About NIMD

Our organization, departments, staff and researchers

Masatake Fujimura

The research group I work for : Pathomechanism Group(Group Leader), International Contribution / Information Group

Specialty: Neurotoxicology, neuropharmacology
Academic affiliations: Molecular Biology Society of Japan, Japanese Society of Toxicology

The main target organ of methylmercury is the cerebral nerve system and its irreversible neuronal dysfunction remains one of the most serious problems. Our laboratory aims to elucidate the causal factor and the characteristics of the neuronal dysfunction caused by methylmercury through the comprehensive approach on the molecular level (gene, protein), the cellular level (cultivated cell), the individual level (experimental animal), and the human level (pathological tissue) and to apply the study results to diagnosis, prevention, and treatment. A part of our study results has been adopted on the cover sheet of the Neurotoxicology (January 2009) and the Toxicol. Appl. Pharmacol. (January 2011, February 2015, and May 2016) that are journals specialized in toxicology.
Our laboratory is also engaged in the hair mercury survey for regions in the world where mercury contamination is concerned and has been designated as a reference laboratory for a standard sample of hair mercury COPHES (Consortium to Perform Human Biomonitoring on a European Scale) since 2011.
Esteban et al., Environ. Res. (IF2021: 8.431), 141, 24-30 (2015).

Research theme - Areas of work

Project Research

Basic Research Program

Work

Main research achievements
Externally-funded research
Main career history, academic history, academic degrees, awards, etc.

Born in Sasebo City, Nagasaki, Japan

  • Bachelor of Science (Faculty of Science, Kagoshima University)
  • →Master of Science (Graduate School of Science, Kagoshima University)
  • →Chief Scientist (Yoshitomi Pharmaceutical, currently Mitsubishi Tanabe Pharma Corporation)
  • →Doctor of Pharmacy (Graduate School of Pharmaceutical Sciences, Kyushu University)
  • →Senior Researcher (YRING, U.K., currently PsyRING)
  • →Chief, Physiology Section (National Institute for Minamata Disease)
  • →Chief, Pathology Section (National Institute for Minamata Disease)
  • →Chief, Toxicologic Pathology Section (National Institute for Minamata Disease)
  • →Director for Research General Coordination/ Director, Department of Basic Medical Sciences (National Institute for Minamata Disease)
  • →Chief Director for Research Planning/ Director for Research General Coordination/ Director, Department of Basic Medical Science (National Institute for Minamata Disease)
  • 2019-2021: Expert advisor to the 2019-2021 Grants-in-Aid for Scientific Research Committee (2-step documentary review, Basic Research B, related to the fields of hygiene and public health: including experimental systems)
  • 2019-: Standing Secretary, Biometals Specialty Section, Japanese Society of Toxicology
  • 2019-: Councilor, Japanese Society of Toxicology
  • 2018-: Steering Committee Member, International Conference on Mercury as a Global Pollutant
  • 2018-: Secretary, Biometals Specialty Section, Japanese Society of Toxicology
  • 2014-: Editorial Board Member, Fundamental Toxicological Sciences
  • 2008-2009: Visiting Professor (University of Bordeaux, France)
Press release

  1. Lessons from Minamata Disease. NHK World-Japan, Science view (2022). From the 1950s to the 1960s, Minamata Bay in Kumamoto Prefecture, located in the western part of Japan, was contaminated with organic mercury contained in wastewater from a factory, causing Minamata Disease. Now, the film MINAMATA starring Johnny Depp has once again brought this issue to global attention. In this episode of Science View, we will look back at what was going on inside the factory, based on an NHK program that contains testimonies of the employees of Chisso, the company responsible for Minamata Disease. Find out why the people working at the factory could not prevent the spread of the disease. Professor Yuki Morinaga of Meiji University, an expert in environmental studies, joins the program to look at the latest research on industrial pollution, share her discussions with her students on this topic, and to help us reexamine the lessons we should be applying to today's society.

