only in girls., Conclusion: We found no evidence of an association between our primary exposure metric, amalgam surfaces, and neurodevelopmental endpoints. Secondary analyses using occlusal points supported these findings, but suggested the possibility of an adverse association with the MDI for girls at 9 months. Given the continued widespread use of dental amalgam, we believe additional prospective studies to clarify this issue are a priority., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Methylmercury (MeHg) is an environmental pollutant that biomagnifies throughout the aquatic food chain, thus representing a toxicological concern for humans subsiding on fish for their dietary intake. Although the developing brain is considered the critical target organ of MeHg toxicity, recent evidence indicates that the cardiovascular system may be the most sensitive in adults. However, data on the mechanisms mediating MeHg-induced cardiovascular toxicity are scarce. Based on the close relationship between cardiovascular disease and dyslipidemia, this study was designed to investigate the effects of long-term MeHg exposure on plasma lipid levels in mice, as well as their underlying mechanisms and potential relationships to MeHg-induced neurotoxicity. Our major finding was that long-term MeHg exposure induced dyslipidemia in rodents. Specifically, Swiss and C57BL/6 mice treated for 21 days with a drinking solution of MeHg (40 mg/l, ad libitum) diluted in tap water showed increased total and non-HDL plasma cholesterol levels. MeHg-induced hypercholesterolemia was also observed in low-density lipoprotein receptor knockout (LDLr⁻/⁻) mice, indicating that this effect was not related to decreased LDLr-mediated cholesterol transport from blood to other tissues. Although the hepatic synthesis of cholesterol was unchanged, significant signs of nephrotoxicity (glomerular shrinkage, tubular vacuolization, and changed urea levels) were observed in MeHg-exposed mice, indicating that the involvement of nephropathy in MeHg-induced lipid dyshomeostasis may not be ruled out. Notably, Probucol (a lipid-lowering drug) prevented the development of hypercholesterolemia when coadministered with MeHg. Finally, hypercholesterolemic LDLr⁻/⁻ mice were more susceptible to MeHg-induced cerebellar glial activation, suggesting that hypercholesterolemia in itself may pose a risk factor in MeHg-induced neurotoxicity. Overall, based on the strong and graded positive association between total as well as LDL cholesterol and risk of cardiovascular diseases, our data support the concept of MeHg-induced cardiovascular toxicity.

Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is the identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. We examined the hypothesis that CPOX4, a genetic variant of the heme pathway enzyme coproporphyrinogen oxidase (CPOX) that affects susceptibility to mercury toxicity in adults, also modifies the neurotoxic effects of Hg in children. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings in children. Subjects were evaluated at baseline and at 7 subsequent annual intervals for neurobehavioral performance and urinary mercury levels. Following the completion of the clinical trial, genotyping assays for CPOX4 allelic status were performed on biological samples provided by 330 of the trial participants. Regression modeling strategies were employed to evaluate associations between CPOX4 status, Hg exposure, and neurobehavioral test outcomes. Among girls, few significant CPOX4-Hg interactions or independent main effects for Hg or CPOX4 were observed. In contrast, among boys, numerous significant interaction effects between CPOX4 and Hg were observed spanning all 5 domains of neurobehavioral performance. All underlying dose-response associations between Hg exposure and test performance were restricted to boys with the CPOX4 variant, and all of these associations were in the expected direction where increased exposure to Hg decreased performance. These findings are the first to demonstrate genetic susceptibility to the adverse neurobehavioral effects of Hg exposure in children. The paucity of responses among same-age girls with comparable Hg exposure provides evidence of sexual dimorphism in genetic susceptibility to the adverse neurobehavioral effects of Hg in children and adolescents., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Mercury is known to be neurotoxic at high levels. There have been few studies of potential peripheral neurotoxicity among persons with exposure to elemental mercury at or near background levels., Objectives: The present study sought to examine the association between urinary mercury concentration and peripheral nerve function as assessed by sensory nerve conduction studies in a large group of dental professionals., Methods: From 1997 through 2006 urine mercury measurements and sensory nerve conduction of the median and ulnar nerves in the dominant hand were performed, and questionnaires were completed, on the same day in a convenience sample of dental professionals who attended annual conventions of the American Dental Association. Linear regression models, including repeated measures models, were used to assess the association of urine mercury with measured nerve function., Results: 3594 observations from 2656 subjects were available for analyses. Urine mercury levels in our study population were higher than, but substantially overlap with, the general population. The only stable significant positive association involved median (not ulnar) sensory peak latency, and only for the model that was based on initial observations and exclusion of subjects with imputed BMI. The present study found no significant association between median or ulnar amplitudes and urine mercury concentration., Conclusions: At levels of urine mercury that overlap with the general population we found no consistent effect of urine mercury concentration on objectively measured sensory nerve function., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Mercury (Hg) is a potent neurotoxicant. We hypothesized that single nucleotide polymorphisms (SNPs) in genes coding glutathione-related proteins, selenoproteins and metallothioneins may modify the relationship of mercury biomarkers with changes in peripheral nerve function. Dental professionals (n=515) were recruited in 2009 and 2010. Sensory nerve function (onset latency, peak latency and amplitude) of the median, ulnar and sural nerves was recorded. Samples of urine, hair and DNA were collected. Covariates related to demographics, nerve function and elemental and methyl-mercury exposure were also collected. Subjects included 244 dentists (47.4%) and 269 non-dentists (52.2%; mostly dental hygienists and dental assistants). The mean mercury levels in urine (1.06 μg/L) and hair (0.51 μg/g) were not significantly different from the US general population (0.95 μg/L and 0.47 μg/g, respectively). In multivariate linear models predicting nerve function adjusting for covariates, only 3 out of a total of 504 models showed stable and statistically significant interaction of SNPs with mercury biomarkers. Overall, given the possibility of false positives, the results suggested little evidence of effect modification of the SNPs on the relationship between mercury biomarkers with peripheral nerve function at exposure levels that are relevant to the general US population., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Adult zebrafish were treated acutely with methylmercury (1.0 or 5.0 μg g(-1), i.p.) and, 24h after treatment, were tested in two behavioral models of anxiety, the novel tank and the light/dark preference tests. At the smaller dose, methylmercury produced a marked anxiogenic profile in both tests, while the greater dose produced hyperlocomotion in the novel tank test. These effects were accompanied by a decrease in extracellular levels of serotonin, and an increase in extracellular levels of tryptamine-4,5-dione, a partially oxidized metabolite of serotonin. A marked increase in the formation of malondialdehyde, a marker of oxidative stress, accompanied these parameters. It is suggested that methylmercury-induced oxidative stress produced mitochondrial dysfunction and originated tryptamine-4,5-dione, which could have further inhibited tryptophan hydroxylase. These results underscore the importance of assessing acute, low-level neurobehavioral effects of methylmercury., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This study examined the neurobehavioral changes and alteration in gene expression in the brains of metallothionein (MT)-I/II null mice exposed to low-levels of mercury vapor (Hg(0)) during postnatal development. MT-I/II null and wild-type mice were repeatedly exposed to Hg(0) at 0.030 mg/m(3) (range: 0.023-0.043 mg/m(3)), which was similar to the current threshold value (TLV), for 6 hr per day until the 20th day postpartum. The behavioral effects were evaluated with locomotor activity in the open field (OPF), learning ability in the passive avoidance response (PA) and spatial learning ability in the Morris water maze (MM) at 12 weeks of age. Hg(0)-exposed MT-I/II null mice showed a significant decrease in total locomotor activity in females, though learning ability and spatial learning ability were not affected. Immediately after Hg(0) exposure, mercury concentrations in the brain did not exceed 0.5 µg/g in any animals. Hg(0) exposure resulted in significant alterations in gene expression in the brains of both strains using DNA microarray analysis. The number of altered genes in MT-I/II null mice was higher than that in wild-type mice and calcium-calmodulin kinase II (Camk2a) involved in learning and memory in down-regulated genes was detected. These results provide useful information to elucidate the development of behavioral toxicity following low-level exposure to Hg(0).

