Identifying And Evaluating Sources Of Variability In Rodent Studies

识别和评估啮齿动物研究中变异的来源

基本信息

批准号：
8929719
负责人：
grace e kissling
金额：
$ 5.58万
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

We contributed to several mouse studies of the role of genetic differences in responses to environmental agents. Compared to normal mice, we found that mice that express higher levels of the NAG-1 gene (nonsteroidal anti-inflammatory drug-activated gene, an anti-cancer gene) have a less body fat. In addition, the NAG-1 mice have less inflammation when exposed to a systemic inflammatory agent, lipopolysaccharides (LPS). This lower body fat and inflammation response may help explain the mechanism for why these mice also have lower rates of cancer. In another mouse study, we compared normal mice to mice lacking one of the estrogen receptors. The mice lacking the estrogen receptor tend to be less fertile than normal mice, but the mechanism for the reduced fertility is not known. We found that among the organs involved in fertility, only the ovaries are affected by absence of the receptor and that they do not produce adequate levels of hormones to stimulate ovulation. In addition to these studies of genetic differences, we also investigated a new assay of a functional aspect of mitochondria (mitochondrial respiration) using rat liver. Because mitochondria provide energy to the cell, it is important that its function is not impaired by environmental agents. We evaluated this assay using known inhibitors of mitochondrial function, along with a range of perfluoroalkane chemicals. We were able to show that mitochondrial respiration was greatly reduced by known inhibitors, indicating that the assay was operating well, and that respiration was differentially affected by the perfluoroalkane chemicals in a manner associated with their molecular size and composition. Finally, we studied behavioral differences between male and female rats that were treated with estrogenic compounds during gestation and after birth until weaning. There were a number of behavioral and physical effects of these compounds, with females more affected than males.

我们为遗传差异在对环境药物反应中的作用的作用做出了贡献。与正常小鼠相比，我们发现表达较高水平的NAG-1基因（非甾体抗炎药激活基因，抗癌基因）的小鼠的体内脂肪较小。另外，当暴露于系统性炎症剂脂多糖（LPS）时，NAG-1小鼠的炎症较少。这种下半身脂肪和炎症反应可能有助于解释为什么这些小鼠的癌症发生率也较低的机制。在另一项小鼠研究中，我们将正常小鼠与缺乏雌激素受体之一的小鼠进行了比较。缺乏雌激素受体的小鼠往往比正常小鼠肥沃，但尚不清楚生育能力的机制。我们发现，在涉及生育能力的器官中，只有卵巢不受受体的影响，并且不会产生足够水平的激素来刺激排卵。除了这些遗传差异的研究外，我们还研究了使用大鼠肝脏的线粒体功能方面（线粒体呼吸）的新测定。由于线粒体为细胞提供能量，因此重要的是，其功能不会受到环境剂的损害。我们使用已知的线粒体功能抑制剂以及一系列全氟烷化学物质评估了该测定法。我们能够表明，已知抑制剂大大降低了线粒体呼吸，表明该测定法的运行良好，并且呼吸受到与分子大小和组成相关的方式受到全氟烷烷化学物质的差异影响。最后，我们研究了男性和雌性大鼠之间在妊娠期间和出生后用雌激素化合物治疗的男性和雌性大鼠之间的行为差异。这些化合物有许多行为和物理作用，女性比男性更受影响。