Mechanisms of Cadmium Toxicity in Epithelial Cells

描述（申请人提供）：镉（Cd2+）是一种重要的工业和环境污染物，可对肺、肾、肝、骨等多种器官造成严重损害。此外，Cd2+已被证明具有致畸和致癌活性。尽管Cd2+作为一个环境健康问题很重要，但人们对其产生不利影响的具体细胞和分子机制知之甚少。这个项目的长期目标是确定其中的一些机制。文献证据表明，体内Cd2+的一些作用可能是由于破坏了各种上皮和内皮表面细胞之间的连接。最近的研究结果表明，Cd2+可以选择性地破坏培养中各种类型上皮细胞之间的Ca2+依赖性连接，这些影响很可能是Cd2+与Ca2+依赖性细胞粘附分子E-cadherin相互作用的结果。最近的更多研究表明，Cd2+可以破坏肺中E-cadherin和ve -cadherin依赖的细胞-细胞连接，并改变E-cadherin和N-cadherin在肾脏中的定位。培养细胞的其他结果表明，钙粘蛋白介导的粘附丧失导致钙粘蛋白结合蛋白β -连环蛋白从连接复合物转移到细胞核，并可能改变基因表达。这些结果表明，钙粘蛋白/ β -连环蛋白复合物可能是肺和肾上皮细胞Cd2+毒性的重要早期靶点。本提案中描述的工作是这些先前研究的直接延伸，旨在解决两个主要问题。第一个目标是继续进行正在进行的研究，检查Cd2+对体内钙粘蛋白/连环蛋白复合物的影响，并确定这种机制是否可能有助于Cd2+对特定靶器官（如肺和肾脏）的毒性作用，这些器官是Cd2+毒性在人体中的重要靶点。第二个目的是研究Cd2+诱导的钙粘蛋白/ β -连环蛋白复合物的破坏是否可能导致β -连环蛋白从连接复合物转移到细胞核，以及β -连环蛋白调节基因表达的改变。这些问题将通过采用多学科方法来解决，包括利用各种生理学、形态学和生化技术的体外和体内研究。这些研究的结果应该为Cd2+产生某些毒性作用的机制提供重要的新见解。此外，这些研究的结果可能会对有毒物质影响生物体的机制产生更普遍的影响。

DESCRIPTION (provided by applicant): Cadmium (Cd2+) is an important industrial and environmental pollutant that can cause severe damage to a variety of organs including the lung, kidney, liver, and bone. In addition, Cd2+ has been shown to have teratogenic and carcinogenic activities. In spite of its importance as an environmental health problem, relatively little is known about the specific cellular and molecular mechanisms by which Cd2+ produces its adverse effects. The long-term objective of this project is to identify some of these mechanisms. Evidence from the literature suggests that some of the effects of Cd2+ in vivo may result from the disruption of the junctions between cells in various epithelial and endothelial surfaces. Results of recent studies have shown that Cd2+ can selectively disrupt the Ca2+-dependent junctions between various types of epithelial cells in culture, and that these effects most likely result from the interaction of Cd2+ with the Ca2+-dependent cell adhesion molecule, E-cadherin. More studies that are recent have shown that Cd2+ can disrupt E-cadherin- and VE-cadherin-dependent cell-cell junctions in the lung and alter the localization of E-cadherin and N-cadherin in the kidney. Additional results on cells in culture suggest that the loss of cadherin-mediated adhesion results in the translocation of the cadherin-binding protein beta-catenin from the junctional complexes to the cell nucleus and possible alterations in gene expression. These results suggest that the cadherin/beta-catenin complex may be an important early target of Cd2+ toxicity in epithelial cells of the lung and kidney. The work described in this proposal is a direct extension of these previous studies, and is aimed at resolving two major issues. The first objective is to continue ongoing studies examining the effects of Cd2+ on the cadherin/catenin complex in vivo, and to determine if this mechanism might contribute to the toxic effects of Cd2+ in specific target organs such as the lung and the kidney, which are important targets of Cd2+ toxicity in humans. The second objective is to examine the possibility that the Cd2+-induced disruption of the cadherin/beta-catenin complex may lead to the translocation of beta-catenin from the junctional complexes to the nucleus and alterations in beta-catenin-regulated gene expression. These issues will be addressed by employing a multidisciplinary approach that includes both in vitro and in vivo studies that utilize a variety of physiologic, morphologic and biochemical techniques. Results of these studies should provide important new insights into the mechanisms by which Cd2+ produces some of its toxic effects. Furthermore, the results of these studies could have more general implications regarding the mechanisms by which toxic substances affect living organisms.