Effects of Methylmercury on Neuronal Cell Migration

甲基汞对神经元细胞迁移的影响

• 批准号: 7663263
• 负责人: Hitoshi Komuro
• 金额: $ 31.79万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663263
• 关键词: Affect; Algae; Ataxia; Bacteria; Biological Models; Body Weight; Brain; Cerebellum; Cerebral Palsy; Cerebrum; Characteristics; Clinical; Control Groups; Convulsions; Cyclic AMP; Cyclic GMP; Data; Deformity; Development; Diffuse; Disasters; Dose; Dysarthria; Environment; Epidemiologic Studies; Exposure to; Fetus; Food Chain; Functional disorder; Gliosis; Goals; Growth; Human; Impairment; In Vitro; Infant; Intoxication; Iraq; Japan; Limb structure; Medical; Mental Retardation; Mercury; Methylmercury Compounds; Minamata Disease; Molecular; Motor; Mus; Myoepithelial cell; Nerve Degeneration; Neurologic; Neurons; Patients; Play; Poisoning; Process; Production; Public Health; Pyramidal Cells; Reactive Oxygen Species; Risk; Role; Signal Pathway; Signal Transduction; Symptoms; Syndrome; Testing; anthropogenesis; brain malformation; cell motility; fetal; granule cell; in vivo; insight; man; migration; nervous system disorder; neuron loss; neurotoxic; postnatal; prenatal; public health relevance; pup; sex; stellate cell; therapy development; white matter

DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a well-recognized neurotoxic agent that can affect the fetus. In the tragic disasters that took place at Minamata, Japan, and subsequently in Iraq, many infants were exposed transplacentally to MeHg. The victims manifested a cerebral palsy-like syndrome characterized by severe mental retardation, motor dysfunction, and repeated convulsions. Histological examination revealed widespread neuronal degeneration, abnormal arrangement of neurons in the cerebrum and cerebellum, and diffuse white matter gliosis in the brain of victims. Even now, MeHg is a major environmental problem, since it accumulates in the aquatic food chain and consequently creates a risk to the human brain, especially that of the fetus. The long-term goal of the present proposal is to elucidate the cellular and molecular mechanisms underlying MeHg-induced malformation of the brain. We will focus on the effects of MeHg on neuronal cell migration in the developing brain since it has been suggested that MeHg can disturb the process of neuronal cell migration. To this end, we will use the cerebellum as a model system because the effect of methylmercury on brain growth is marked in the cerebellum. We will determine the effects of MeHg on the migration of cerebellar neurons. First, we will determine how MeHg administration affects the migration in vivo and in vitro. Second, we will determine if MeHg alter migration by altering the Ca2+ signaling pathway. Third, we will determine if the interaction between the Ca2+, cAMP and cGMP signaling pathways synergistically alters the effects of MeHg on migration. Fourth, we will determine if the interaction between the Ca2+ signaling and the ROS production plays a crucial role in MeHg-induced impairment of migration. The fundamental mechanisms whereby MeHg administration leads to the disturbances of brain development have not been delineated definitively. Answers to the questions raised in this project will provide a new understanding as to how prenatal and early postnatal exposure to MeHg causes malformation of the brain. Lay Summary PUBLIC HEALTH RELEVANCE In the late 1950s, many infants born in Minamata of Japan developed characteristic neurological symptoms, including mental retardation and cerebral palsy. Later it has revealed that methylmercury (MeHg) induced congenital intoxication via the transplacental transfer of mercury to the fetus. The term fetal Minamata disease (FMD) was used to describe such medical phenomenon. The most characteristic symptoms of FMD are mental retardation, dysarthria, cerebellar symptoms (such as ataxia), and deformity of the limbs. Furthermore, histological studies revealed that in FMD disruption of the cerebral and cerebellar cytoarchitecture was prominent. Many neurons appeared to be hypoplastic, ectopic, dysplastic, and disoriented, strongly indicative of disrupted migration, maturation, and growth. Extensive neuronal loss occurred throughout the brain. MeHg exposure remains a major public health concern because of natural and anthropogenic release of inorganic mercury into the aquatic environment, where it is biotransformed by algae and bacteria into MeHg. This can pass along the food chain and, eventually, to man. The long-term goal of the present proposal is to reveal the cellular and molecular mechanisms underlying the MeHg-induced malformation of the brain. In particular, we focus on the study examining whether MeHg exposure impairs neuronal cell migration in the developing brain. The fundamental mechanisms whereby MeHg exposure leads to disturbances of brain development have not been delineated definitively. Answers to the questions raised in this project will provide insights for development of therapies that counter MeHg-induced brain malformation.

描述（由申请人提供）：甲基汞（MEHG）是一种良好认可的神经毒性剂，可以影响胎儿。在日本Minamata以及随后在伊拉克发生的悲惨灾难中，许多婴儿被移植到MEHG。受害者表现出一种脑瘫样综合征，其特征在于严重的智力低下，运动功能障碍和反复的抽搐。组织学检查显示，大脑和小脑中神经元的神经元异常排列以及受害者大脑中的弥漫性白质神经病。即使是现在，MEHG还是一个主要的环境问题，因为它在水生食物链中积累，因此会对人脑（尤其是胎儿的大脑）造成风险。本建议的长期目标是阐明MEHG诱导的大脑畸形的细胞和分子机制。我们将重点关注MEHG对发育中大脑中神经元细胞迁移的影响，因为已经提出MEHG可以干扰神经元细胞迁移的过程。为此，我们将使用小脑作为模型系统，因为甲基汞对脑生长的影响在小脑中标记。我们将确定MEHG对小脑神经元迁移的影响。首先，我们将确定MEHG给药如何影响体内和体外的迁移。其次，我们将通过改变Ca2+信号通路来确定MEHG是否改变了迁移。第三，我们将确定CA2+，CAMP和CGMP信号通路之间的相互作用是否协同改变MEHG对迁移的影响。第四，我们将确定Ca2+信号传导与ROS产生之间的相互作用是否在MEHG诱导的迁移损害中起着至关重要的作用。 MEHG给药导致大脑发育干扰的基本机制尚未得到明确描述。对该项目提出的问题的答案将为产前和早期产后对MEHG的暴露如何引起大脑畸形。在1950年代后期，摘要公共卫生相关性，许多在日本Minamata出生的婴儿出现了特征性的神经系统症状，包括智力低下和脑瘫。后来，它揭示了甲基信（MEHG）通过将汞移植向胎儿引起先天性中毒。胎儿米纳马塔病（FMD）一词用于描述这种医学现象。 FMD的最特征症状是智力低下，构音障碍，小脑症状（例如共济失调）和四肢畸形。此外，组织学研究表明，在FMD中断，大脑和小脑的细胞结构是突出的。许多神经元似乎是异常，异位，异型症和迷失方向的，强烈指示迁移，成熟和生长的破坏。整个大脑中发生了广泛的神经元丧失。 MEHG暴露仍然是一个主要的公共卫生关注点，因为无机汞的天然和人为释放到水生环境中，藻类和细菌将其生物转化为MEHG。这可以沿着食物链，最终传递给人类。本提案的长期目标是揭示MEHG诱导的大脑畸形的细胞和分子机制。特别是，我们专注于研究MEHG暴露是否会损害发育中大脑中的神经元细胞迁移。 MEHG暴露会导致大脑发育干扰的基本机制并未确切地描述。对该项目提出的问题的答案将为反对MEHG引起的大脑畸形的疗法的发展提供见解。