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 以及实验动物的发育毒性。 虽然出版了 报告指出，不同的应变敏感性，以诱导NTDs， 产前砷暴露的动物模型尚不清楚。 因此，在本发明中， 需要了解它们之间相互作用的机制， 砷和母体/胚胎基因型在发展过程中，以及 了解疑似人类发育毒物的机制， 例如砷，与胚胎发育的关键方面相互作用。 这对于前体细胞群体尤其如此， 早期胚胎和早期器官分化。 拟议的研究计划将调查发展的危险 与遗传敏感小鼠模型中的砷暴露相关， 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 增加砷诱导NTDs的产前风险。 假设是 在本申请中检查的是异常叶酸结合蛋白 基因型增加了砷诱导的NTDs的风险， 其中与颅神经嵴基因的改变有关 表达（即神经嵴功能）。 通过Folbp敲除育种 小鼠到Wnt1-cre/LoxP小鼠，将产生新的"复合"小鼠模型 它对砷诱导NTDs是"遗传敏感的"， 神经嵴是不可磨灭的（遗传）标记。 这样的小鼠模型将 能够分析砷对神经嵴形成、迁移 和在不同Folbp基因型的条件下增殖（特异性目的 1）。此外，激光捕获显微切割（神经 嵴细胞）和DNA微阵列技术应用于该动物模型将 促进产生分离的神经嵴"基因表达谱" 在神经管形态发生和砷诱导的NTDs条件下 在不同Folbp基因型的胚胎中（特定目标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).