Fetal Minamata Disease Research Articles

The role of calcium and cyclic nucleotide signaling in cerebellar granule cell migration under normal and pathological conditions.

In the developing brain, immature neurons migrate from their sites of origin to their final destination, where they reside for the rest of their lives. This active movement of immature neurons is essential for the formation of normal neuronal cytoarchitecture and proper differentiation. Deficits in migration result in the abnormal development of the brain, leading to a variety of neurological disorders. A myriad of extracellular guidance molecules and intracellular effector molecules is involved in controlling the migration of immature neurons in a cell type, cortical layer and birth-date-specific manner. To date, little is known about how extracellular guidance molecules transfer their information to the intracellular effector molecules, which regulate the migration of immature neurons. In this article, to fill the gap between extracellular guidance molecules and intracellular effector molecules, using the migration of cerebellar granule cells as a model system of neuronal cell migration, we explore the role of second messenger signaling (specifically Ca(2+) and cyclic nucleotide signaling) in the regulation of neuronal cell migration. We will, first, describe the cortical layer-specific changes in granule cell migration. Second, we will discuss the roles of Ca(2+) and cyclic nucleotide signaling in controlling granule cell migration. Third, we will present recent studies showing the roles of Ca(2+) and cyclic nucleotide signaling in the deficits in granule cell migration in mouse models of fetal alcohol spectrum disorders and fetal Minamata disease.

Cerebellar Abnormalities Typical of Methylmercury Poisoning in a Fledged Saltmarsh Sparrow, Ammodramus caudacutus

A fledged, 12-15day-old saltmarsh sparrow, Ammodramus caudacutus, was collected from an accidental kill on Cinder Island, Long Island, NY, USA. The sparrow was assessed for feather mercury levels and the brain analyzed for cerebellar abnormalities by microscopic examination. In humans, fetal Minamata disease is caused by maternal ingestion of mercury. It is characterized by disrupted and disordered cerebellar neuronal migration in the fetus or infant. Results from this sparrow show cerebellar abnormalities typical of Minamata disease. It is the first known avian or mammalian specimen taken from the wild to show the abnormalities typical of the human fetal syndrome.

Rescue of neuronal migration deficits in a mouse model of fetal Minamata disease by increasing neuronal Ca2+spike frequency

In the brains of patients with fetal Minamata disease (FMD), which is caused by exposure to methylmercury (MeHg) during development, many neurons are hypoplastic, ectopic, and disoriented, indicating disrupted migration, maturation, and growth. MeHg affects a myriad of signaling molecules, but little is known about which signals are primary targets for MeHg-induced deficits in neuronal development. In this study, using a mouse model of FMD, we examined how MeHg affects the migration of cerebellar granule cells during early postnatal development. The cerebellum is one of the most susceptible brain regions to MeHg exposure, and profound loss of cerebellar granule cells is detected in the brains of patients with FMD. We show that MeHg inhibits granule cell migration by reducing the frequency of somal Ca(2+) spikes through alterations in Ca(2+), cAMP, and insulin-like growth factor 1 (IGF1) signaling. First, MeHg slows the speed of granule cell migration in a dose-dependent manner, independent of the mode of migration. Second, MeHg reduces the frequency of spontaneous Ca(2+) spikes in granule cell somata in a dose-dependent manner. Third, a unique in vivo live-imaging system for cell migration reveals that reducing the inhibitory effects of MeHg on somal Ca(2+) spike frequency by stimulating internal Ca(2+) release and Ca(2+) influxes, inhibiting cAMP activity, or activating IGF1 receptors ameliorates the inhibitory effects of MeHg on granule cell migration. These results suggest that alteration of Ca(2+) spike frequency and Ca(2+), cAMP, and IGF1 signaling could be potential therapeutic targets for infants with MeHg intoxication.

Long-term exposure to methylmercury and psychiatric symptoms in residents of Minamata, Japan

IntroductionIt is well-known that prenatal or postnatal exposure to methylmercury can produce neurological signs in adults and children, exemplified by a case of large-scale poisoning in Minamata, Japan, in the 1950s. However, evidence regarding whether pre- or postnatal exposure to methylmercury causes psychiatric symptoms (e.g., impairment of intelligence and mood and behavioral dysfunction) is still limited—excluding cases of fetal Minamata disease patients. MethodsWe evaluated the effects of pre- or postnatal exposure to methylmercury on psychiatric symptoms using data derived from a 1971 population-based survey in Minamata and neighboring communities. We adopted residential areas as an exposure indicator and psychiatric symptoms as the outcome. Then, we estimated the adjusted prevalence odds ratio (POR) and confidence interval (CI) of psychiatric symptoms in relation to residential area. ResultsThere were 904 participants in Minamata (high exposure area), 1700 in Goshonoura (middle exposure area), and 913 in Ariake (low exposure area). Compared to the Ariake area, participants in the Minamata area manifested psychiatric symptoms more frequently: PORs for impairment of intelligence and mood and behavioral dysfunction were 5.2 (95% CI: 3.7–7.3) and 4.4 (95% CI: 2.9–6.7), respectively. Furthermore, participants with psychiatric symptoms in the Minamata area more frequently had neurological signs. Peaks in prevalence of psychiatric symptoms occurred around age 20 and in older age adults in the area. These findings did not change when we excluded those who had been officially certified as Minamata disease patients by that time. ConclusionsThe present study suggests a relationship between pre- or postnatal exposure to methylmercury and psychiatric symptoms among the general population in Minamata even after excluding officially certified patients.

