National Institute for Minamata Disease

Minamata, Japan

National Institute for Minamata Disease

Minamata, Japan
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Fujimura M.,National Institute for Minamata Disease | Yamashita A.,Yokohama City University
Scientific Reports | Year: 2013

We demonstrate that methylmercury (MeHg)-susceptible cells preconditioned with an inhibitor of endoplasmic reticulum (ER) Ca2+-ATPase, thapsigargin, showed resistance to MeHg cytotoxicity through favorable stress responses, which included phosphorylation of eukaryotic initiation factor 2 alpha (Eif2α), accumulation of activating transcription factor 4 (Atf4), upregulation of stress-related proteins, and activation of extracellular signal regulated kinase pathway. In addition, ER stress preconditioning induced suppression of nonsense-mediated mRNA decay (NMD) mainly through the phospho-Eif2α-mediated general suppression of translation initiation and possible combined effects of decreased several NMD components expression. Atf4 accumulation was not mediated by NMD inhibition but translation inhibition of its upstream open reading frame (uORF) and translation facilitation of its protein-coding ORF by the phospho-Eif2α. These results suggested that ER stress plays an important role in MeHg cytotoxicity and that the modulation of ER stress has therapeutic potential to attenuate MeHg cytotoxicity, the underlying mechanism being the induction of integrated stress responses.

Fujimura M.,National Institute for Minamata Disease | Cheng J.,Shanghai JiaoTong University | Zhao W.,Shanghai JiaoTong University
Brain Research | Year: 2012

Methylmercury (MeHg) is an environmental pollutant that is toxic to the developing central nervous system (CNS) in children, even at low exposure levels. Perinatal exposure to MeHg is known to induce neurological symptoms with neuropathological changes in the CNS. However, the relationship between the neurological symptoms and neuropathological changes induced in offspring as a result of exposure to low-dose MeHg is not well defined. In the present study, neurobehavioral analyses revealed that exposure to a low level of MeHg (5 ppm in drinking water) during developmental caused a significant deficit in the motor coordination of rats in the rotating rod test. In contrast, general neuropathological findings, including neuronal cell death and the subsequent nerve inflammation, were not observed in the region of the cerebellum responsible for regulating motor coordination. Surprisingly, the expression of synaptophysin (SPP), a marker protein for synaptic formation, significantly decreased in cerebellar granule cells. These results showed that perinatal exposure to low-dose MeHg causes neurobehavioral impairment without general neuropathological changes in rats. We demonstrated for the first time that exposure to low-dose MeHg during development induces the dysfunction of motor coordination due to changes of synaptic homeostasis in cerebellar granule cells. © 2012 Elsevier B.V.

Grandjean P.,University of Southern Denmark | Grandjean P.,Harvard University | Satoh H.,Tohoku University | Murata K.,Akita University | Eto K.,National Institute for Minamata Disease
Environmental Health Perspectives | Year: 2010

Background: The scientific discoveries of health risks resulting from methylmercury exposure began in 1865 describing ataxia, dysarthria, constriction of visual fields, impaired hearing, and sensory disturbance as symptoms of fatal methylmercury poisoning.Objective: Our aim was to examine how knowledge and consensus on methylmercury toxicity have developed in order to identify problems of wider concern in research.Data sources and extraction: We tracked key publications that reflected new insights into human methylmercury toxicity. From this evidence, we identified possible caveats of potential significance for environmental health research in general. Synthesis: At first, methylmercury research was impaired by inappropriate attention to narrow case definitions and uncertain chemical speciation. It also ignored the link between ecotoxicity and human toxicity. As a result, serious delays affected the recognition of methylmercury as a cause of serious human poisonings in Minamata, Japan. Developmental neurotoxicity was first reported in 1952, but despite accumulating evidence, the vulnerability of the developing nervous system was not taken into account in risk assessment internationally until approximately 50 years later. Imprecision in exposure assessment and other forms of uncertainty tended to cause an underestimation of methylmercury toxicity and repeatedly led to calls for more research rather than prevention.Conclusions: Coupled with legal and political rigidity that demanded convincing documentation before considering prevention and compensation, types of uncertainty that are common in environmental research delayed the scientific consensus and were used as an excuse for deferring corrective action. Symptoms of methylmercury toxicity, such as tunnel vision, forgetfulness, and lack of coordination, also seemed to affect environmental health research and its interpretation.

Voegborlo R.B.,Kwame Nkrumah University Of Science And Technology | Matsuyama A.,National Institute for Minamata Disease | Adimado A.A.,Kwame Nkrumah University Of Science And Technology | Akagi H.,International Mercury Laboratory
Food Chemistry | Year: 2011

Concentrations of methylmercury (MeHg) residues were determined in different marine and freshwater fishes from Ghana. Samples were treated with ethanolic potassium hydroxide in water bath at 100°C for 1h. After neutralising with HCl and washing with hexane, MeHg was extracted with dithizone in toluene, cleaned up and determined by gas chromatography with electron capture detection (GC-ECD). The method was sensitive with good precision, detection limit of 0.0005μgg-1 (0.5μgkg-1) and provided good separation for organomercury compounds. The validity of the method was established using dogfish muscle certified reference material, DORM-2. The method was applied to different fish species. Concentration of MeHg in the edible muscle tissue of the tested fish ranged from 0.009 to 0.107μgg-1 wet weight. The concentrations of MeHg in the fish samples obtained do not however, constitute any significant mercury exposure to the general population through consumption of the tested fish species. © 2010 Elsevier Ltd.