The present studies were conducted to changes arising from mercury poisoning in the central nervous system (CNS), with a focus on determining the receptors and neurotransmitters involved. Currently, little is known regarding the neurological basis of the cardiopulmonary effects of mercury poisoning. We evaluated changes in systolic arterial pressure (SAP), diastolic arterial pressure (DAP), respiratory rate (RR) and heart rate (HR) following a 5 μl intracisternal (i.c) injection of mercuric chloride (HgCl(2)) and the participation of the autonomic nervous system in these responses. 58 animals were utilized and distributed randomly into 10 groups and administered a 5 μL intracisternal injection of 0.68 μg/kg HgCl(2) (n=7), 1.2 μg/kg HgCl(2) (n=7), 2.4 μg/kg HgCl(2) (n=7), 60 μg/kg HgCl(2) (n=7), 120 μg/kg HgCl(2) (n=3), saline (control) (n=7), 60 μg/kg HgCl(2) plus prazosin (n=6), saline plus prazosin (n=6), 60 μg/kg HgCl(2) plus metilatropina (n=4) or saline plus metilatropina (n=4)HgCl(2). Anesthesia was induced with halothane and maintained as needed with urethane (1.2 g/kg) administered intravenously (i.v.) through a cannula placed in the left femoral vein. The left femoral artery was also cannulated to record systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and heart rate (HR). A tracheotomy was performed to record respiratory rate. Animals were placed in a stereotaxic frame, and the cisterna magna was exposed. After a stabilization period, solutions (saline or HgCl(2)) were injected i.c., and cardiopulmonary responses were recorded for 50 min. Involvement of the autonomic nervous system was assessed through the i.v. injection of hexamethonium (20 mg/kg), prazosin (1 mg/kg) and methylatropine (1 mg/kg) 10 min before the i.c. injection of HgCl(2) or saline. Treatment with 0.68, 1.2, 2.4 μg/kg HgCl(2) or saline did not modify basal cardiorespiratory parameters, whereas the 120 μg/kg dose induced acute toxicity, provoking respiratory arrest and death. The administration of 60 μg/kg HgCl(2), however, induced significant increases (p<0.05) in SAP at the 30°, 40° and 50° min, timepoints and DAP at the 5°, 10°, 20°, 30°, 40° and 50° timepoints. RR was significantly decreased at the 5°, 10°, 20°, 40° and 50° min timepoints; however, there was no change in HR. Hexamethonium administration, which causes non-specific inhibition of the autonomic nervous system, abolished the observed cardiorespiratory effects. Similarly, prazosin, a α(1)-adrenoceptor blocker that specifically inhibits sympathetic nervous system function, abolished HgCl(2) induced increases in SAP and DAP without affecting HR and RR. Methylatropine (1 mg/Kg), a parasympathetic nervous system inhibitor, exacerbated the effects of HgCl(2) and caused slow-onset respiratory depression, culminating in respiratory arrest and death. Our results demonstrate that increases in SAP and DAP induced by the i.c. injection of mercuric chloride are mediated by activation of the sympathetic nervous system., (Copyright © 2011 Elsevier Inc. All rights reserved.)

