EFFECTS OF CARCINOGENIC METALS ON GENE EXPRESSION

砷（III）和铬（VI）被认为是人类肺癌致癌物，砷还与皮肤癌、膀胱癌和肾癌的风险增加有关。拟议研究的总体目标是确定这些有毒金属作为人类致癌物的机制。该项目的具体目标是确定这些致癌金属对诱导基因表达的优先效应的机制基础。我们之前的研究表明，砷和铬对几种模型的表达有很强的优先作用，而砷和铬对大多数其他基因的表达有很强的优先作用。这些基因特异性作用似乎至少部分是由这些金属调节特定转录因子和细胞信号通路的能力介导的，这些转录因子和细胞信号通路调节这些靶基因的表达。特别是，我们观察到砷和铬对糖皮质激素受体功能的深远影响，导致糖皮质激素受体依赖基因表达的改变。这些结果表明，砷和铬，也许还有其他有毒金属，可能代表了一类新的“内分泌干扰物”，它们能够通过与类固醇受体的直接相互作用来改变细胞表型。本研究的具体目标是确定这些效应的分子基础，遗传和生化方法来研究这些效应在模型细胞系统中的作用。我们的具体目标将是：1)确定砷（III）和铬（VI）特异性改变糖皮质激素受体功能和受体介导的基因表达以及其他类固醇受体的机制；2)确定其他反式转录因子和/或其顺式作用的DNA调控元件是否有助于介导砷（III）和铬（VI）对诱导基因表达的特异性影响；3)确定表达被低剂量砷（III）或铬（VI）暴露特异性改变的真核基因亚组。我们假设这些选择性基因效应可能通过以组织特异性的方式改变细胞表型来促进致癌过程。其中一些相互作用，如类固醇受体功能的改变，也可能导致这些金属对器官和全身的影响。这也可能导致与其他金属效应的协同作用，例如铬（VI）直接导致DNA损伤和突变的能力。

Arsenic (III) and chromium (VI) are considered human lung carcinogens, and arsenic is also associated with increased risk of skin, bladder and kidney cancer. The overall goal of the proposed research is to determine the mechanism by which these toxic metals act as human carcinogens. The specific goal of the project is to determine the mechanistic basis for the preferential effects of these carcinogenic metals on inducible gene expression. Our previous studies have demonstrated that arsenic and chromium have strong preferential effects on the expression of several model inducible that arsenic and chromium have strong preferential effects on the expression of whereas most other genes are refractory to these treatments. These gene-specific effects appear to be mediated, at least in part, by the ability of these metals to modulate specific transcription factors and cell signaling pathways that regulate the expression of these targeted genes. In particular, we observed profound effects of arsenic and chromium on the function of the glucocorticoid receptor, leading to alterations in glucocorticoid receptor-dependent gene expression. These results suggest that arsenic and chromium, and perhaps other toxic metals, may represent a new class of "endocrine disrupters" that are capable of altering cell phenotype through direct interactions with steroid receptors. The specific objectives of this research are to determine the molecular basis for these effects, genetic and biochemical approaches to investigate these effects in model cell systems. Our specific aims will be to: 1) determine the mechanism by which arsenic (III) and chromium (VI) specifically alter glucocorticoid receptor function and receptor- mediated gene expression as well as other steroid receptors; 2) determine whether other trans acting transcription factors and/or their cis acting DNA regulatory elements contribute to mediating the specific effects of arsenic (III) and chromium (VI) on inducible gene expression; and 3) determine the sub set of eukaryotic genes whose expression is specifically altered by low dose arsenic (III) or chromium (VI) exposures. We hypothesize that these selective gene effects may contribute to the carcinogenic process by altering cell phenotype in a tissue-specific manner. Some of these interactions, such as alterations in steroid receptor function, may also lead to more global organ and systemic effects of these metals. This may also result in synergy with other metal effects, such as the ability of chromium (VI) to directly cause DNA damage and mutations.