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CHROMIUM DISTRIBUTION AND TOXICITY IN MAMMALIAN CELLS

哺乳动物细胞中铬的分布和毒性

基本信息

批准号：
3420167
负责人：
EDWIN M UYEKI
金额：
$ 11.9万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-09-01 至 1991-08-31
项目状态：
已结题

项目摘要

We will examine chromium distribution and genotoxicity by doing a systematic morphometric analysis of in vivo chromium toxicity in the liver, lung, kidney of mice injected with chromium. To date, in vivo studies have looked mainly for tumor induction at the sites of administration and have characterized chromium- induced malignancies at the level of the whole organ. Our research approach to the study of in vivo Cr effects will be the use of an innovative CAM (Computer-Assisted Microscopy) system to quantify changes in individual cells, as analyzed by cytochemical, histological, and radioautographic assays. Our in vitro findings led us to hypothesize that the chromium-sensitive cells are on the order of One Cell Among Many (OCAM), and that the ability to quantify individual cells was critical. With the computer's precision, speed, and memory, we can experimentally define and quantify Cr effects on individual cells (particularly, nuclei). Chromium genotoxicity, in vivo, will be studied systematically using the following research approaches: 1) To study acute and chronic toxic effects on the liver, lung, and kidney (with liver being the prototype organ) after chromium administration, using CAM-enhanced morphometric analysis. Acute toxicity studies will provide the basis for chronic studies. 2) To measure Cr distribution in tissues, using radioautographic and histochemical techniques augmented by the CAM system, to quantify Cr- binding in the nucleus and cytoplasm of individual cells. 3) To develop and verify other CAM-enhanced techniques to characterize nuclear or genomic changes in single cells: a) in situ hybridization, using mouse cDNA probes; b) textural analysis of nuclei obtained from different cellular states to characterize cell death (apoptosis and necrosis); c) electrophoresis/high performance liquid chromatography of chromatin components to characterize cell death. 4) The ultimate goal of our research is to correlate the findings of the chromium organ toxicity and distribution studies. With the CAM-stored database on chromium-induced changes, we will generate cell archetypes of liver, kidney and lungs, which have been sorted by treatment interval and dosage.

我们将通过以下方式检查铬的分布和遗传毒性：体内铬毒性的系统形态计量学分析在注射铬的小鼠的肝、肺、肾中。到迄今为止，体内研究主要着眼于肿瘤诱导，给药部位并对铬进行了表征- 在整个器官水平上诱发恶性肿瘤。我们研究体内铬效应的研究方法将是使用创新的CAM（计算机辅助显微镜）系统来量化单个细胞的变化，如通过细胞化学、组织学和放射自显影测定。我们在体外研究结果使我们假设，细胞是多细胞中的一个细胞（OCAM）的数量级，并且量化单个细胞的能力至关重要。与计算机的精度、速度和内存，我们可以通过实验确定和量化Cr对单个细胞的影响（尤其是核）。将系统研究铬的体内遗传毒性采用以下研究方法：1）研究急性和对肝、肺和肾的慢性毒性作用（包括肝作为原型器官）给药后，使用 CAM增强的形态测定分析。急性毒性研究将为长期研究提供基础。 2)测量Cr 组织中的分布，使用放射自显影和组织化学通过CAM系统增强的技术，以量化Cr- 结合在单个细胞的细胞核和细胞质中。 3)到开发和验证其他CAM增强技术，表征单细胞中的核或基因组变化：原位杂交，使用小鼠cDNA探针; B）结构分析从不同的细胞状态获得的细胞核来表征细胞死亡（凋亡和坏死）; c）电泳/高染色质组分的高效液相色谱法，表征细胞死亡。 4)我们研究的最终目标是将铬器官毒性的发现与分布研究。在CAM存储的数据库打开时，铬诱导的变化，我们将产生细胞原型，肝、肾和肺，按治疗分类间隔和剂量。