STUDIES OF INTERACTIVE TOXICITY IN RENAL CORTICAL SLICES

本提案的目的是研究 使用兔肾的化学废物堆中存在的代表性金属 皮质切片 虽然化学混合物的毒性已经受到 注意在一些组织，很少的努力已经花费在 与环境有关的化学品的相互毒性， 肾 由于金属保持其元素特性，即使在 降解过程，其主要排泄部位是 肾脏，肾脏本身作为相互作用的关键部位。 精密切割的肾皮质切片已被证明是一种可靠的体外 肾脏系统，使我们能够检查许多潜在的相互作用， 容易应用各种分析，并产生特定部位的病变， 在体内进行模拟。 具体目的是：1）确定 两种金属毒物影响肾单位的同一部位。 我们 询问是否存在影响肾单位同一区域的两种金属， 它们会产生协同、相加还是拮抗作用？ （二） 检查两种金属毒物的影响，影响不同的，但 肾单位中的相邻部位。 我们现在问是否存在两种金属 它们会影响不同但相邻的部位， 协同、相加还是拮抗？ 3)确定是否改变运输 或由一种金属毒物引起的吸收过程影响吸收， 第二种毒物的毒性。 吸收和运输的重要性 有机肾毒物中的作用是有据可查的。 了解较少 a.金属肾毒物的摄取和转运。 我们问， 特异性配体和转运蛋白对表达的重要性 一种特定金属毒物的毒性和影响第二种金属毒物的因素 有毒物质对这些过程的影响 4)确定金属是否成为 定位在特定的靶肾细胞中，如果第二种毒物影响 这个摄取。 一些研究强调了以下方面的重要性： 肾脏中金属的阈值水平产生毒性作用。 结合分析核心和其他项目，我们将测量 金属毒物的吸收，另一种金属毒物如何影响 这种吸收，以及肾细胞中金属的整体动态平衡。 通过 了解这些相互作用的机制，我们希望预测 化学废物中的金属之间的未来相互作用 转储并提供用于风险分析的额外信息。

The object of this proposal will be to study the interactive toxicity of representative metals present in chemical waste dumps using rabbit renal cortical slices. Although the toxicity of chemical mixtures has received attention in a number of tissues, little effort has been expended towards the interactive toxicity of environmentally relevant chemicals in the kidney. Since metals retain their elemental identity, even during degradative processes, and their principal site for excretion is the kidney, the kidney lends itself as a pivotal site for interaction. Precision-cut renal cortical slices have proven to be a reliable in vitro renal system that allows us to examine the numerous potential interactions, readily apply a variety of analyses, and produce site-specific lesions which mimic in vivo. The Specific Aims are: 1) Determine the effect of two metal toxicants that affect the same site of the renal nephron. We are asking if two metals that affect the same area of the nephron are present, will they produce a synergistic, additive, or antagonistic effect? 2) Examine the effect of two metal toxicants that affect different but adjacent sites in the renal nephron. We now ask if two metals are present and they affect different but adjacent sites will the resulting toxicity be synergistic, additive, or antagonistic? 3) Determine if altered transport or uptake processes caused by one metal toxicant affect the uptake and toxicity of the second toxicant. The importance that uptake and transport plays in organic nephrotoxicants is well documented. Less is known about a metallic nephrotoxicants uptake and transport. We ask what is the importance of the specific ligands and transporters on the expression of toxicity of a specific metal toxicant and what affect a second metallic toxicant has on these processes? 4) Determine if metals do become localized in a specific target renal cells and if a second toxicant affects this uptake. A number of studies have highlighted the importance of threshold levels of metals in the kidney to produce their toxic effects. In conjunction with the Analytical Core and other projects, we will measure the uptake of the metallic toxicants, how another metal toxicant affects this uptake, and the overall homeostasis of metals in renal cells. By understanding the mechanism of these interactions, we hope to predict future interactions between metals which are present in chemical waste dumps and provide additional information for risk analysis.