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: 8488019
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488019
• 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物质的肝毒性的改变作用。影响肝功能的感染因子可以改变许多异物的生物处理过程