Molecular effects of low level exposure to arsenic

低浓度砷暴露的分子效应

• 批准号: 6577207
• 负责人: A J GANDOLFI
• 金额: $ 14.22万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6577207
• 关键词: arsenic; biological signal transduction; cytotoxicity; environmental contamination; environmental exposure; environmental health; environmental toxicology; gene environment interaction; gene expression; genetic mapping; hazardous substances; human tissue; kidney; laboratory rabbit; protein structure function; serine; skin; threonine; water pollution; water supply

Arsenic (As) is an inorganic environmental contaminant of major concern in the desert Southwest due to its ubiquitous presence and its occurrence in drinking waters due to wells penetrating arsenic layers in the earth along with standards under consideration. Chronic exposure to arsenic frequently results in skin, lung, bladder, and kidney cancer. The hypothesis of this proposal is that inorganic arsenicals regulate specific genes and therefore specific proteins, and it target tissues are being studied to demonstrate the uniformity or specificity of the signaling and gene responses to arsenic exposure. These investigations will only utilize low level arsenic exposures to more closely mimic to the concentrations observed from environmental exposures and to better reflect the current proposal of lowering the drinking water standard from its current 50 ppb level. To address our hypothesis , we propose 4 independent and non- overlapping specific aims. 1.) Identify proteins that associate with a serine/threonine kinase involved in arsenic signaling. 2.) Characterize the activity of proteins that are regulated by arsenic and correlate protein activity with cellular toxicity. Once a specific protein involved in arsenic signal transduction is identified, we need to determine how arsenic affects the activity of that protein and whether the activity of that protein correlates with cytotoxicity. 3) Identify specific genes whose expression pattern changes after low level exposure to inorganic arsenic. We have already shown that nanomolar levels of arsenate and arsenite increase the binding of specific transcription factors and induce gene expression in renal tissue. Acute, repeated, and chronic exposures of arsenic will be investigated and differential expression of specific genes is predicted. 4) Examine the expression of key genes induced by inorganic arsenic exposure and correlate gene expression with cellular injury. Specific gene expression by the chemical species of arsenic will be correlated with the subsequent response of the target cells to the toxicant. If there is any production of proteins or other biochemical markers that are the result of the specific genes induced, these genes and proteins may potentially serve as early indicators of biomarkers for low-level exposure of this tissue to arsenic. The study of these two tissues will provide a further understanding of the importance of the arsenic-induced signaling processes and gene expression that are responsible for tissue injury.

砷 (As) 是西南沙漠地区主要关注的无机环境污染物，因为它无处不在，而且由于钻入地球砷层的井以及正在考虑的标准，砷 (As) 也出现在饮用水中。长期接触砷经常会导致皮肤癌、肺癌、膀胱癌和肾癌。该提案的假设是，无机砷调节特定基因，从而调节特定蛋白质，并且正在研究它的靶组织，以证明信号传导和基因对砷暴露的反应的一致性或特异性。这些调查将仅利用低浓度的砷暴露来更接近地模拟从环境暴露中观察到的浓度，并更好地反映当前将饮用水标准从目前的 50 ppb 水平降低的提议。为了解决我们的假设，我们提出了 4 个独立且不重叠的具体目标。 1.) 鉴定与参与砷信号转导的丝氨酸/苏氨酸激酶相关的蛋白质。 2.) 表征受砷调节的蛋白质的活性，并将蛋白质活性与细胞毒性相关联。一旦确定了参与砷信号转导的特定蛋白质，我们就需要确定砷如何影响该蛋白质的活性以及该蛋白质的活性是否与细胞毒性相关。 3) 识别低水平接触无机砷后表达模式发生变化的特定基因。我们已经证明，纳摩尔水平的砷酸盐和亚砷酸盐会增加特定转录因子的结合并诱导肾组织中的基因表达。将研究砷的急性、重复和慢性暴露，并预测特定基因的差异表达。 4) 检查无机砷暴露诱导的关键基因的表达，并将基因表达与细胞损伤相关联。砷化学物质的特定基因表达将与靶细胞对毒物的后续反应相关。如果特定基因诱导产生任何蛋白质或其他生化标记物，这些基因和蛋白质可能会作为该组织低水平砷暴露的生物标记物的早期指标。对这两种组织的研究将进一步了解砷诱导的信号传导过程和导致组织损伤的基因表达的重要性。