Neurophysiological evidence of methylmercury neurotoxicity

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. The reports addressing both neurophysiological measures and methylmercury exposure in humans were identified and evaluated. 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. 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.

On the exacerbation of the symptoms of fetal Minamata disease patients An urgent proposal of the urgent follow-up study for the urgent follow-up study for the victims by environmental health hazards (Kogai)

On the exacerbation of the symptoms of fetal Minamata disease patients An urgent proposal of the urgent follow-up study for the urgent follow-up study for the victims by environmental health hazards (Kogai)

Migration of granule neurons in cerebellar organotypic cultures is impaired by methylmercury

To examine whether abnormal migration of granular cells in the external granule layer during cerebellar development is in part of the etiology of fetal Minamata disease, organotypic culture of rat cerebellar slice was established. Migration of external granule cells pulse-labeled with bromodeoxyuridine (BrdU) toward the internal granular layer was inhibited by the presence of methylmercury (0–10 μM) in a dose-dependent manner. Nuclear condensation and DNA fragmentation visualized by the indirect immunofluorescence method with anti-BrdU antibody and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method indicated that a large fraction of cells in the external granular layer underwent apoptotic death in the slices treated with 10 μM methylmercury. Thus, methylmercury inhibits the migration of cerebellar granule cells in a model system for neural development. The impaired migration was a possible cause of the apoptotic death of external granule cells.

Ultrastructural changes of human sural nerves in the neuropathy induced by intrauterine methylmercury poisoning (so-called fetal Minamata disease)

Biopsy of the sural nerve was performed on three patients with severe Minamata disease of more than 10 years duration. There were so many unmyelinated and poorly myelinated nerve fibers that myelinated fibers scattered irregularly in small numbers or in groups of peculiar features in the intraneural bundle. Abnormaly thin or poorly formed myelin sheaths were noticed. Incomplete myelination and abnormal myelination varied in size and shape appeared as fetal anomaly. Regenerated axons extremely small in size remained singly or in groups following regenerative sprouting. Sometimes, extremely small axons with normal myelination were noticeable, while the axons were lost, leaving myelin sheaths. Axons occasionally contained increased neurofilaments. Schwann cells were not so increased as in adult Minamata disease. Degenerative changes of nerve fibers still proceeded, presumably because the patients lived in the mercury-contaminated district. Myelin degenerations and glycogen deposits in the axoplasm were identified.

水俣地区における人歯牙含有水銀量に関する研究

The mercury materials concern as environmental pollution. Ikejiri, et al (1971) and Aoki reported the oral symptoms of the fetal Minamata Disease. The dental profession used mercury about 4% of the total amount used in the U.S.. The hazards of health have brought in dental office and its auxiliary. Under these situation, the mercury content in human teeth couldn't contact untill Kitamura and Kusaba (1975) used the non-flame atomic absorption spectrophotometer. In this report the mercury concentration was studied in the Minamata Area, which reduced ramdomly. 1. The mercury concentration in normal teeth at Minamata and control area showed no significant difference. 2. The mercury concentration in the age group of forties was significantly higher than that of twenties. 3. The teeth-age was defined as the term after the eruption. The teeth-age of thirty which were erupted during the Chisso plants increasing the production were higher level of mercury than the teeth-age of twenty that of after the World War II. 4. The mercury level in dentine carried the some correlation between the mean concentration of the teeth-age. 5. Kitakyushu, et al and Minamata were situated under the same environmental condition because the mean level of the teeth-age had almost same transition. The Minamata Disease could be reconsidered from the causal point of views. 6. The mercury concentration in normal adult teeth with the Minamata Disease reached slightly higher than that of healthy person. 7. The four degree of caries indicated higher level of mercury concentration which was caused from enamel substance. The enamel of caries could suggest the oral hygine situation. The mecury level was analyzed in each group. The term of teeth-age reveals the retrospective mercury level in person and the environmental condition.

歯牙発生過程の口腔領域における塩化メチル水銀-^<203>Hg の組織細胞内分布とその推移

Distribution of methylmercury in tissue cells in dental fields of adult and fetal rats during the process of dental development and its time course change were compared and the following results were obtained. 1. Many tissues and cells in the oral cavity could be exposed to methylmercury in various degrees. 2. Intongue, relatively intense deposition of methylmercury was noted in the mucous membrane of the tip and body of the tongue and in the lingual muscles. Especially in the former, the mechanism of excretion of methylmercury along with epithelial desquamation was suggested. 3. Among the perioral tissues, the deposition was not as intense in the epidermis as in lingual mucous membrane, but deposition and accumulation of methylmercury was noted in the hair. In the muscle tissues of the same portion, the deposition was almost as intense as in the lingual muscle. 4. In the parotid gland, marked deposition was noted in the glandular cells and ducts in the initial period of administration. This was followed by a rapid decrease as time progressed. An excretory mechanism via the saliva is suggested indicating recontamination in the oral cavity. 5. The dental tissues of mature rats showed the lowest mercury uptake among the tissues studied. 6. Tissues and cells in the process of dental development, on the other hand, readily take up methylmercury. The main findings included the following : 1) Intense deposition is generally seen in the epidermal tissues of ectodermal origin in the lamina-shaped stage and bud-shaped stage. Along with the formation of the enamel organ, intense deposition is seen in the inner enamel epithelial cells. 2) In tissues of mesodermal origin, marked deposition of methylmercury was noted in the tissue cells of mesenchymal nature along with formation of the dental papilla, and a considerable uptake was noted in the odontoblasts. 7. Through each period of dental development, such findings of deposition of methylmercury gives a suggestion on the pathogenesis of dental developmental anomaly in patients with fetal Minamata disease.