    National Institute for Minamata Disease

  2. National Institute for Minamata Disease elucidated mechanism of neuronal cell death: excessive activation by methylmercury. Kumamoto Nichinichi Shimbun (2018). A research group led by Dr. Masatake Fujimura, Director of the Department of Basic Medical Sciences at the National Institute for Minamata Disease (NIMD, Minamata City), has confirmed that oxidative stress caused by methylmercury intake leads to excessive activation and necrosis of neurons in the deep cerebral cortex. The study was published in the Dutch journal "Neurotoxicology.” According to Dr. Fujimura, intake of methylmercury during fetal and childhood periods results in widespread brain damage, and in adults, neuronal cell death occurs intensively in the deeper parts of the cortex, which covers the surface of the cerebrum. It was already known that antioxidants were effective in reducing methylmercury toxicity, although its mechanism was unknown. In previous experiments, Dr. Fujimura and his colleagues confirmed that the effects of methylmercury intake on the cerebrum appear only in the deep part of the cortex. In the current study, they examined the relationship between methylmercury and cell death using cultured cells derived from human nerves. The results showed that the addition of methylmercury to cultured cells increased oxidative stress to about twice the normal level. This was followed by a 5-fold increase in the value of an index of cell activation, which then decreased to normal levels, followed by necrosis of the cells. “We have elucidated the mechanism by which oxidative stress causes neuronal cell death in the deep cerebral cortex,” said Dr. Fujimura.
  3. Cause of severe fetal Minamata disease partially elucidated, Kindai University. Asahi Shimbun Digital (2016). A research group at Kindai University announced on April 27 that they have clarified part of the reason why the symptoms of fetal Minamata disease are more severe than those in adults. Their findings suggest that methylmercury may slow the flow of fluid that fills the brain's crevices (ventricles), thereby preventing the movement of nerve cells needed to form the brain. The results were published in an international journal in the field of neurotoxicology. Fetal Minamata disease is caused when methylmercury contained in fish eaten by the mother enters the fetus. It was known that the symptoms were more severe than those in adults and that the brain was not formed properly in affected fetuses, but the detailed mechanism was unknown. Dr. Shigeru Yoshida, a former professor of neurophysiology at Kindai University, and his colleagues developed a device that allows them to observe thin-sliced brain tissue of mice while the cells are still alive. When they added methylmercury at concentrations that cause poisoning in humans, the movement of hairs growing on the surface of the ventricles weakened, and did not return to normal even after the methylmercury was removed. The fluid that fills the ventricles is circulated by the movement of these hairs to support the function of neurons, and in the fetus, this fluid also carries neurons to specific locations in the brain. Dr. Yoshida said, "The suppression of hair movement may prevent the brain from being completed, resulting in the development of severer symptoms.” Dr. Masatake Fujimura, chief of the Toxicologic Pathology Section at the National Institute for Minamata Disease, said, "Focusing on cells other than neurons is new from an academic standpoint. Whether this phenomenon actually occurs in the human body needs to be investigated in further studies.”
  4. Mysteries remain in Minamata disease: towards elucidating the process after mercury entrance into the brain and placenta. Nikkei (2016). In neurons, the axon, which extends from the center of the neuron and connects to other neurons, is first affected by methylmercury. This is because Rac1, a gene that elongates the nerve fiber in the axon, is suppressed, causing the nerve to fail to grow and die. A substance that preserves the function of Rac1 has been found, and research has begun to use this substance to improve the symptoms of Minamata disease. The research team developed rats that could continue to live while maintaining the symptoms of Minamata disease. Using these rats, "If neurons remain, it may be possible to restore axons. We would like to explore that possibility," said Dr. Masatake Fujimura, chief of the Toxicologic Pathology Section.
  5. A ray of hope for the birth of the first therapeutic drug for Minamata disease: therapeutic effect found in an existing glaucoma drug. Asahi Shimbun (2015). A study by the Ministry of the Environment's National Institute for Minamata Disease (NIMD, Minamata City, Kumamoto Prefecture) has found that an ingredient of a drug used to treat glaucoma may alleviate neurological symptoms unique to Minamata disease, such as numbness in the hands and feet. The government plans to support this research as a priority measure toward the creation of the first therapeutic drug for Minamata disease. Minamata disease is a neurological toxicosis caused by eating large amounts of seafood contaminated with methylmercury. The disease causes a variety of symptoms, including numbness in the hands and feet, sensory disturbance, and ataxia. With no curative treatment or medication available, patients have relied on rehabilitation and other conservative therapies to alleviate their symptoms. According to the NIMD, symptoms are caused by shrinkage of the cables (axons) that connect the cell bodies of nerves and transmit nerve signals. Methylmercury inhibits proteins that extend the cables of peripheral nerves, causing the cables to shrink and nerve transmission to fail, resulting in functional decline and eventual death of neurons.