To scrutinize whether the provisional tolerable weekly intake (PTWI, 3.4 microg/kg body weight/week) of methylmercury in Japan is safe for adults, we conducted an intervention study using heart rate variability (HRV) that has been considered to reflect cardiac events. Fifty-four healthy volunteers were recruited and divided into experimental and control groups. The experimental group was exposed to methylmercury at the PTWI level through consumption of bigeye tuna and swordfish for 14 weeks, and HRV parameters were compared between the two groups. In the experimental group, mean hair mercury levels, determined before and after the dietary methylmercury exposure and after 15-week wash-out period following the cessation of exposure, were 2.30, 8.76 and 4.90 microg/g, respectively. The sympathovagal balance index of HRV was significantly elevated after the exposure, and decreased to the baseline level at the end of this study. Still, such changes in HRV parameters were not found in the control group with a mean hair mercury level of around 2.1 microg/g. In conclusion, the PTWI does not appear to be safe for adult health, because methylmercury exposure from fish consumption induced a temporary sympathodominant state. Rather, long-term exposure to methylmercury may pose a potential risk for cardiac events involving sympathovagal imbalance among fish-consuming populations., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

The article covers results of long-standing research on clinical peculiarities and course of toxic encephalopathy in distant period of occupational neurointoxications, on main concepts and pathogenetic steps of formation and progress of toxic encephalopathy. Through investigation covered firemen after exposure to complex of toxic chemicals and patients in post-contact period of chronic mercury intoxication. Modelling of chronic inhalation of metallic mercury vapors was performed.

Background: Methylmercury is an environmental pollutant that can cause irreversible effects on the development of children. Although there is no doubt that high exposure can cause neurodevelopmental deficits, the threshold that will adversely affect the developing fetus is not well defined. Our objective was to systematically review the evidence of neurodevelopmental risks of methylmercury to the unborn child from maternal fish consumption to define the lowest observable adverse effect hair concentration (LOAEHC)., Methods: A systematic review was conducted of all original research reporting on the effects of methylmercury on the human fetus. A literature search was undertaken using SCOPUS, Medline-Ovid, PubMed, Google Scholar, and EMBASE. Papers were selected based on the following inclusion criteria: 1) child neurodevelopmental outcome; 2) comparison groups; and 3) methylmercury exposure through fish consumption., Results: Forty-eight publications met these inclusion criteria. Thirty articles reported on longitudinal studies and 18 were cross-sectional studies. Variations in study design precluded formal meta-analysis. Based on an evaluation of these studies, we defined the LOAEHC at 0.3 microg/g of maternal hair mercury. The longitudinal studies yielded a LOAEHC of 0.5 microg/g., Conclusion: In the clinical context, the majority of pregnant women consume mercury-containing fish in amounts that are lower than the LOAEHC defined in this study. However, the LOAEHC is in the same order of magnitude of mercury exposure that occurs in significant numbers of women. Hence, although it appears safe to suggest that eating the recommended types and amounts of fish poses no measurable risks for neurodevelopmental deficits, analysis of hair mercury content before pregnancy might be suggested because dietary modification can decrease body content and risk.

This study examined the effects of inorganic mercury exposure on behavioral and biochemical parameters and investigated the possible preventive effects of zinc on the alterations induced by mercury. Pups were exposed from 3rd to 7th postnatal day to ZnCl2 (27 mg/kg/day, s.c.) and subsequently to HgCl2 (5 doses of 5 mg/kg/day, s.c.). Each litter contained two rats for each treatment. The rats were submitted to behavioral task and litters were killed at 13 or 33 days old for acetylcholinesterase activity assays and for the determination of metal levels. Based on the results obtained from 13-day-old rats, they were divided in two groups of litters that were defined at the end of the experimental period (33 days) as less sensitive rats to mercury and more sensitive rats to mercury in accordance with the recovery of body weight until day 33. The mercury exposure caused accumulation of this metal in cerebrum and cerebellum in all mercury treated rats, and inhibited the cerebellum acetylcholinesterase activity from 13-day-old rats. Besides, the mercury-animals of the most sensitive litters to mercury presented impairment in motor function and muscular strength verified in the beaker test, as well as a reduction of the locomotor and exploratory activities in the open field task. Zinc partially prevented all the alterations induced by mercury exposure and reduced the mercury level accumulated in cerebrum and cerebellum. This study confirms the preventive effect of zinc on behavioral alterations induced by mercury in young rats and demonstrates that the mercury behavioral effects are present even for a long time after the end of the exposure.

