Molecular effects of low level exposure to arsenic

砷（As）是一种无机环境污染物的主要关注在沙漠西南部，由于其无处不在的存在和它的发生在饮用沃茨由于威尔斯穿透砷层在地球沿着考虑中的标准。长期接触砷通常会导致皮肤癌、肺癌、膀胱癌和肾癌。这一建议的假设是，无机砷调节特定的基因，因此特定的蛋白质，它的目标组织正在研究，以证明砷暴露的信号和基因反应的一致性或特异性。这些调查将只利用低水平的砷暴露，以更接近地模拟从环境暴露中观察到的浓度，并更好地反映目前将饮用水标准从目前的50 ppb水平降低的建议。为了解决我们的假设，我们提出了4个独立和不重叠的具体目标。1.）确定蛋白质与丝氨酸/苏氨酸激酶参与砷信号。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)鉴定低水平无机砷暴露后表达模式发生变化的特定基因。我们已经发现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。急性，反复和慢性砷暴露将进行调查和特定基因的差异表达进行预测。4)检测无机砷暴露诱导的关键基因表达，并将基因表达与细胞损伤相关。砷化学物质的特异性基因表达将与靶细胞对毒物的后续反应相关。如果有任何蛋白质或其他生物化学标记物的产生，这是特定基因诱导的结果，这些基因和蛋白质可能作为生物标志物的早期指标，该组织低水平暴露于砷。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基因表达对组织损伤的重要性。

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.