Fujimura M.,National Institute for Minamata Disease | Usuki F.,National Institute for Minamata Disease
Toxicology and Applied Pharmacology | Year: 2015

Methylmercury (MeHg) is an environmental toxin which induces cell death specific for the nervous systems. Here we show that MeHg causes neuronal cell death through the suppression of the tropomyosin receptor kinase A (TrkA) pathway, and that compounds activating the TrkA pathway prevent MeHg-induced nerve damage in vitro and in vivo. We first investigated the mechanism of MeHg-induced neurotoxicity in differentiating neurons using PC12 cells. Exposure to 100. nM MeHg for 1. day induced apoptosis in differentiating PC12 cells. Further, MeHg-induced apoptosis was preceded by inhibition of neurite extension, as determined by ELISA analyses of the neurite-specific protein neurofilament triplet H protein (NF-H). To determine the mechanism of MeHg-induced apoptosis, we evaluated the effects of MeHg on the TrkA pathway, which is known to regulate neuronal differentiation and viability. Western blot analysis demonstrated that, like the TrkA phosphorylation inhibitor K252a, MeHg inhibited phosphorylation of TrkA and its downstream effectors. Furthermore, GM1 ganglioside and its analog MCC-257, which enhance TrkA phosphorylation, overcame the effect of MeHg in neurons, supporting the involvement of the TrkA pathway in MeHg-induced nerve damage. Finally, we demonstrated that MCC-257 rescued the clinical sign and pathological changes in MeHg-exposed rats. These findings indicate that MeHg-induced apoptosis in neuron is triggered by inhibition of the TrkA pathway, and that GM1 ganglioside and MCC-257 effectively prevent MeHg-induced nerve damage. © 2014 Elsevier Inc.

Marumoto K.,National Institute for Minamata Disease | Matsuyama A.,National Institute for Minamata Disease
Atmospheric Environment | Year: 2014

To better understand the methylation and demethylation of mercury (Hg) in the atmosphere, monomethyl mercury (MMHg) concentrations in wet deposition samples collected in the Minamata Bay area from September, 2009 to August, 2010 were determined. The concentrations of total Hg (dissolved Hg+particulate Hg) and dissolved reactive Hg were also measured. The volume-weighted mean concentrations of dissolved MMHg and total Hg were 0.061 and 5.9ngL-1, respectively. Almost 90% of total Hg was in the dissolved phase and dissolved reactive Hg was the dominant Hg species in the wet deposition. The wet deposition fluxes of total Hg and reactive Hg increased in the rainy season (summer and fall), while the concentrations and wet deposition fluxes of MMHg were higher in winter and spring than in summer. Factors affecting this seasonal variation of MMHg were also considered. The MMHg in wet depositions may be decomposed by the increased levels of UV radiation in summer months, although MMHg can also be emitted from anthropogenic and biogenic sources and/or produced by photochemical reactions. Long-range transport from the Asian continent may also contribute to the seasonal variation of the wet MMHg deposition flux. © 2013 Elsevier Ltd.

Fujimura M.,National Institute for Minamata Disease | Usuki F.,National Institute for Minamata Disease
Toxicology and Applied Pharmacology | Year: 2015

Methylmercury (MeHg) is an environmental neurotoxicant. The developing nervous system is susceptible to low concentrations of MeHg; however, the effect of MeHg on neural progenitor cell (NPC) proliferation, a key stage of neurogenesis during development, remains to be clarified. In this study, we investigated the effect of low concentrations of MeHg on NPCs by using a primary culture system developed using the embryonic rat cerebral cortex. NPC proliferation was suppressed 48. h after exposure to 10. nM MeHg, but cell death was not observed. Western blot analyses for cyclins A, B, D1, and E demonstrated that MeHg down-regulated cyclin E, a promoter of the G1/S cell cycle transition. Cyclin E has been shown to be degraded following the phosphorylation by glycogen synthase kinase 3β (GSK-3β). The time course study showed that GSK-3β was up-regulated 3. h after exposure to 10. nM MeHg, and cyclin E degradation 48. h after MeHg exposure. We further demonstrated that GSK-3β inhibitors, lithium and SB-415286, suppressed MeHg-induced inhibition of NPC proliferation by preventing cyclin E degradation. These results suggest that the inhibition of NPC proliferation induced by low concentration of MeHg was associated with up-regulation of GSK-3β at the early stage and subsequent degeneration of cyclin E. © 2015 Elsevier Inc.

