Priming of liver disease by arsenic exposure

描述（由申请人提供）：无机砷是一种天然的饮用水污染物，也是一种已知的肝毒素。然而，造成明显肝损伤所需的砷暴露水平可能高于美国供水中的砷暴露水平。初步研究表明，在不引起明显肝毒性的接触水平下长期接触砷，会使肝脏对随后由于注射脂多糖而引起的炎症“打击”敏感。这一新发现表明，砷，即使在暴露水平本身不是肝毒性，可能会增加肝脏疾病的风险，由于第二次肝毒性事件。基于这些初步研究，我们假设低剂量砷会使肝脏发生随后的肝毒性损伤。这一假设将通过以下具体目标进行检验。1）。验证砷对LPS诱导的小鼠肝损伤增敏的假设。初步研究显示，饮用水中的砷长期暴露会增强LPS引起的肝脏炎症和损伤。然而，在这项初步研究中使用的饮用水中砷的浓度仍然高于美国人体暴露的相关浓度。因此，我们将用更低、更相关的砷水浓度来检验我们的假设。具体的子目标是：a）确定引起LPS致敏的最小低剂量砷暴露条件。B）确定砷预暴露增强LPS引起的肝损伤的潜在机制。2）。在非酒精性脂肪性肝病（NAFLD）小鼠模型中检验低剂量砷暴露使肝脏对肝毒性敏感的假设。目前在美国人群中流行的肝脏疾病是肥胖诱导的NAFLD。在这里，使用特定目标1中确定的最小暴露条件，将测试低剂量砷暴露将增强已建立的NAFLD模型中的慢性肝损伤的假设。具体的子目标是：a）确定砷对脂肪肝疾病的早期，中期和晚期的影响。B）确定砷是否增强实验性NAFLD中祖细胞和/或癌前病变的形成。两者合计，这些结果也将建立新的模型砷引发的肝脏疾病，其中新的假设和/或治疗方案可以进行测试。如果砷引起这样的启动效应，这项工作对美国人口的意义是重大的。具体而言，这些结果表明，砷暴露引起的肝损伤的相对风险可能必须进行修改，以考虑其他缓解因素，如II型糖尿病和/或NAFLD。饮用水中的砷暴露是一个主要的健康问题。我们的初步研究表明，砷暴露，即使低于明显肝毒性的水平，也可能增加肝脏中刺激的炎症反应，可能增加严重慢性肝病的风险（例如，非酒精性脂肪肝疾病）。该项目将开发一种新的砷暴露模型，该模型本身不会研究直接毒性，而是测试砷加剧既定肝脏毒性模型反应的假设。

DESCRIPTION (provided by applicant): Inorganic arsenic is a natural drinking water contaminant and a known hepatotoxin. However, the exposure levels of arsenic required to cause overt liver damage may be higher than found in the US water supply. In preliminary studies, it was shown that chronic exposure to arsenic at exposure levels that caused no overt hepatoxicity, sensitized the liver to a subsequent inflammatory `hit' owing to injection of lipopolysaccharide (LPS). This new finding suggests that arsenic, even at exposure levels that are not hepatotoxic per se, may increase the risk of liver disease owing to a second hepatotoxic event. Based on these Preliminary Studies, it is hypothesized that low-dose arsenic primes liver to a subsequent hepatotoxic insult. This hypothesis will be tested via the following specific aims. 1). To test the hypothesis that arsenic sensitizes to LPS-induced liver injury in the mouse. In the Preliminary Studies, it was shown chronic exposure of arsenic in drinking water enhances hepatic inflammation and damage caused by LPS. However, the drinking water concentration of arsenic used in this preliminary study is still higher than relevant to human exposure in the US. We will therefore test our hypothesis with lower, more relevant, water concentrations of arsenic. Specific subaims are: a) To determine the minimal low dose arsenic exposure conditions to cause sensitization to LPS. b) To identify potential mechanisms by which arsenic preexposure enhances liver damage caused by LPS. 2). To test the hypothesis that low-dose arsenic exposure sensitizes liver to hepatotoxicity in mouse models of non alcoholic fatty liver disease (NAFLD). A liver disease that is currently endemic to the US population is obesity-induced NAFLD. Here, using minimal exposure conditions determined in Specific Aim 1, the hypothesis that low dose arsenic exposure will enhance chronic liver damage in established models of NAFLD will be tested. Specific subaims are: a) To determine the effect of arsenic on early, intermediate and late stages of fatty liver diseases. b) To determine whether arsenic enhances the formation of progenitor cells and/or preneoplastic lesions in experimental NAFLD. Taken together, these results will also establish new models of arsenic priming of liver disease in which new hypotheses and/or treatment regimens may be tested. Should arsenic cause such a priming effect, the significance of this work to the US population is significant. Specifically, such results would suggest that the relative risk of hepatic damage caused by arsenic exposure may have to be modified to take into account other mitigating factors, such as type II diabetes and/or NAFLD. Exposure to arsenic in the drinking water is a major health concern. Our preliminary studies indicate that arsenic exposure, even below levels that are overtly hepatotoxic, may increase the stimulated inflammatory response in the liver, possibly increasing the risk of serious chronic liver diseases (e.g., non-alcoholic fatty liver diseases). The project will develop a new model of arsenic exposure that will not investigate direct toxicity per se, but rather test the hypothesis that arsenic exacerbates the response in established liver toxicity models.