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.

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor (NGF) family and has been shown to promote neuronal survival and contribute to neural development. Although methylmercury, a neurotoxin, induces the cell death of neurons in vitro, there is little information regarding the effects of neurotrophins on the methylmercury-induced cell death of neurons. In the present study, we investigated the effect of BDNF on methylmercury-induced cell death in a primary culture of rat cerebellar granular cells. BDNF increased the viability of the cultured cells when treated alone, but unexpectedly accelerated the cell death induced by administration of methylmercury. Among other growth factors tested, only neurotrophin-4 (NT-4) demonstrated a similar acceleration of methylmercury-induced cell death. The cell death-accelerating effect of BDNF was inhibited by a BDNF-neutralizing antibody or a MAPK inhibitor. To determine whether the effect of BDNF occurs via TrkB, a receptor of BDNF and NT-4, we investigated the effects of BDNF and methylmercury in a TrkB transformant of rat neuroblastoma B35 cells. The methylmercury-induced cell death of the TrkB transformant was accelerated by BDNF, while that of the mock transformant was not. These results indicate that BDNF accelerates methylmercury-induced cell death via TrkB, at least in vitro, and suggest that BDNF and TrkB may also contribute to the sensitivity of neurons to methylmercury toxicity.

Human exposure to the life-span developmental neurotoxicant, methylmercury (MeHg), is primarily via the consumption of fish or marine mammals. Fish are also excellent sources of important nutrients, including selenium and n-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA). Laboratory models of developmental MeHg exposure can be employed to assess the roles of nutrients and MeHg and to identify potential mechanisms of action if the appropriate exposure measures are used. When maternal exposure is protracted, relationships between daily intake and brain mercury are consistent and orderly across species, even when large differences in blood:brain ratios exist. It is well established that low-level developmental MeHg produces sensory deficits. Recent studies also show that perseveration in reversal-learning tasks occurs after gestational exposures that produce low micromolar concentrations in the brain. A no-effect level has not been identified for this effect. These exposures do not affect the acquisition or performance of discrimination learning, set shifting (extradimensional shift), or memory. Reversal-learning deficits may be related to enhanced impact of reinforcers as measured using progressive ratio reinforcement schedules, an effect that could result in perseveration. Also reported is enhanced sensitivity to dopamine reuptake inhibitors and diminished sensitivity to pentobarbital, a GABA(A) agonist. Diets rich in PUFAs or selenium do not protect against MeHg's effects on reversal learning but, by themselves, may diminish variability in performance, enhance attention or psychomotor function and may confer some protection against age-related deficits in these areas. It is hypothesized that altered reward processing, dopamine and GABAergic neurotransmitter systems, and cortical regions associated with choice and perseveration are especially sensitive to developmental MeHg at low exposure levels. Human testing for MeHg's neurotoxicity should emphasize these behavioral domains.

John Martin Wood, Emeritus Professor of Medical Biochemistry at the University of Bradford died in Wieck by Greifswald, Germany after a short illness on February 5, 2008 - just short of his 70(th) year. John worked as a pioneering biochemist and educator in the US and in Britain across two research careers. He devoted the first twenty-five years to the role of transition metals in biology, and his last twenty-years to cutaneous enzymology and melanogenesis. Working together with his wife Professor Karin U. Schallreuter, his research on oxidative stress handling in skin and on the expression of a cutaneous catecholaminergic system will help direct research in these fields for many years to come. John impressed on his fellow cutaneous researchers and students the critical importance of appreciating the true role of enzymes in skin health and disease. This obituary aims to contextualize the significant contributions made by this remarkable man to experimental dermatology.