Marumoto K.,National Institute for Minamata Disease | Imai S.,National Institute for Minamata Disease
Marine Chemistry | Year: 2015

Dissolved gaseous Hg (DGM) in seawater and atmospheric gaseous Hg were measured at six sites in Minamata Bay to investigate mercury (Hg) evasion flux from the sea surface. Minamata Bay was severely polluted with mono-methyl Hg (MMHg). Total Hg and MMHg, seawater characteristics such as water temperature and salinity, and meteorological parameters were also observed to estimate the air-sea exchange of Hg. The mean concentration of DGM was 116±76pgL-1 (N=75), ranging from 19 to 442pgL-1, and the concentrations were higher in summer than in other seasons. DGM concentration showed a significantly positive correlation with solar radiation, and air and water temperatures. Inversely, DGM showed a significantly negative correlation with salinity and redox potential (ORP). Hg evasion fluxes from the sea surface of the bay were calculated using a two-layer gas exchange model and ranged between 0.11 and 33ngm-2h-1 (mean, 5.4±6.3ngm-2h-1). The estimated flux was slightly higher in the spring and fall when wind speed increased because the gas exchange coefficient used for estimating Hg evasion flux strongly depends on wind speed. The annual evasion flux of Hg from the sea surface of Minamata Bay was estimated to be 47±56μgm-2, which was on the same order of magnitude as the direct atmospheric deposition flux of Hg (24μgm-2) during the observation period. Therefore, Hg evasion from the sea surface likely plays an important role in the Hg cycle of Minamata Bay. © 2014 Elsevier B.V.

Fujimura M.,National Institute for Minamata Disease | Usuki F.,National Institute for Minamata Disease
Archives of Toxicology | Year: 2014

Methylmercury (MeHg), an environmental neurotoxicant, induces site-specific toxicity in the brain. Although oxidative stress has been demonstrated with MeHg toxicity, the site-specific toxicity is not completely understood. Among the cerebellar neurons, cerebellar granule cells (CGCs) appear vulnerable to MeHg, whereas Purkinje cells and molecular layer neurons are resistant. Here, we use a MeHg-intoxicated rat model to investigate these cerebellar neurons for the different causes of susceptibility to MeHg. Rats were exposed to 20 ppm MeHg for 4 weeks and subsequently exhibited neuropathological changes in the cerebellum that were similar to those observed in humans. We first isolated the three cerebellar neuron types using a microdissection system and then performed real-time PCR analyses for antioxidative enzymes. We observed that expression of manganese-superoxide dismutase (Mn-SOD), glutathione peroxidase 1 (GPx1), and thioredoxin reductase 1 (TRxR1) was significantly higher in Purkinje cells and molecular layer neurons than in CGCs. Finally, we performed immunohistochemical analyses on the cerebellum. Immunohistochemistry showed increased expression of Mn-SOD, GPx1, and TRxR1 in Purkinje cells and molecular layer neurons, which was coincident with the mRNA expression patterns. Considering Mn-SOD, GPx1, and TRxR1 are critical for protecting cells against MeHg intoxication, the results indicate that low expression of these antioxidative enzymes increases CGCs vulnerability to MeHg toxicity. © 2013 Springer-Verlag Berlin Heidelberg.

Yanagisawa R.,Japan National Institute of Environmental Studies | Koike E.,Japan National Institute of Environmental Studies | Win-Shwe T.-T.,Japan National Institute of Environmental Studies | Yamamoto M.,National Institute for Minamata Disease | Takano H.,Kyoto University
Environmental Health Perspectives | Year: 2014

Background: Hexabromocyclododecane (HBCD) is an additive flame retardant used in the textile industry and in polystyrene foam manufacturing. Because of its lipophilicity and persistency, HBCD accumulates in adipose tissue and thus has the potential of causing metabolic disorders through disruption of lipid and glucose homeostasis. However, the association between HBCD and obesity remains unclear. Objectives: We investigated whether exposure to HBCD contributes to initiation and progression of obesity and related metabolic dysfunction in mice fed a normal diet (ND) or a high-fat diet (HFD). Methods: Male C57BL/6J mice were fed a HFD (62.2 kcal% fat) or a ND and treated orally with HBCD (0, 1.75, 35, or 700 μg/kg body weight) weekly from 6 to 20 weeks of age. We examined body weight, liver weight, blood biochemistry, histopathological changes, and gene expression profiles in the liver and adipose tissue. Results: In HFD-fed mice, body and liver weight were markedly increased in mice treated with the high (700 μg/kg) and medium (35 μg/kg) doses of HBCD compared with vehicle. This effect was more prominent in the high-dose group. These increases were paralleled by increases in random blood glucose and insulin levels and enhancement of microvesicular steatosis and macrophage accumulation in adipose tissue. HBCD-treated HFD-fed mice also had increased mRNA levels of Pparg (peroxisome proliferator-activated receptor-γ) in the liver and decreased mRNA levels of Glut4 (glucose transporter 4) in adipose tissue compared with vehicle-treated HFD-fed mice. Conclusions: Our findings suggest that HBCD may contribute to enhancement of diet-induced body weight gain and metabolic dysfunction through disruption of lipid and glucose homeostasis, resulting in accelerated progression of obesity.

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