MECHANISMS OF CADMIUM TOXICITY IN EPITHELIAL CELLS

镉（Cd 2+）是一种重要的工业和环境污染物， 已被证明会对多种器官造成严重损害， 致突变、致畸和致癌活性。尽管其 作为一个环境健康问题的重要性，相对来说知之甚少 关于Cd 2+的特定细胞和分子机制 产生了许多影响。该项目的长期目标是 确定其中一些机制。文献中的报告表明， Cd 2+在体内的某些作用可能是由于破坏了细胞内的 在各种上皮或内皮表面的细胞之间的连接。到 为了更详细地研究这种可能性，进行了研究， 研究Cd 2+对细胞间连接的影响， 猪肾上皮细胞株LLC-PK 1。这些研究的结果有 显示Cd 2+对粘附具有特定的破坏作用， 封闭LLC-PK 1细胞之间的连接，这些作用可能 涉及Cd 2+与E-cadherin的相互作用，E-cadherin是一种Ca 2+依赖的 在上皮细胞-细胞粘附中起关键作用的糖蛋白。的 本提案中描述的工作是对这些先前工作的直接延伸。 研究和解决三个重要问题。第一个目标 目的是确定Cd 2+干扰E-cadherin依赖的 LLC-PK 1细胞系中的细胞-细胞连接。待测试的假设 Cd ~（2+）可以竞争性地取代E ~-上结合位点的Ca ~（2+）， 钙粘蛋白，从而改变分子的粘附性质。的 第二个目标是确定Cd 2+是否可以选择性地破坏 血管内皮细胞中的钙依赖性细胞-细胞连接。这 是一个重要的问题，因为血管内皮是一个重要的因素， Cd 2+在体内毒性的主要目标。 第三大目标是 确定Cd 2+是否可以选择性地损伤钙粘蛋白依赖的细胞-细胞 连接在体内，以及这种机制是否可能有助于明显的 Cd 2+的毒性作用这些问题将通过使用 多学科方法，包括形态学，生物物理学和 生化技术这些研究结果将提供重要的 对Cd 2+产生其毒性的机制的新见解 这将为今后在这一领域的研究奠定基础。 此外，这些研究的结果可能具有更普遍的意义。 关于有毒物质损害机制的影响 活细胞

Cadmium (Cd2+) is an important industrial and environmental pollutant that has been shown to cause severe damage to a variety of organs, and to have mutagenic, 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 many effects. The long-term objective of this project is to identify some of these mechanisms. Reports in the literature suggest that some of the effects of Cd2+ in vivo may result from the disruption of the junctions between cells in various epithelial or endothelial surfaces. To examine this possibility in more detail, studies were undertaken to examine the effects of Cd2+ on cell-cell junctions in the established porcine renal epithelial cell line, LLC-PK1. Results of these studies have shown that Cd2+ has specific damaging effects on the adhering and occluding junctions between LLC-PK1 cells and that these effects may involve the interaction of Cd2+ with E-cadherin, a Ca2+-dependent glycoprotein that plays a key role in epithelial cell-cell adhesion. The work described in this proposal is a direct extension of these previous studies and is aimed at resolving three important issues. The first goal is to identify the mechanisms by which Cd2+ disrupts E-cadherin dependent cell-cell junctions in the LLC-PK1 cell line. The hypothesis to be tested is that Cd2+ can competitively displace Ca2+ from binding sites on E- cadherin and thereby alter the adhesive properties of the molecule. The second goal is to determine whether or not Cd2+ can selectively disrupt calcium-dependent cell-cell junctions in vascular endothelial cells. This is an important issue because the vascular endothelium is one of the primary targets for Cd2+ toxicity in vivo. The third major goal is to determine whether Cd2+ can selectively damage cadherin-dependent cell-cell junctions in vivo, and whether such a mechanism may contribute to overt toxic effects of Cd2+. These issues will be addressed by using a multidisciplinary approach that includes morphologic, biophysical and biochemical techniques. Results of these studies should provide important new insights into the mechanisms by which Cd2+ produces some of its toxic effects and should lay the groundwork for future studies in this area. Furthermore, the results of these studies could have more general implications concerning the mechanisms by which toxic substances damage living cells.