  6. National Institute for Minamata Disease: Enzyme inhibitor as a potential treatment for sensory disturbance. Mainichi Shimbun (2014).
    The Ministry of the Environment's National Institute for Minamata Disease (NIMD) in Minamata City, Kumamoto Prefecture, announced on 8th that an enzyme inhibitor used in the treatment of subarachnoid hemorrhage shows promise for improving sensory disturbances observed in Minamata disease, such as numbness in the hands and feet. The enzyme inhibitor is likely to inhibit the harmful effects of methylmercury, the causative agent of Minamata disease, on neurons. NIMD plans to conduct clinical trials on this enzyme inhibitor as a treatment for Minamata disease in a 4-year plan. Dr. Masatake Fujimura, 50, chief of the Toxicologic Pathology Section at NIMD, and his colleagues made this discovery in animal experiments. In 2009, Dr. Fujimura and his colleagues published a paper showing that methylmercury causes shrinkage of axons, which are the protruding parts of neurons. They also demonstrated that when axons do not grow, neurons do not connect to each other and die. In a subsequent experiment, when rats exposed to methylmercury were treated with the enzyme inhibitor, the shrinkage of axons in peripheral nerves was suppressed. In an experiment using cultured cells, the same effect was seen in central nerves of the brain. The enzyme inhibitor is already in use as a drug to suppress the constriction of cerebral blood vessels after subarachnoid hemorrhage. NIMD will continue to study the administration method and other aspects of this drug so that it can also be applied to Minamata disease, and will seek cooperation from local medical associations and other parties to establish a system for conducting clinical trials. At the same time, they plan to conduct clinical studies to evaluate the effectiveness of state-of-art treatments for neurological diseases, mainly in patients with fetal or pediatric Minamata disease. For these projects, the Ministry of the Environment has included 23 million yen in its budget request for the next fiscal year. Dr. Fujimura said, "If neurons are alive, the combination of enzyme inhibitors and rehabilitation may be effective in reducing or improving neurological dysfunction.” With no curative treatment available, treatment for Minamata disease has been mainly symptomatic, including rehabilitation, hot spring therapy, and painkillers.
  7. Minamata disease symptoms can be alleviated by a cerebrovascular drug, confirmed by National Institute for Minamata Disease. Kumamoto Nichinichi Shimbun (2014).
    The National Institute for Minamata Disease (NIMD, Minamata City) announced on 8th that a therapeutic drug for subarachnoid hemorrhage may be effective in alleviating sensory disturbance, a symptom unique to Minamata disease. The institute has confirmed the effectiveness of the drug in animal experiments, and plans to further improve the experimental accuracy over the next 4 years starting in FY2015, aiming for clinical trials in patients. Treatment of Minamata disease symptoms has been mainly symptomatic, such as rehabilitation, and there has been no therapeutic drug, except for antidotes for the acute symptoms of the disease.
    The Ministry of the Environment has allocated a portion of the 23 million yen "research expenses for Minamata disease treatments" included in its budget request for the next fiscal year, for research on therapeutic drug development. As part of its future plans, the Ministry intends to seek cooperation from pharmaceutical companies and local medical community. According to Dr. Masatake Fujimura, 50, a neuropharmacologist and chief of the Toxicologic Pathology Section at the NIMD, methylmercury, the causative agent of Minamata disease, causes shrinkage of axons, which are part of neurons. This interferes with the transmission of nerve signals and causes the cells to die, resulting in the symptoms of Minamata disease, such as numbness in the hands and feet and difficulty walking. Dr. Fujimura noted that "ROCK inhibitor," a cerebrovascular therapeutic drug for subarachnoid hemorrhage, inhibit the generation of an enzyme (ROCK) that causes shrinkage of axons. He injected the inhibitor to rats experimentally exposed to methylmercury and noted that the shrinkage of axons in peripheral nerves was suppressed. In an experiment using cells, the same effect was seen in central nerves of the brain. Dr. Fujimura said, "We would like to improve the experimental accuracy with a view to conducting experiments using human neurons made from artificial stem cells.” Kazuhito Tsuruta, director of Junwakai Memorial Hospital (Miyazaki City), who has treated many Minamata disease patients, said, "This experiment is an important attempt that could lead to the treatment of Minamata disease. However, rats and humans differ in the areas of the nervous system affected by methylmercury. We hope that the researchers will be careful in determining whether the drug can be used in humans."
