MECHANISMS OF TOXIC CHEMICAL INTERACTION IN THE LIVER--HEPATOTOXICITY

肝脏中有毒化学相互作用的机制——肝毒性

• 批准号: 6217699
• 负责人: Ruth E Billings
• 金额: $ 14.74万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6217699
• 关键词: Kupffer's cell; arsenic; benzene; biomarker; cancer risk; chloroform; chromium; hepatotoxin; laboratory rat; lead; liver; liver cells; macrophage; mixed tissue /cell culture; phenols; physical chemical interaction; polymerase chain reaction; trichloroethylene

This project will utilize 5-chemical mixture, which models groundwater contamination, to explore interactions among metals and organics in the induction of stress response proteins such as metallothionein, heme oxygenase, and nitric oxide synthase, and the induction of inflammatory cytokines (i.e. tumor necrosis factor-alpha, interleukin-`1, and interleukin-6). These cytokines ar associated with both liver injury and induciton of these same stress response proteins. The focus of the project is on delineating mechanisms of interactions. The rationale for the experimental plan is based upon the hypothesis that induction of these genes will influence the toxicity of components int he mixture and can be used as sensitive indicators of chemical exposure. We postulate that interactions betweeen chemicals which occur in the stress response will mimic toxic interactions. However, alterations in gene expression will occur at lower doses and with shorter duration exposure than overt toxicity is detected. The chemical mixture used for these studies is also being investigated in Projects 1 and 2 and the mechanistic information obtained in this project 3 will pertain to all 3 projects while the mixture contains metals (chromium, lead, arsenic) and organics benzene, and phenol, we will initially concern are on the metals. Chemical interactions and interactions with endogenous mediators (cytokines) will be determined in liver cells obtained from rats treated in vivo (Specific Aim 1) and in ok 49 (Specific Aim 2). In Specific Aim 3, Differential Display Polymerase Chain Reaction technology and transcription factor activation studies will be conducted in order to determine the profile of stress response genes which are differentially expressed in liver cells from rats treated with chemical mixtures. Throughout this project, both a TOP-DOWN and a BOTTOM- UP approach will be utilized. That is, single chemicals will be investigated as well as the chemical mixtures. This will be followed by combining single chemicals into 2-[component, 3-component mixtures, and also fractionating the mixture. By simultaneously pursuing both ends of the spectrum, we expect the data to converge in a way which will limit the number of combinations which must be tested. The data generated in this project will be used in Project 1 for mathematical modeling by Response Surface Methodology. With this modeling approach it is expected that the data will be more predictive of interactions between chemicals in other mixtures and more effectively utilized in risk assessment procedures.

该项目将利用5-化学混合物，模拟地下水 污染，探讨金属和有机物之间的相互作用， 诱导应激反应蛋白如金属硫蛋白、血红素 氧合酶和一氧化氮合酶，以及诱导炎症 细胞因子（即肿瘤坏死因子-α、白细胞介素-1和 白细胞介素-6）。 这些细胞因子与肝损伤和 诱导这些相同的应激反应蛋白。 该项目的重点 是描述相互作用的机制。 的理由 实验计划是基于这样的假设，即诱导这些 基因将影响混合物中组分的毒性， 用作化学品暴露的敏感指标。 我们推测 压力反应中化学物质之间的相互作用 模拟毒性相互作用。 然而，基因表达的改变将 与明显毒性相比，发生剂量较低且暴露持续时间较短 被检测到。 用于这些研究的化学混合物也正在 在项目1和2中进行了调查，并获得了机械信息 在这个项目中，3将涉及所有3个项目，而混合物包含 金属（铬，铅，砷）和有机物苯，苯酚，我们将 首先关注的是金属。 化学反应和 与内源性介质（细胞因子）的相互作用将在 从体内（特定目的1）和正常情况下处理的大鼠中获得的肝细胞 49（具体目标2）。 在特异性目的3中，差异显示聚合酶 链式反应技术和转录因子激活研究将 为了确定应激反应基因的概况， 这些基因在接受过以下处理的大鼠的肝细胞中差异表达： 化学混合物。 在整个项目中，自上而下和自下而上- 将使用UP方法。 也就是说，单一的化学物质将 以及化学混合物。 随后将 将单一化学品组合成2-[组分，3-组分混合物，和 也分馏混合物。 通过同时追求 频谱，我们期望数据以一种限制 必须测试的组合数量。 在此生成的数据 项目1中将使用一个项目，通过响应进行数学建模 表面方法学。 通过这种建模方法，预计 数据将更能预测其他化学物质之间的相互作用， 混合物和更有效地利用风险评估程序。