Mechanisms of Cadmium Toxicity in Epithelial Cells

镉对上皮细胞的毒性机制

• 批准号: 7090849
• 负责人: Walter C Prozialeck
• 金额: $ 20.12万
• 依托单位: MIDWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090849
• 关键词: cadherins; cadmium; carcinogens; cell adhesion molecules; cytotoxicity; electron microscopy; environmental exposure; enzyme linked immunosorbent assay; epithelium; gene expression; histopathology; intercellular connection; kidney; laboratory rat; lung; teratogens; western blottings

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.

描述（由申请人提供）：镉（Cd 2+）是一种重要的工业和环境污染物，可对多种器官（包括肺、肾、肝和骨）造成严重损害。 此外，Cd 2+已被证明具有致畸和致癌活性。 尽管它作为一个环境健康问题的重要性，相对知之甚少的具体细胞和分子机制，Cd 2+产生的不利影响。 本项目的长期目标是确定其中一些机制。 来自文献的证据表明，Cd 2+在体内的一些影响可能是由于破坏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，Cd ~（2+）可以选择性地破坏培养中各种类型上皮细胞之间的Ca ~（2+）依赖性连接，这些作用很可能是由于Cd ~（2+）与Ca ~（2+）依赖性细胞粘附分子E-cadherin的相互作用。 最近的更多研究表明，Cd 2+可以破坏肺中依赖于E-钙粘蛋白和VE-钙粘蛋白的细胞间连接，并改变肾脏中E-钙粘蛋白和N-钙粘蛋白的定位。 培养细胞的其他结果表明，钙粘蛋白介导的粘附的损失导致钙粘蛋白结合蛋白β-连环蛋白从连接复合物易位到细胞核，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一个重要的早期目标镉+毒性的上皮细胞的肺和肾。 本建议中所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。 第一个目标是继续正在进行的研究，检查镉的钙粘蛋白/连环蛋白复合体在体内的影响，并确定这种机制是否可能有助于镉的毒性作用，在特定的靶器官，如肺和肾脏，这是镉的毒性在人类的重要目标。 第二个目的是研究镉诱导的钙粘蛋白/β-连环蛋白复合物的破坏可能导致β-连环蛋白从连接复合物易位到细胞核和β-连环蛋白调节的基因表达的改变的可能性。 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，形态学和生物化学技术的体外和体内研究。 这些研究的结果应提供重要的新的见解的机制，镉2+产生的一些毒性作用。 此外，这些研究的结果可能对有毒物质影响生物体的机制产生更普遍的影响。