  8. Drug for subarachnoid hemorrhage may be effective in alleviating symptoms of Minamata disease. Kyodo News (2014).
    The National Institute for Minamata Disease (NIMD), Minamata City, Kumamoto Prefecture, announced on 8th that a therapeutic drug for subarachnoid hemorrhage may be effective in alleviating symptoms unique to Minamata disease, such as numbness in the hands and feet. The institute plans to conduct clinical trials on the drug within a few years, and expects to put it to practical use as the first treatment for Minamata disease. With no curative treatment available, treatment options for Minamata disease have been limited to rehabilitation therapy and the administration of painkillers. For this reason, the Ministry of the Environment has included 23 million yen in its FY2015 budget request for research expenses to strengthen therapeutic drug development. This drug, called a "ROCK inhibitor," has the characteristic of reducing the function of a specific protein. It is already in practical use as a treatment for subarachnoid hemorrhage.
  9. National Institute for Minamata Disease, Ministry of the Environment, to conduct clinical trials of the first therapeutic drug for Minamata disease: effective in reducing numbness. Nishinippon Shimbun (2014).
    The Ministry of the Environment's National Institute for Minamata Disease (NIMD, Minamata City, Kumamoto Prefecture) has confirmed in animal experiments that a therapeutic drug for subarachnoid hemorrhage is effective in reducing sensory disturbance (numbness in the hands and feet) unique to Minamata disease, which is caused by methylmercury. Treatment for Minamata disease has focused on symptom relief through rehabilitation, with no curative treatment available. The institute plans to conduct clinical trials of the drug on patients, and if the safety of the drug can be confirmed, it is expected to be applied to improving symptoms of the disease. This drug is an "enzyme inhibitor" that has already been in practical use as a cerebrovascular therapeutic drug for subarachnoid hemorrhage and is currently undergoing clinical trials as a therapeutic drug for glaucoma. Dr. Masatake Fujimura, a neuropharmacologist and chief of the Toxicologic Pathology Section at the NIMD, has confirmed the effectiveness of the drug. The Ministry of the Environment has included 23 million yen in its budget request for the next fiscal year for "research on treatment methods" and intends to allocate part of the amount to clinical trials of the drug. According to Dr. Fujimura, when people move their bodies, a part of neurons (nerve fibers) stretch to transmit signals to muscles, and methylmercury inhibits a protein that stretches nerve fibers, causing them to shrink. If the effects of methylmercury become severe enough, the neurons themselves will be damaged, resulting in symptoms specific to Minamata disease, such as sensory disturbance and difficulty walking. Dr. Fujimura noted that the enzyme inhibitor suppresses the function of another protein that causes nerve fibers to shrink. When the enzyme inhibitor was administered to rats exposed to methylmercury, nerve fibers of peripheral nerves, which are otherwise damaged by mercury toxicity, suffered almost no damage. In an experiment using cultured rat cells, the same effect was seen in central nerves of the brain. Therefore, the drug is expected to be effective not only for Minamata disease patients with relatively mild symptoms, but also for those with numbness in their hands and feet and other sensory disturbances who are eligible for relief under the Law for Relief of Minamata Disease Victims. Dr. Fujimura said, "The combination of the drug and rehabilitation is expected to provide greater improvement in symptoms. It will also be beneficial for victims in emerging countries where mercury pollution is serious. "The institute plans to recruit participants for clinical trials in the future. Dr. Kazuhito Tsuruta, a neurologist and the director of Junwakai Memorial Hospital (Miyazaki City), who has experience in treating many Minamata disease patients, said, "The research findings are commendable. Further experiments are needed to determine the effects of the drug not only on peripheral nerves, but also on the central nervous system."
  10. National Institute for Minamata Disease dispatches researchers to Guiana, a French territory in Latin America. Nishinippon Shimbun (2009).
  11. Mercury pollution in French Guiana, South America: confirmed by National Institute for Minamata Disease by hair analysis. Kumamoto Nichinichi Shimbun (2009).
  12. Methylmercury-induced cell death in the cerebral cortex: mechanism elucidated by Dr. Fujimura, chief of the National Institute for Minamata Disease; hopes for future therapeutic drug development. Mainichi Shimbun (2008).
