GENETIC TOXICITY IN BACTERIA AND RODENTS

细菌和啮齿动物的遗传毒性

基本信息

批准号：
8602490
负责人：
LES RECIO
金额：
$ 92.34万
依托单位：
INTEGRATED LABORATORY SYSTEMS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2012-12-31
项目状态：
已结题

项目摘要

The Genetic Toxicity Testing contract provides for the assessment of potential adverse genetic effects from exposure to compounds under study by the NTP. Testing systems employed include both in vitro (animal cell-based and bacterial) and in vivo (rats and mice) assays. Three main tests are conducted routinely: in vitro bacterial mutagenicity assays, in vivo rodent peripheral blood micronucleus (MN) assays, and in vivo rodent DNA damage (Comet) assays in multiple tissues. The MN assays now routinely collect data by flow cytometric analysis of prepared blood samples rather than by scoring slides. This innovation has provided greater ability to detect induced chromosomal damage and has improved the objectivity of the test, as well as the speed of data collection. MN and Comet assays are typically conducted with the same set of animals, thereby maximizing data collection from a single treated animal, reducing animal usage, and reducing costs. During the past fiscal year, 18 microbial mutagenicity assays and 26 in vivo micronucleus assays have been initiated or completed. Twelve in vivo Comet assays have been conducted in one or multiple tissues including blood, liver, kidney, stomach, colon, and brain. In addition, in vitro Comet assays have been conducted to compare DNA repair activities among several different cell lines in an effort to better understand the role of certain mutant genes associated with particular cancers. During the next fiscal year, additional emphasis is expected on in vitro measures of gene mutation and chromosomal damageso as to continue to reduce and refine our use of whole animal tests. During this past fiscal year, another animal mutation endpoint that holds promise for application in human clinical and biomonitoring studies in the future, has been investigated in the testing laboratory: the pig-a mutation assay (phosphatidylinositol glycan anchor biosynthesis, class A gene). Mutations in this gene are easily detected in red blood cell samples from laboratory rodents, and updated methods to streamline the assay have been developed, so that integration into existing toxicity tests can be more be accomplished. During the next fiscal year, we will attempt to multiplex this assay with the in vivo MN and Comet assays, increasing the genetic toxicity information that we obtain from test animals to provide an even more comprehensive profile of the genetic toxicity potential of a chemical.

遗传毒性测试合同规定评估因暴露于 NTP 正在研究的化合物而产生的潜在不利遗传影响。所采用的测试系统包括体外（基于动物细胞和细菌）和体内（大鼠和小鼠）测定。常规进行三项主要测试：体外细菌致突变性测定、体内啮齿动物外周血微核（MN）测定以及体内啮齿动物多个组织的DNA损伤（彗星）测定。 MN 检测现在通常通过对制备的血液样本进行流式细胞术分析而不是通过对载玻片进行评分来收集数据。这项创新提供了更强的检测诱导染色体损伤的能力，并提高了测试的客观性以及数据收集的速度。 MN 和 Comet 检测通常在同一组动物中进行，从而最大限度地收集单个接受治疗的动物的数据，减少动物使用并降低成本。在上一财年，已启动或完成了 18 项微生物致突变性测定和 26 项体内微核测定。已在一种或多种组织中进行了十二项体内彗星测定，包括血液、肝脏、肾脏、胃、结肠和脑。此外，还进行了体外彗星试验来比较几种不同细胞系之间的 DNA 修复活性，以便更好地了解与特定癌症相关的某些突变基因的作用。在下一财年，预计将更加重视基因突变和染色体损伤的体外测量，以继续减少和完善我们对整体动物试验的使用。在上一财年，另一个有望在未来应用于人类临床和生物监测研究的动物突变终点已在测试实验室进行了研究：猪-a突变测定（磷脂酰肌醇聚糖锚定生物合成，A类基因）。在实验室啮齿动物的红细胞样本中很容易检测到该基因的突变，并且已经开发出简化检测的更新方法，以便可以更好地集成到现有的毒性测试中。在下一财年，我们将尝试将该检测与体内 MN 和彗星检测结合起来，增加我们从测试动物中获得的遗传毒性信息，以提供化学物质遗传毒性潜力的更全面的概况。