Methylmercury (MeHg) is a widespread environmental and food toxicant which has long been known to affect neurodevelopment in both humans and experimental animals. Risk assessment for MeHg is mainly based on human data coming from the massive episodes of poisoning in Japan and Iraq, as well as from large scale epidemiological studies concerning childhood development and neurotoxicity in relation to in utero exposure in various fish eating communities around the world. Despite the extensive literature and research, the threshold dose for MeHg neurotoxic effects is still unclear, in particular when it comes to subtle effects on neurobehaviour. In this article clinical and epidemiological findings concerning the neurodevelopmental toxicity of MeHg are reviewed. Much attention is focussed on the potential impact of factors, such as diet and nutrition, gender, pattern of exposure and co-exposure to other neurotoxic pollutants, which may modulate MeHg toxic effects. These factors, together with the notion that some symptoms may ensue or exacerbate with aging, contribute to the difficulties in the definition of safe levels for developmental exposure.

Methylmercury (MeHg) is one of the most significant public health hazards. The clinical findings in the victims of the Japanese and Iraqi outbreaks have disclosed the pronounced susceptibility of the developing brain to MeHg poisoning. This notion has triggered worldwide scientific attention toward the long-term consequences of prenatal exposure on child development in communities with chronic low level dietary exposure. MeHg neurodevelopmental effects have been extensively investigated in laboratory animals under well-controlled exposure conditions. This article provides an updated overview of the main neuromorphological and neurobehavioral changes reported in non-human primates and rodents following developmental exposure to MeHg. Different aspects of MeHg's effects on the immature organism are reported, with particular reference to the delayed onset of symptoms and the persistency of central nervous system (CNS) injury/dysfunction. Particular attention is paid to the comparative toxicity assessment across species, and to the degree of concordance/discordance between human and animal data. The contribution of animal studies to define the role of potential effect modifiers and variables on MeHg dose-response relationships is also addressed. The ultimate goal is to discuss the relevance of laboratory animal results, as a complementary tool to human data, with regard to the human risk assessment process.

Minamata disease is methylmercury poisoning from consuming fish and shellfish contaminated by industrial waste. The polluted seafood was widely consumed in the area around Minamata, but many individuals were never examined for or classified as having Minamata disease. Following the determination of the Supreme Court of Japan in October 2004 that the Japanese Government was responsible for spreading Minamata disease, over 13,000 residents came forward to be examined for Minamata disease. We studied 197 residents from the Minamata area who had a history of fish consumption during the polluted period to determine the importance of sensory symptoms and findings in making a diagnosis of Minamata disease. We divided the exposed subjects into non-complicated (E) and complicated (E+N) groups based on the absence or presence of other neurological or neurologically related disorders and compared them to residents in control area (C) after matching for age and sex. We quantitatively measured four somatosensory modalities (minimal tactile sense by Semmes-Weinstein monofilaments, vibration sense, position sense, and two-point discrimination) and did psychophysical tests of fine-surface-texture discrimination. Subjective complaints were higher in groups E and E+N than C. Over 90% of E+N and E subjects displayed a sensory disturbance on conventional neurological examination and 28% had visual constriction. About 50% of the E and E +N groups had upper and lower extremity ataxia and about 70% had truncal ataxia. The prevalence of these neurological findings was significantly higher in exposed subjects than controls. All sensory modalities were impaired in the E and E+N groups. All four quantitatively measured sensory modalities were correlated. The prevalence of complaints, neurological findings, and sensory impairment was similar or a little worse in group E+N than in group E. We conclude that sensory symptoms and findings are important in making the diagnosis of Minamata disease and that they can be determined even in the presence of neurological or neurologically related diseases.

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.

