Molecular effects of low level exposure to arsenic

砷(As)是西南沙漠地区一种主要的无机环境污染物，由于其普遍存在，以及由于钻井穿透地球中的砷层而出现在饮用水中，以及正在考虑的标准，因此是一种重要的无机环境污染物。长期接触砷常常会导致皮肤癌、肺癌、膀胱癌和肾癌。这一建议的假设是，无机砷化合物调节特定的基因，从而调节特定的蛋白质，它以组织为靶标，以证明对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，以更接近于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50ppb水平降低的建议。为了解释我们的假设，我们提出了四个独立且不重叠的具体目标。1)确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.)表征受砷调控的蛋白质的活性，并将蛋白质活性与细胞毒性联系起来。一旦确定了参与砷信号转导的特定蛋白，我们就需要确定砷是如何影响该蛋白的活性的，以及该蛋白的活性是否与细胞毒性相关。3)确定低水平无机砷暴露后表达模式发生变化的特定基因。我们已经证明，亚砷酸盐和亚砷酸盐的纳摩尔水平增加了特定转录因子的结合，并诱导了肾组织中的基因表达。将调查急性、重复和慢性砷暴露，并预测特定基因的差异表达。4)检测无机砷暴露诱导的关键基因表达及其与细胞损伤的关系。砷的化学物种的特定基因表达将与靶细胞随后对毒物的反应相关。如果有任何特定基因诱导的蛋白质或其他生化标记物的产生，这些基因和蛋白质可能会作为该组织低水平暴露于砷的早期生物标记物。对这两个组织的研究将进一步了解砷诱导的信号过程和基因表达的重要性，这些过程和基因表达是导致组织损伤的原因。

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.