Priming of liver disease by arsenic exposure

说明(申请人提供)：无机砷是一种天然饮用水污染物，也是一种已知的肝毒素。然而，导致明显肝脏损害所需的砷暴露水平可能高于美国供水中的水平。在初步研究中，研究表明，长期暴露在没有引起明显肝毒性的水平上的砷，会使肝脏对随后的炎症性“打击”敏感，这是由于注射脂多糖(LPS)造成的。这一新的发现表明，即使暴露在本身没有肝毒性的水平上，砷也可能会由于第二次肝毒性事件而增加患肝病的风险。在这些初步研究的基础上，推测低剂量的砷会使肝脏受到随后的肝毒性损害。这一假设将通过以下具体目标进行检验。1)。验证砷对脂多糖诱导的小鼠肝损伤敏感的假说。在初步研究中，有研究表明，长期接触饮用水中的砷会加剧内毒素引起的肝脏炎症和损害。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类暴露的相关浓度。因此，我们将用更低、更相关的水中砷浓度来检验我们的假设。具体的次级目标是：a)确定引起对内毒素敏感的最低剂量砷暴露条件。B)确定砷预暴露增强脂多糖引起的肝脏损伤的潜在机制。2)。目的：在小鼠非酒精性脂肪性肝病(NAFLD)模型上验证低剂量砷暴露使肝脏对肝毒性敏感的假说。目前在美国人群中流行的一种肝病是肥胖引起的非酒精性脂肪肝。在这里，使用特定目标1中确定的最低暴露条件，将在已建立的NAFLD模型中检验低剂量砷暴露将增强慢性肝损害的假设。具体的分目标是：a)确定砷对脂肪肝疾病的早、中、晚期的影响。B)确定砷是否促进实验性NAFLD祖细胞和/或癌前病变的形成。综上所述，这些结果还将建立新的砷引发肝病模型，其中可能会测试新的假设和/或治疗方案。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。具体地说，这些结果将表明，暴露于砷造成的肝脏损害的相对风险可能必须进行修改，以考虑到其他缓解因素，如II型糖尿病和/或NAFLD。接触饮用水中的砷是一个主要的健康问题。我们的初步研究表明，砷暴露，即使低于明显的肝脏毒性水平，也可能增加肝脏中被刺激的炎症反应，可能增加严重慢性肝病(例如，非酒精性脂肪性肝病)的风险。该项目将开发一种新的砷暴露模型，该模型不会调查直接毒性本身，而是在已建立的肝脏毒性模型中测试砷加剧反应的假设。

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.