ABERRATIONS IN GENE EXPRESSION IN ARSENIC-TREATED HUMAN EPIDERMAL CELLS

基因表达中的异常 在砷处理的人表皮细胞中 砷(As)是一种全球公共卫生关注的环境毒物，是人体毒性和致癌性的主要原因。砷以人体皮肤为靶标，主要通过饮用水长期暴露于砷会增加患皮肤癌的风险。在这项初步研究中，我们建议调查长期暴露于三氧化二砷浓度下的人角质形成细胞全基因组表达谱的时程变化。我们 假设在长期暴露于三氧化二砷的角质形成细胞中，模拟角质形成细胞的分化，三氧化二砷的毒性损伤将导致基因表达的变化，从而导致癌症的发生。我们的假设是基于观察到的正常人类上皮角质形成细胞(HEP)在砷处理2、5、8或14天后的整体转录变化。 我们已经证明，长期接触三氧化二砷对角质形成细胞的遗传毒性和细胞毒性有不同的影响。我们研究的具体目的是：(1)评估三氧化二砷对角质形成细胞的慢性毒性；(2)阐明长期暴露于三氧化二砷的培养细胞基因表达的整体变化；以及(3)分析角质形成细胞在第2天向鳞状细胞分化过程中的基因表达变化。 5、第8天和第14天。低水平的长期(慢性)砷暴露是在砷流行区发生的。这项拟议研究的长期目标是了解皮肤的表皮细胞成分，即基底角质形成细胞和鳞状细胞对皮肤癌的贡献。我们的方法将使我们能够确定作为对慢性砷暴露的初始反应的一部分的潜在途径。它还将为我们提供更好的图像，了解这些分子途径是如何 随着细胞在暴露期间(2-14天)适应砷毒性而发生变化。我们的前期研究的意义在于，皮肤细胞在实验室条件下长期暴露于三氧化二砷，为了解砷致癌机制提供了一个实验模型。

ABERRATIONS IN GENE EXPRESSION IN ARSENIC-TREATED HUMAN EPIDERMAL CELLS Arsenic (As) is recognized as an environmental toxicant of global public health concern and leading cause of toxicity and carcinogenicity in humans exposed to it. Arsenic targets the human skin and longterm exposure to arsenic principally through drinking water has been correlated with increased risk to skin cancer. In this pilot study, we propose to investigate the time course alteration in genome-wide expression profiles of human keratinocytes exposed to chronic concentrations of arsenic trioxide. We hypothesize that in keratinocytes chronically exposed to arsenic trioxide over a time course of two weeks, mimicking keratinocyte differentiation, toxic insult by arsenic trioxide will cause alterations in gene expression leading to carcinogenesis. Our hypothesis is based on observed global transcriptional alterations in normal human epithelial keratinocytes (hEp) treated with arsenic for 2, 5, 8 or 14 days. We have shown that chronic exposure to arsenic trioxide (As2O3) has a differential effect on the genotoxicity and cytotoxicity of keratinocytes. The specific aims of our investigation are to: (1) Evaluate chronic toxicity of arsenic trioxide to keratinocytes; (2) Elucidate the global alterations in gene expression of culture cells that have been chronically exposed to arsenic trioxide; and (3) Analyze the gene expression changes during the differentiation of keratinocytes into squamous cells at day 2, day 5, day 8 and day 14. Low-level long-term (chronic) human exposure to arsenic is what happens in arsenic endemic areas. The long-term goal of the proposed research is to understand the contribution of the epidermal cellular elements of the skin, namely basal keratinocytes and squamous cells to skin cancer. Our approach will allow us to identify potential pathways that are part of the initial response to chronic arsenic exposure. It will also provide us with a better picture of how these molecular pathways change as the cells adapt to arsenic toxicity during exposure (2-14 days). The significance of our pilot study is that skin cells chronically exposed arsenic trioxide under laboratory conditions provide an experimental model to understand the mechanism of arsenic-induced carcinogenesis.