STUDIES OF INTERACTIVE TOXICITY IN RENAL CORTICAL SLICES

这项建议的目的将是研究 利用兔肾研究化学废弃场中的代表性金属 大脑皮层切片。尽管化学混合物的毒性已经收到了 在许多组织中，很少有人在这方面付出努力 与环境有关的化学物质的交互毒性 肾脏。因为金属保持了它们的元素特性，即使在 降解过程，它们的主要排泄部位是 肾脏，肾脏是相互作用的关键部位。 精密切割的肾皮质切片在体外已被证明是可靠的 肾脏系统，使我们能够检查众多潜在的相互作用， 容易地应用各种分析，并产生特定部位的损伤 这是在体内模拟的。具体目标是：1)确定 影响肾单位同一部位的两种金属毒物。我们是 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、相加或拮抗的效果吗？ 检查两种金属毒物对不同BUT的影响 肾单位的邻近部位。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，由此产生的毒性 协同作用、相加作用或拮抗作用？3)确定是否改变了运输 或由一种金属毒物引起的摄取过程影响摄取和 第二种毒物的毒性。摄取和运输的重要性 在有机肾毒物中的作用是有很好的文献记载的。鲜为人知的是 一种金属肾毒物的摄取和转运。我们问什么是 特定的配体和转运体对基因表达的重要性 一种特定金属毒剂的毒性及其对第二种金属的影响 毒物对这些过程有影响吗？4)决定金属是否会成为 定位于特定的靶肾细胞，如果第二种毒物影响 这种领悟。许多研究都强调了 肾脏中产生毒性作用的金属的阈值水平。 与分析核心和其他项目一起，我们将衡量 金属毒物的摄取，另一种金属毒物如何影响 这种摄取，以及肾脏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 化学废物中存在的金属之间的未来相互作用 转储并为风险分析提供其他信息。

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.