Perinatal Methylmercury Targets Hippocampal Stem Cells, and Reduces Neurogenesis

围产期甲基汞以海马干细胞为目标，并减少神经发生

基本信息

批准号：
8338426
负责人：
Emanuel Murray DiCicco-Bloom
金额：
$ 16.76万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-22 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8338426
关键词：
Adolescent Adult Affect Age Animals Apoptosis Behavior Behavioral Biochemical Genetics Biological Models Brain Bromodeoxyuridine Cell Count Cell Death Cells Cerebral Palsy Chronic Data Detection Development Environmental Exposure Environmental Risk Factor Event Exhibits Exploratory/Developmental Grant Fetus Generations Glial Fibrillary Acidic Protein Goals Hippocampus (Brain)Hour Injection of therapeutic agent Iraq Label Lead Learning Light Memory Mental Retardation Methylmercury Compounds Mitosis Modeling Molecular Mothers Neuroglia Neurons Neurotoxins Newborn Infant Organ Perinatal Perinatal Exposure Population Production Rattus Sample Size Seizures Stem cells Structure System Teratogens Time Toxic effect Work base caspase-3 cell type cellular targeting dentate gyrus design injured killings malformation morris water maze nerve stem cell nestin protein neurogenesis neuron loss novel postnatal research study response stem cell population toxicant

项目摘要

DESCRIPTION (provided by applicant): Methylmercury (MeHg) is a widespread and persistent environmental factor that adversely affects the developing brain, which is far more sensitive than the adult organ. From previous poisonings, we know that exposure of the developing fetus in the mother to MeHg can cause severe consequences, from mental retardation to seizures and malformations, many times without harming the mother. However, there are concerns that more subtle exposures may harm the developing brain, altering learning and memory, for which the hippocampus is critical. In previous work, we found that exposing postnatal rats to moderate levels of MeHg rapidly impaired production of neurons and later produced deficiencies in hippocampal structure and function. We have now discovered that hippocampal neural stem cells, that produce neurons and glia, are exquisitely sensitive to MeHg, which causes them to die within hours. We now plan to define the lowest levels of MeHg that can cause stem cell death, and define its relationship to later loss of neurons and memory functions. In Aim 1 we will define how little MeHg in newborn rats can cause stem cell death, and identify which of several stem cell types are affected. Subsequently, 2 weeks later, we will count total number and types of neurons and glia to see whether killing precursors leads to later losses of specific populations of hippocampal cells, as we see with higher exposures. In Aim 2, we will determine whether lower exposures and losses of cells can impact learning and memory of the animals at 4 weeks of age. When complete, these studies will identify a new, highly sensitive target of MeHg, hippocampal stem cells, and will establish a novel model system. By focusing on the stem cells, rather than simply the whole brain organ as is frequently done, we may detect toxic effects of environmental factors that are otherwise missed. Or we may find that levels of known factors, like MeHg, thought to be safe, may actually have previously unrecognized harmful effects. This model system offers the possibility of defining the temporal sequence of molecular and cellular events that lead to subtle structural and functional changes in the brain during a critical window of developmental vulnerability. This information may shed light on the ways environmental exposures can impair learning and memory.

描述（由申请人提供）：甲基汞（MEHG）是一种广泛而持久的环境因素，对发展中的大脑产生不利影响，这比成人器官更敏感。从以前的中毒中，我们知道，母亲在母亲中的胎儿暴露会导致严重的后果，从智力低下到癫痫发作和畸形，而无需伤害母亲。但是，人们担心更微妙的暴露可能会损害发展中的大脑，改变学习和记忆，海马至关重要。在先前的工作中，我们发现将产后大鼠暴露于中等水平的MEHG迅速受损神经元的产生，后来导致海马结构和功能缺乏。我们现在发现，产生神经元和神经胶质的海马神经干细胞对MEHG非常敏感，这会导致它们在数小时内死亡。现在，我们计划定义可能导致干细胞死亡的最低水平的MEHG，并定义其与后来神经元和记忆功能的丧失的关系。在AIM 1中，我们将定义新生大鼠中的MEHG很少会导致干细胞死亡，并确定几种干细胞类型中的哪些受到影响。随后，2周后，我们将计算神经元和神经胶质的总数和类型，以查看杀死前体是否会导致海马细胞特定人群的后来损失，就像我们看到的较高的暴露情况一样。在AIM 2中，我们将确定较低的细胞暴露和损失是否会影响4周龄时动物的学习和记忆。完成后，这些研究将确定MEHG，海马干细胞的新型，高度敏感的靶标，并将建立一种新型的模型系统。通过专注于干细胞，而不是像经常进行的整个脑器官一样，我们可能会发现环境因素的有毒作用，否则这些因素被遗漏了。或者我们可能会发现，诸如MEHG这样的已知因素被认为是安全的，实际上可能没有识别出有害影响。该模型系统提供了定义分子和细胞事件的时间序列的可能性，在发育脆弱性的临界窗口中，大脑中的细微结构和功能变化。这些信息可能会阐明环境暴露会损害学习和记忆的方式。