Arsenic Embryotoxocity: Cellular and Molecular Targets

描述(由申请人提供) 砷是一种普遍存在的环境污染物，具有成人毒性 对人类的毒性和对实验动物的发育毒性。在出版期间 报告显示差异应变对诱发NTDS的敏感性 出生前暴露于砷的动物模型仍不清楚。因此， 有必要了解相互作用的潜在机制 发育过程中的砷和母体/胚胎基因型，以及 了解疑似人类发育毒物的机制， 如砷，与胚胎发育的关键方面相互作用。 这一点对于居住在 早期胚胎，并在器官发生的早期分化。 拟议的研究计划将调查发育危害 与砷暴露相关的遗传敏感的小鼠模型 其中叶酸结合蛋白Folbp1或Folb2已经失活。 初步分析表明，缺乏Flobps的动物表现出 砷致神经管畸形的产前风险增加。假设是 在本申请中检查的是一种异常的叶酸结合蛋白 基因型增加了砷诱导的NTDS的风险，而NTDS是导致的表型 其中与脑神经脊线基因的改变有关 表达式(即神经波峰函数)。通过Folbp基因敲除育种 从Wnt1-cre/loxP小鼠到Wnt1-cre/loxP小鼠，将会产生一种新的“复合”小鼠模型 它对砷诱导的NTDS具有“遗传敏感性”，在这种情况下 神经脊是(遗传的)不可磨灭的标记。这样的老鼠模型将 能够分析砷对神经脊形成、迁移的影响 以及在不同FolBP基因型条件下的增殖(特定目的 1)。此外，激光捕获显微切割术在神经外科的应用 Crest细胞)和DNA微阵列技术应用于这种动物模型 促进分离的神经脊“基因表达谱”的产生 神经管形态发生和砷致神经管畸形的条件 在不同FolBP基因型别的胚胎中(特异性目标2)。

DESCRIPTION (provided by applicant) Arsenic represents a ubiquitous environmental contaminant with adult toxicity in humans and developmental toxicity in laboratory animals. While published reports indicate differential strain sensitivity to induction of NTDs in animal models following prenatal arsenic exposure remain unclear. As such, the need exists to understand the mechanisms underlying interactions between arsenic and maternal/embryonic genotype during development, as well as understand the mechanisms by which suspected human developmental toxicants, such as arsenic, interact with critical aspects of embryonic development. This is particularly true regarding precursor cell populations which populate the early embryo and differentiate during early organogenesis. The proposed research program will investigate the developmental hazards associated with arsenic exposure in a genetically sensitive mouse model in which the folate binding proteins, Folbp1 or Folb2 have been inactivated. Preliminary analysis indicates that animals lacking Flobps demonstrate an increased prenatal risk for arsenic-induced NTDs. The hypothesis to be examined in the present application is that an abnormal folate binding protein genotype increases the risk for arsenic-induced NTDs, the resulting phenotype of which is associated with alterations in cranial neural crest gene expression (i.e. neural crest function). Through breeding of Folbp knockout mice to Wnt1-cre/LoxP mice, a novel "composite" mouse model will be generated which is "genetically sensitive" to arsenic induction of NTDs and in which the neural crest are indelibly (genetically) marked. Such a mouse model will enable analysis of the effects of arsenic on neural crest formation, migration and proliferation under conditions of differing Folbp genotypes (Specific Aim 1). In addition, the application of laser capture microdissection (of neural crest cells) and DNA microarray technologies to this animal model will facilitate generation of isolated neural crest "gene expression profiles" during neural tube morphogenesis and under conditions of arsenic-induced NTDs among embryos of differing Folbp genotypes (Specific Aim 2).