The first well-documented outbreak of acute methyl mercury (MeHg) poisoning by consumption of contaminated fish occurred in Minamata, Japan, in 1953. The clinical picture was officially recognized and called Minamata disease (MD) in 1956. However, 50 years later there are still arguments about the definition of MD in terms of clinical symptoms and extent of lesions. We provide a historical review of this epidemic and an update of the problem of MeHg toxicity. Since MeHg dispersed from Minamata to the Shiranui Sea, residents living around the sea were exposed to low-dose MeHg through fish consumption for about 20 years (at least from 1950 to 1968). These patients with chronic MeHg poisoning continue to complain of distal paresthesias of the extremities and the lips even 30 years after cessation of exposure to MeHg. Based on findings in these patients the symptoms and lesions in MeHg poisoning are reappraised. The persisting somatosensory disorders after discontinuation of exposure to MeHg were induced by diffuse damage to the somatosensory cortex, but not by damage to the peripheral nervous system, as previously believed.

The incidence of mercury intoxication has decreased considerably because of stricter public health regulations. However, it has not been completely eliminated and should be considered in a child with unexplained tachycardia, hypertension, mood changes, weight loss, and acrodynia. Mercury intoxication can be difficult to differentiate from pheochromocytoma and Kawasaki's disease. Here, the authors report the case of an 8-year-old boy with history of mercury exposure, signs and symptoms suggestive of mercury intoxication, and good response to chelation therapy, but with only mild increase in urinary mercury levels. This case highlights the fact that urinary mercury levels do not necessarily correlate with the severity of clinical signs and symptoms of mercury intoxication.

Background: A variety of neurophysiological measures are useful in hospital settings for diagnostic and other clinical purposes. Previously, abnormal changes in various sensory evoked potentials (EPs), and heart rate variability (HRV) were observed in patients with acquired and fetal Minamata disease (MD; methylmercury poisoning). In recent years, some of these methods have been used for the risk assessment of low-level methylmercury exposure in asymptomatic children. The objectives of this article were to present an overview of neurophysiological findings involved in methylmercury neurotoxicity and to examine the usefulness of those measures., Methods: The reports addressing both neurophysiological measures and methylmercury exposure in humans were identified and evaluated., Results: The neurological signs and symptoms of MD included paresthesias, constriction of visual fields, impairment of hearing and speech, mental disturbances, excessive sweating, and hypersalivation. Neuropathological lesions involved visual, auditory, and post- and pre-central cortex areas. Neurophysiological changes involved in methylmercury, as assessed by EPs and HRV, were found to be in accordance with both clinical and neuropathological observations in patients with MD., Conclusions: EPs and HRV appear to be useful and objective methods for assessing methylmercury neurotoxicity. However, subtle changes due to low-level methylmercury exposure may not necessarily be of clinical relevance, and interpretation of small deviations from expectations must be cautious., ((c) 2007 Wiley-Liss, Inc.)

Objectives: The main purposes of this study are to compare the current statuses and activities of daily living (ADL) scores with the same parameters 15 years ago in fetal-type Minamata disease patients and to identify the communication disorders in these patients., Methods: An interview survey was conducted on 31 fetal-type Minamata disease patients mainly in 2002 concerning family structure, present status of care, their demand for care, communication status, and ADLs. Changes in ADLs during the past 15 years were also studied in 22 of the patients., Results: Their mean ages were 45.5+/-3.5 (n=20) for males, and 46.1+/-1.9 (n=ll) for females. The average numbers of family of the patients was 2, and 15 patients lived alone. An analysis of ADLs showed that about 50% of the patients could not walk or take a bath, and 30 to 40% of the patients could not eat, excrete, change their clothes, or wash their face alone. Approximately 80% of the patients could understand daily conversation to some degree. However, their ability to express their demands and thoughts, put an idea into action, remember events, and live like ordinary people were significantly worse than their ability to understand daily conversation. The changes in the ADLs of the 22 patients were not significant for the past 15 years. However, two patients showed a rapid decrease for ADL of movement and 2 other patients died after an interview before 50 years of age., Conclusions: Appropriate care in daily living is an important issue for fetal-type Minamata disease patients. Further, the individual health care of such patients is an urgent issue and can prevent their health from rapidly deteriorating.