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2002 Progress Report: Screening Disinfection Byproducts (DBPs) for Their Ability To Promote Autoimmunity
EPA Grant Number: R829417E02Title: Screening Disinfection Byproducts (DBPs) for Their Ability To Promote Autoimmunity
Investigators: Gilbert, Kathleen M. , Pumford, Neil R.
Institution: University of Arkansas at Little Rock
EPA Project Officer: Winner, Darrell
Project Period: May 24, 2002 through May 23, 2004 (Extended to May 23, 2005)
Project Period Covered by this Report: May 24, 2002 through May 23, 2003
Project Amount: $250,000
RFA: EPSCoR (Experimental Program to Stimulate Competitive Research) (2001)
Research Category: EPSCoR (The Experimental Program to Stimulate Competitive Research)
Description:
Objective:The overall objective of this research project is to use a two-level in vivo screening procedure to directly examine the autoimmune-promoting capacity of disinfection byproducts (DBPs). The specific objectives of this research project are to:
1. Treat inbred MRL/+ mice for 4 weeks with trichloroethylene (TCE) CYP2E1 metabolites (i.e., chloral hydrate, 1,1,2-trichloroethane, and 1,1-dichloroethane) in the drinking water. To determine whether the autoimmune-promoting capacity of DBPs is limited to TCE metabolites, three other DBPs of the halomethane class that have been reported to induce immune system alterations (i.e., chloroform, bromodichloromethane, and chlorodibromomethane) also will be tested. The mice will be examined for serological signs of autoimmune disease, as well as T-cell expression of CD44.
2. Use the level two screen to confirm that two DBPs identified as effective in Objective 1 can induce autoimmune disease and CD4+ T-cell alterations when administered to MRL/+ mice at lower concentrations for a longer time period (40 weeks) because chronic treatment with a low dose of DBPs is probably most relevant to actual environmental exposure.
3. Develop an in vitro screening assay in which flow cytometry will be used to determine whether DBPs upregulate CD44 on CD4+ T cells in vitro.
Progress Summary:A postdoctoral fellow supported by this grant, Dr. Sarah Blossom, has made excellent progress on the project. She has demonstrated that treatment of MRL+/+ mice with low doses of DBPs in vivo results in the development of immune system alterations commensurate with autoimmune disease. This work has been submitted to the Journal of Autoimmunity. Dr. Blossom also has found that in vivo or in vitro exposure to certain DBPs inhibits activation-induced cell death in T cells, a mechanism that has been shown to promote autoimmune disease. Based on this work, Dr. Blossom has been awarded a travel grant to present her data at the 12th International Congress of Immunology in Montreal in July 2004. In addition, she is examining the mechanism by which DBPs alter T cell apoptosis, and this work is expected to produce some very exciting and novel results. Dr. Gilbert has recently published work showing that one of the DBPs described in the grant can promote signaling via Schiff base formation in T cells in vitro. The connection between T cell signaling and alterations in T cell apoptosis is now being explored. Dr. Pumford, our collaborator at the University of Arkansas in Fayetteville, has continued to provide invaluable help with toxicological evaluations of the treated mice, and recently has published a manuscript concerning the ability of toxicants including DBPs to promote autoimmune hepatitis in mice.
Future Activities:As described above, one focus of this research project will be to examine how DBPs alter T cell apoptosis. In addition, we are in the middle of the long-term study designed to determine how chronic exposure to very low concentrations of DBPs alters immune function and to delineate DBP-induced autoimmune pathology. Dr. Blossom was not able to start work in the laboratory until 6 months after the initial project start date. Consequently, it is anticipated that the project schedule will need to be extended.
Journal Articles on this Report: 2 Displayed | Download in RIS Format
| Other project views: | All 5 publications | 2 publications in selected types | All 2 journal articles |
| Type | Citation | ||
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Blossom SJ, Pumford NR, Gilbert KM. Disinfection by-products trichloroacetaldehyde and trichloroacetic acid in the water supply promote T cell activation in mice. Journal of Autoimmunity, 2004. 23(3): 211-220. |
R829417E02 (2002) R829417E02 (2003) |
not available |
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Gilbert KM, Whitlow A, Pumford NR. Environmental contaminant and disinfection by-product trichloroacetaldehyde stimulates T cells in vitro. International Journal of Immunopharmacology 2004;4(1):25-36. |
R829417E02 (2002) R829417E02 (2003) R829417E02 (Final) |
not available |
lupus, immunotoxicology, disinfection byproducts, DBPs, autoimmunity. , POLLUTANTS/TOXICS, Water, INTERNATIONAL COOPERATION, Geographic Area, Scientific Discipline, Health, RFA, PHYSICAL ASPECTS, Drinking Water, Risk Assessments, Health Risk Assessment, Physical Processes, Water Pollutants, Environmental Chemistry, State, drinking water system, water quality, ecological risk assessment, bioindicator, alternative disinfection methods, disinfection byproducts, human health risk, chemical byproducts, disinfection byproducts (DPBs), other - risk assessment, autoimmunity, environmental risks, drinking water treatment, exposure, biomarker, human exposure, animal model, diagnostic tool, Arkansas
Progress and Final Reports:
Original Abstract
2003 Progress Report
Final Report