Murine strain sensitivity to cadmium teratogenesis

小鼠品系对镉致畸的敏感性

• 批准号: 6518176
• 负责人: MICHAEL David COLLINS
• 金额: $ 30.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518176
• 关键词: binding proteins; cadmium; chemosensitizing agent; chromosomes; congenital disorders; developmental genetics; embryo /fetus cell /tissue; environmental toxicology; gene environment interaction; gene expression; gene induction /repression; genetic disorder; genetic regulation; genetic strain; genome; genotype; laboratory mouse; limbs; metallothionein; molecular cloning; placenta; postnatal growth disorder; quantitative trait loci; retinoate; teratogens

DESCRIPTION: (Adapted from the Applicant's Abstract): Mouse teratogenesis, like many biomedical sciences, has numerous instances where strain differences are well documented. Previously, in a majority of cases, these genotype-based differences were reported without a systemic approach for determining the factors causing the variability in response. This proposal suggests a genetic approach to characterizing the difference between the C57BL/6N and the SWV strains to cadmium-induced postaxial forelimb ectrodactyly (missing digits). The C57BL/6 mouse is highly sensitive to this defect while the SWV mouse at the same dose is totally resistant. It is suggested that the use of polymorphic micro satellite markers to perform a whole genome scan or quantitative trait locus analysis will identify chromosomal loci representative of specific genes responsible for this teratogenic strain difference. Two subsequent genome scans will be performed for teratogenic outcomes with a similar strain response. One with the same teratogen (cadmium) at a different gestational time and one in which a different agent (all-trans-retinoic acid) induces the same malformation. The goal of these latter genome scans is to determine to what extent the genes responsible for the common strain difference are the same. Experiments will be performed to determine if cadmium gets to the embryo or placenta to a greater extent in the sensitive strain, and whether the strains differ in terms of metallothionein, a cadmium-binding protein. Congenic mice will be produced and then bred to make polycongenics to examine the interaction of genes in strain susceptibility. Two different genes that are thought to be important in cadmium-sensitivity to teratogenesis, cdm and a chromosome 6 locus labeled Cadfar, will be mapped to specific locations in the genome as a prelude to cloning these genes. An additive oligogenic model involving nine genes for the induction of the forelimb defect has been proposed.

描述：(改编自申请者摘要)：小鼠畸形，如 许多生物医学科学，都有许多菌株差异是 有据可查。以前，在大多数情况下，这些基于基因的 报告的差异没有系统的方法来确定 造成反应变化性的因素。这一建议表明，基因 关于C57BL/6N与SWV区别的探讨 菌株对镉诱导的后肢前肢缺指(缺指)。 C57BL/6小鼠对这一缺陷高度敏感，而SWV小鼠在 同样的剂量是完全耐药的。建议使用多态 执行全基因组扫描或数量性状的微卫星标记 基因座分析将识别代表特定基因的染色体基因座 造成这种致畸菌株差异的原因。随后的两次基因组扫描 将对具有类似菌株反应的致畸结果进行检测。一 同一致畸因素(镉)在不同的怀孕时间和一年内 哪一种不同的药剂(全反式维甲酸)可以诱导出相同的结果 畸形。后一种基因组扫描的目标是确定 在一定程度上，导致共同菌株差异的基因是相同的。 将进行实验以确定镉是否进入胚胎或 胎盘在更大程度上属于敏感菌株，而该菌株是否 不同的是金属硫蛋白，一种镉结合蛋白。同源基因小鼠 将被产生，然后被培育成多基因来检验相互作用 基因在菌株敏感性中的作用。两种不同的基因被认为是 在镉致畸敏感性中的重要作用，CDM和6号染色体基因座 标记为CadFar的基因将被映射到基因组中的特定位置作为前奏 克隆这些基因。一种涉及9个基因的加性寡核苷酸模型 提出了前肢缺陷的诱因。