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比美国供水中发现的要高。在初步研究中，研究表明，长期暴露于砷的暴露水平不会引起明显的肝毒性，但会使肝脏对随后因注射脂多糖（LPS）而引起的炎症“打击”敏感。这一新发现表明，即使砷本身不具有肝毒性，也可能由于第二次肝毒性事件而增加肝病的风险。基于这些初步研究，我们假设低剂量的砷会导致肝毒性损伤。这一假设将通过以下具体目标进行检验。1)。为了验证砷对lps诱导的小鼠肝损伤致敏的假设。在初步研究中显示，长期接触饮用水中的砷会增加肝脏炎症和LPS引起的损伤。然而，本初步研究中使用的饮用水砷浓度仍然高于美国人体接触砷的相关浓度。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。具体子目标有：a)确定引起脂多糖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，验证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一种肝脏疾病是肥胖引起的NAFLD。在这里，使用在Specific Aim 1中确定的最小暴露条件，在已建立的NAFLD模型中，低剂量砷暴露将增强慢性肝损伤的假设将被验证。具体子目的有：a)确定砷对脂肪肝早、中、晚期的影响。b)确定砷是否能促进实验性NAFLD中祖细胞和/或癌前病变的形成。综上所述，这些结果还将建立砷引发肝病的新模型，从而可以测试新的假设和/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。具体来说，这些结果表明，砷暴露引起的肝损伤的相对风险可能必须加以调整，以考虑到其他缓解因素，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，接触砷，即使低于明显的肝毒性水平，也可能增加肝脏中受刺激的炎症反应，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，该模型将不调查直接毒性本身，而是测试砷在已建立的肝毒性模型中加剧反应的假设。

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.