Impact of infection and inflammation on the toxicity of environmental chemicals

感染和炎症对环境化学物质毒性的影响

• 批准号: 8663277
• 负责人: Charles Knutson
• 金额: $ 9万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663277
• 关键词: 4 hydroxynonenal; 4-oxo-2-nonenal; Acute; Adult; Aflatoxin B1; Amino Acids; Animal Model; Arsenic; Bacteria Infectious Agent; Biochemical; Biological Markers; Biological Process; Carcinogens; Cells; Chemical Exposure; Chemicals; Chronic; Citrobacter rodentium; Colon; Cytochrome P450; Development; Digestion; Disease; Disease Progression; Dose; Endothelial Cells; Enteral; Environmental Exposure; Environmental Impact; Environmental Pollution; Epoxy Compounds; Ethanol; Event; Exhibits; Exposure to; Food Supply; Glutathione S-Transferase; Goals; Guanine; Helicobacter hepaticus; Hepatic; Hepatitis; Hepatitis B; Hepatotoxicity; Histidine; Homeostasis; Human; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; International Agency for Research on Cancer; Intestines; Investigation; Joints; Knockout Mice; Label; Lead; Link; Lipid Peroxidation; Liver; Liver Fibrosis; Lysine; Metabolic; Metabolic Activation; Metabolic Biotransformation; Microbe; Modeling; Monitor; Mus; Mycotoxins; Organ; Outcome; Pathology; Phagocytes; Phenotype; Plant Resins; Population; Portal Hypertension; Predisposition; Primary carcinoma of the liver cells; Process; Production; Proteins; Research; Risk; Risk Factors; Role; Safety; Serum; Serum Albumin; Signal Transduction; Testing; Tissues; Toxic Environmental Substances; Toxic effect; Toxin; Vascular blood supply; Water Supply; Work; adduct; analytical method; base; design; detoxication; enteric pathogen; environmental agent; environmental chemical; exposed human population; gastrointestinal infection; in vivo Model; insight; liver function; liver inflammation; oxidative damage; pathogen; pathogenic bacteria; public health relevance; response; safety testing; streptavidin-agarose; synergism; toxicant

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.

描述（由申请人提供）：本项目的总体目标是了解感染和炎症对环境化学品肝毒性的改变作用。影响肝功能的感染性病原体可以改变许多外源性肝细胞的生物学过程。 化学品这些对肝功能的干扰可能会影响个体对环境暴露的易感性。因此，了解感染原与器官功能之间的生化关联对于人群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。砷是一种普遍存在于全球水源中的环境污染物，与人类肝门脉高压和肝纤维化有关。黄曲霉毒素B1是一种存在于食品供应中的真菌毒素，与肝细胞癌（HCC）发生的风险增加密切相关。为了研究这些毒素和感染之间的相互作用，我们将用肠道细菌病原体（C。rodentium或H. hepaticus）以促进肝脏炎症，然后用砷或黄曲霉毒素B1攻击小鼠以研究所产生的组合毒理学结果。这两种细菌都是肠道的感染因子，是人类病原体的模式生物。这项工作将测试的假设，肠道病原体产生肝脏炎症将增加毒性的环境因素，目标肝脏。具体目标一是研究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。这项工作将导致新的生化分析的发展，以评估与疾病进展相关的组织中氧化损伤的作用。具体目标二将确定炎症如何改变黄曲霉毒素B1的生物加工以及对与黄曲霉毒素B1生物活化相关的大分子损伤的影响。使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品的综合影响提供生化基础。