    A part of the mechanism by which methylmercury, the causative agent of Minamata disease, causes the death of neurons in the cerebral cortex was revealed in a study conducted in rats by Dr. Masatake Fujimura, 44, chief of the Pathology Section at the National Institute for Minamata Disease (NIMD, Minamata City). The study included an experiment to prevent cell death, which may provide a clue for future therapeutic drug development to prepare for methylmercury pollution. However, it seems difficult at this point to apply the findings to the treatment of Minamata disease patients who have suffered from the disease for more than half a century since the official confirmation of the disease. The cerebral cortex is a layer of neurons that extends over the surface of the cerebrum and is responsible for perception and movement. Neurons consist of "dendrites," which surround a central cell body, and "axons," which extend from the cell body in the form of a string. Dr. Fujimura added methylmercury solution to neurons extracted from fetal rats and observed changes in the cells after 1 to 7 days. He noted that axons gradually disappeared before the entire cell died. He then identified the cause of axon disappearance and found that giving a reagent that blocks this process prevents its disappearance. However, once the concentration of methylmercury exceeded a certain level, the disappearance of axons could not be prevented, and once they disappeared, they could not be regenerated. Although several research papers have been published on the effects of methylmercury on the brain, particularly on cell death in the peripheral nerves and cerebellum, research on its effects on the cerebral cortex has not progressed. "We had a hard time showing the neuronal changes in a visible way. We are still in the stage of cell-based experiments, but we hope that the mechanisms we have uncovered will lead to clinical applications." said Dr. Fujimura. The research findings were presented at a forum hosted by the Division of Pharmaceutical Health Sciences and Environmental Toxicology of the Pharmaceutical Society of Japan, which was held in Kumamoto City for two days starting on 17th, and will be published in the U.S. medical journal Neurotoxicology.
  13. Hair mercury level of residents of French Guiana, South America, found 3 to 7 times higher than that of Japanese: National Institute for Minamata Disease conducts worldwide survey of mercury-contaminated areas. Yomiuri Shimbun (2008).
    The National Institute for Minamata Disease (NIMD, Minamata City, Japan) summarized the results of their survey on the effects of mercury pollution on the residents of affected areas in 8 countries around the world. The hair mercury levels in men and women in French Guiana in South America, where gold mining is active, were found to be about 3 and 7 times higher than the Japanese average, respectively, while the levels in other areas where gold mining is similarly active were lower. The fact that fish is eaten in Guiana but not so much in other areas led them to speculate that "the presence or absence of fish-eating habits may have something to do with this finding.” The institute has been monitoring mercury concentrations in rivers and soil in mercury-polluted areas around the world. Mercury is used in gold mines for refining, and its pollution of rivers and other waterways has become a problem, but the full picture of the health hazards associated with this pollution has not yet been revealed. For this reason, the institute began a survey in 2003 to understand the extent of the harm caused by mercury on a global scale. They asked researchers, environmental groups, and other parties in various countries to send them hair samples from residents in areas of concern. They collected hair from about 2,100 people in Guiana, Colombia, Indonesia, and Venezuela, which have gold mining areas; Kazakhstan, where mercury pollution from factories is a concern; and China, South Korea, and Benin, where people eat a lot of fish. In Guiana, a total of 269 people were surveyed for mercury levels. The average levels for males and females were 7.8 ppm and 9.5 ppm, respectively, which were much higher than those of the Japanese (2.7 ppm for males and 1.5 ppm for females). However, no one showed levels that reached the World Health Organization (WHO) threshold of 50 ppm for the possibility of developing mercury poisoning, with no apparent health hazards identified. The fact that in Guiana, people have the habit of eating fish and the percentage of those with methylmercury detected was high, led to the speculation that people were exposed to mercury by eating fish. In the other areas, the levels ranged from 0.4 to 2.6 ppm for both men and women. Dr. Masatake Fujimura, chief of the Pathology Section at the NIMD, said, "Mercury contamination from gold mining and factory emissions is a problem in many parts of the world, and there is concern about contamination of the local population. We would like to monitor the mercury levels of residents in areas where contamination is suspected and thereby contribute to raising awareness of this issue."