Impact of infection and inflammation on the toxicity of environmental chemicals

描述(申请人提供)：本项目的总体目标是了解感染和炎症对环境化学品肝脏毒性的改变影响。影响肝功能的感染性因素可以改变许多外来物种的生物过程 化学制品。这些对肝功能的干扰可能会影响个体对环境暴露的敏感性。因此，了解感染性病原体与器官功能之间的生化联系对于人类人群的安全性评估至关重要。为了研究炎症和感染对环境化学品毒性的影响，本项目将研究两种肝脏毒素：砷和黄曲霉毒素B1。这两种化学物质都被国际癌症研究机构(IARC)列为人类致癌物质。砷是一种普遍存在的全球供水环境污染物，与人类肝门脉高压症和肝纤维化有关。黄曲霉毒素B1是一种存在于食物中的真菌毒素，与增加患肝细胞癌的风险密切相关。为了研究这些毒素与感染之间的相互作用，我们将用肠道细菌病原体(轮状念珠菌或肝片杆菌)感染小鼠以促进肝脏炎症，然后用砷或黄曲霉毒素B1攻击小鼠，以研究由此产生的联合毒理学结果。这两种细菌都是肠道的感染性病原体，是人类病原体的模式生物。这项工作将检验这样一种假设，即产生肝脏炎症的肠道病原体会增加针对肝脏的环境因子的毒性。具体目的一是探讨低剂量砷暴露对急性肝脏炎症的影响，以及砷暴露对慢性肝脏炎症的影响。这项工作将导致开发新的生化分析，以评估氧化损伤在与疾病进展相关的组织中的作用。具体目标二将确定炎症如何改变黄曲霉毒素B1的生物加工过程，以及由此对与黄曲霉毒素B1生物激活相关的大分子损伤的影响。利用小鼠作为人类暴露的模型，这些研究将为病原微生物和环境化学物质的综合影响提供生物化学基础。

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the altering effects of infection and inflammation on the hepatic toxicity of environmental chemicals. Infectious agents that influence liver function can alter the biological processing of many foreign chemicals. These perturbations to liver function may influence an individual's susceptibility to environmental exposures. Therefore, understanding the biochemical associations between infectious agents and organ function are of critical importance for safety assessment in human populations. To investigate the impact of inflammation and infection on the toxicity of environmental chemicals, this project will study two liver toxins: arsenic and aflatoxin B1. Both chemicals are classified as human carcinogens by the International Agency for Research on Cancer (IARC). Arsenic is a ubiquitous environmental contaminant of global water supplies and is associated with hepatic portal hypertension and liver fibrosis in human populations. Aflatoxin B1 is a fungal toxin present in food supplies and is strongly associated with increased risk for the development of hepatocellular carcinoma (HCC). To study the interaction between these toxins and infection, we will infect mice with enteric bacterial pathogens (C. rodentium or H. hepaticus) to promote liver inflammation and then challenge mice with either arsenic or aflatoxin B1 to study the resulting combined toxicological outcomes. Both bacteria are infectious agents of the intestine that are model organisms of human pathogens. This work will test the hypothesis that enteric pathogens producing hepatic inflammation will increase the toxicity of environmental agents that target the liver. Specific aim one will investigate the effects of acute liver inflammation during exposure to low-dose arsenic and the effects of arsenic exposure during chronic liver inflammation. This work will result in the development of new biochemical analyses to assess the role of oxidative damage in tissues associated with disease progression. Specific aim two will determine how inflammation alters the biological processing of aflatoxin B1 and the resulting effects on macromolecular damage associated with the bioactivation of aflatoxin B1. Using the mouse as a model for human exposures, these studies will provide a biochemical basis for the combined effects of pathogenic microbes and environmental chemicals.