Grantee Research Project Results
Mechanism(s) of Chloroethylene-Induced Autoimmunity
EPA Grant Number: R826409Title: Mechanism(s) of Chloroethylene-Induced Autoimmunity
Investigators: Pumford, Neil R. , Gilbert, Kathleen M.
Institution: University of Arkansas for Medical Sciences
Current Institution: University of Arkansas for Medical Sciences , University of Arkansas
EPA Project Officer: Aja, Hayley
Project Period: March 25, 1998 through March 24, 2001
Project Amount: $374,384
RFA: Exploratory Research - Human Health (1997) RFA Text | Recipients Lists
Research Category: Human Health
Description:
The development of autoimmune diseases (e.g. rheumatoid arthritis, systemic lupus erythematosus, and systemic scleroderma) is believed to be multifactorial, involving both genetic and environmental components. Chemical exposures may be a major environmental influence on the development of autoimmune diseases. Chloroethylenes are industrial chemicals with widespread occupational exposure and are major environmental contaminants. Furthermore, these chemicals are present at many hazardous waste sites at levels from hundreds of thousands of times higher in ground water to millions of times higher in soils and sediment than EPA's maximum regulatory levels in drinking water. There is good evidence for an association of chlorinated ethylenes such as vinyl chloride, trichloroethylene, and tetrachloroethylene in the causation of a life-threatening autoimmune disorder known as systemic sclerosis-like syndrome, or scleroderma; the mechanism by which chlorinated ethylenes cause this sclerosis-like syndrome is unknown. It is our hypothesis that the development of an autoimmune response in certain susceptible individuals may be precipitated by the metabolic activation of chloroethylene's to reactive intermediates that covalently modify proteins, such as cytochrome P450 2E1, in hepatocytes, clara cells, leukocytes, lymphocytes, and keratinocytes. Covalent binding damages the cells causing the release of chemotactic factors that recruit macrophages, leukocytes, and lymphocytes. The damaged cells also release chloroethylene-modified proteins that are phagocytized, processed and presented by macrophages to T cells specific for the chemical modification. In addition, recruited macrophages and lymphocytes may directly metabolize chlorinated ethylenes to reactive intermediates that covalently bind to the proteins that promote T-cell and macrophage interactions, thereby leading to the release of cytokines that stimulate fibroblasts and lead to the fibrosis and vascular damage observed in chloroethylene-induced scleroderma-like disease.
Approach:
Utilizing antisera specific for proteins covalently modified by chlorinated ethylenes we will investigate the metabolic activation in hepatocytes, clara cells, keratinocytes, macrophages, and CD4+ T cells. Immunohistochemical localization of the adducts within the liver, lung, and skin in MRL/++ mice treated with chloroethylenes will help determine the cells involved in metabolic activation and Western blot analysis of tissue will determine the protein targets. The mechanism of immune-cell activation leading to autoimmunity and fibrosis will be determined in autoimmune-prone MRL/++ mice. Chloroethylene-exposed scleroderma patients will be tested for chloroethylene-modified proteins and/or antibodies directed against modified proteins.
Expected Results:
The results should provide insights into the mechanism(s) involved in chemical-induced autoimmunity and may lead to the development of new treatments for patients with autoimmune diseases, such as the development of new drugs to reduce a critical toxification pathway or to induce a detoxification pathway. Investigation of a non-carcinogen endpoint for chlorinated ethylenes will provide an additional endpoint for evaluating potential human risk. The utilization of biomarkers for chloroethylene exposure will help identify susceptible individuals or populations and is important for risk management. Additionally, the identification of a similar mechanism(s) involved in humans is important for a more precise species extrapolation.
Publications and Presentations:
Publications have been submitted on this project: View all 21 publications for this projectJournal Articles:
Journal Articles have been submitted on this project: View all 6 journal articles for this projectSupplemental Keywords:
Volatile organic compounds (VOC), intermediates, metabolism, human health, genetic pre-disposition, sensitive populations, susceptibility., Health, RFA, Scientific Discipline, Waste, Toxics, Hazardous, Susceptibility/Sensitive Population/Genetic Susceptibility, Health Risk Assessment, Risk Assessments, genetic susceptability, Environmental Chemistry, 33/50, Hazardous Waste, Environmental Microbiology, VOCs, Biochemistry, Disease & Cumulative Effects, Genetics, genetic predisposition, health effects, metabolism, sensitive populations, cytokines, scleroderma, environmental hazard exposures, chlorinated ethylenes, autoimmune diseases, chloroethylenes, human exposure, immune response, Lymphocytes, Tetrachloroethylene, Trichloroethylene, cytochrome P450, air emissions, rheumatoid arthritis, chloroethylene autoimmunity, effects assessment, exposure, groundwater, lupus erythematosus, autoimmunity, Vinyl chloride, environmentally caused disease, air contaminant exposure, gene-environment interaction, occupational exposure, human susceptibility, biomarkers, chemical releases, exposure assessmentProgress and Final Reports:
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.