Murine strain sensitivity to cadmium teratogenesis

小鼠品系对镉致畸的敏感性

• 批准号: 6933344
• 负责人: MICHAEL David COLLINS
• 金额: $ 7.06万
• 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/6933344
• 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：（改编自申请人的摘要）：小鼠致畸，例如 许多生物医学科学，都有许多菌株差异的例子 有据可查。以前，在大多数情况下，这些基于基因型的 报告差异时没有采用系统方法来确定 导致反应变化的因素。该提议提出了遗传 描述 C57BL/6N 和 SWV 之间差异的方法 镉诱发的轴后前肢外指畸形（手指缺失）。 C57BL/6 小鼠对此缺陷高度敏感，而 SWV 小鼠则对此缺陷高度敏感。 相同剂量完全耐药。建议使用多态 微型卫星标记进行全基因组扫描或数量性状 位点分析将识别代表特定基因的染色体位点 造成这种致畸菌株差异的原因。随后的两次基因组扫描 将针对具有类似应变反应的致畸结果进行。一 在不同的妊娠时间使用相同的致畸剂（镉），并且其中一种 不同的药剂（全反式视黄酸）会诱导相同的效果 畸形。后面这些基因组扫描的目的是确定什么 造成共同菌株差异的基因在一定程度上是相同的。 将进行实验以确定镉是否进入胚胎或 胎盘在更大程度上存在敏感菌株，以及该菌株是否 不同之处在于金属硫蛋白（一种镉结合蛋白）。同类小鼠 将被生产并培育以进行多同生以检查相互作用 菌株易感性的基因。两个不同的基因被认为是 对镉对致畸、cdm 和 6 号染色体位点的敏感性很重要 标记为Cadfar，将作为前奏映射到基因组中的特定位置 来克隆这些基因。涉及九个基因的加性寡基因模型 已提出前肢缺陷的诱导。