Grantee Research Project Results
2000 Progress Report: 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 , University of Arkansas
EPA Project Officer: Aja, Hayley
Project Period: March 25, 1998 through March 24, 2001
Project Period Covered by this Report: March 25, 1999 through March 24, 2000
Project Amount: $374,384
RFA: Exploratory Research - Human Health (1997) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
The overall estimation for the number of people afflicted with autoimmune diseases in the United States exceeds 8.5 million, or approximately 1 in every 31 Americans. The development of autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, 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. There is ample evidence supporting an association of chlorinated ethylenes with life-threatening autoimmune disorders such as systemic lupus erythematosus and scleroderma; however, the mechanisms by which chlorinated ethylenes cause autoimmunity are unknown.
We hypothesize that chlorinated ethylenes are metabolized to reactive intermediates that initiate an autoimmune response. The autoimmune response involves the activation of CD4+ T-cells that are stimulated by either a specific response against the chlorinated ethylene-modified proteins, or a nonspecific response initiated through the release of serum factors, such as cytokines, growth factors, or unidentified factors. Either pathway will result in the activation of T-cells, which can lead to the development of inflammation.
Progress Summary:
We investigated the possibility that trichloroethylene (TCE) caused oxidative stress in MRL+/+ mice. Liver homogenate was tested for heme-protein adducts using a recently developed assay for oxidative stress. There was a dose-responsive increase in heme-protein adducts at 50 kDa and at approximately 25 kDa. Oxidative stress was even found at the lowest treatment of 21 mg/kg/day. We investigated the expression of stress proteins in the liver for additional evidence of oxidative stress in MRL +/+ mice treated with TCE. We found a dose-dependent increase in the stress proteins BiP/GRP78 and endoplasmin; these are both luminal ER proteins and important chaperones. Our final evidence for oxidative stress as a mechanism in autoimmune disease caused by TCE was the demonstration of a dramatic increase in reactive nitrogen species (RNS). The most sensitive marker for RNS is the reaction of peroxynitrite with tyrosine groups on proteins forming nitrotyrosine protein adducts. Using immunohistochemistry, we showed an increase in nitrotyrosine-protein adducts in the liver following TCE treatment in MRL +/+ mice. The adducts primarily are associated with kupffer cells in the liver.
Endothelial cell damage also was found following treatment with TCE. We tested serum from mice treated with TCE and found a dose-responsive increase in serum levels of Von Willebrand factor, a sensitive marker for endothelial cell damage.
Future Activities:
Our present experiments are focused on determining possible mechanisms for the polyclonal activation of T-cells. We are investigating possible mechanisms for an apparent polyclonal activation of T-cells.
Journal Articles:
No journal articles submitted with this report: View all 21 publications for this projectSupplemental Keywords:
volatile organic compounds, VOCs, intermediates, metabolism, human health, genetic predisposition, sensitive populations, susceptibility., RFA, Health, Scientific Discipline, Toxics, Waste, Genetics, Environmental Chemistry, Health Risk Assessment, VOCs, Risk Assessments, Susceptibility/Sensitive Population/Genetic Susceptibility, Environmental Microbiology, Disease & Cumulative Effects, Hazardous Waste, Biochemistry, genetic susceptability, Hazardous, 33/50, health effects, sensitive populations, biomarkers, chloroethylene autoimmunity, effects assessment, cytochrome P450, lupus erythematosus, scleroderma, chlorinated ethylenes, cytokines, gene-environment interaction, Tetrachloroethylene, exposure, genetic predisposition, Lymphocytes, Trichloroethylene, human exposure, rheumatoid arthritis, chemical releases, hazardous chemicals, environmentally caused disease, human susceptibility, metabolism, chloroethylenes, air emissions, Vinyl chloride, exposure assessment, groundwater, immune response, autoimmune diseases, occupational exposure, autoimmunity, air contaminant exposureProgress and Final Reports:
Original AbstractThe 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.