Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice

https://doi.org/10.1016/j.taap.2007.11.031Get rights and content

Abstract

Trichloroethene (TCE) exacerbates the development of autoimmune responses in autoimmune-prone MRL +/+ mice. Although TCE-mediated autoimmune responses are associated with an increase in serum immunoglobulins and autoantibodies, the underlying mechanism of autoimmunity is not known. To determine the progression of TCE-mediated immunotoxicity, female MRL +/+ mice were chronically exposed to TCE through the drinking water (0.5 mg/ml of TCE) for various periods of time. Serum concentrations of antinuclear antibodies increased after 36 and 48 weeks of TCE exposure. Histopathological analyses showed lymphocyte infiltration in the livers of MRL +/+ mice exposed to TCE for 36 or 48 weeks. Lymphocyte infiltration was also apparent in the pancreas, lungs, and kidneys of mice exposed to TCE for 48 weeks. Immunoglobulin deposits in kidney glomeruli were found after 48 weeks of exposure to TCE. Our results suggest that chronic exposure to TCE promotes inflammation in the liver, pancreas, lungs, and kidneys, which may lead to SLE-like disease in MRL +/+ mice.

Introduction

Trichloroethene (trichloroethylene, TCE), a chlorinated ethene commonly used as an industrial solvent for degreasing metals, is a ubiquitous environmental contaminant (Landrigan et al., 1987, Cohn et al., 1994). Environmental and occupational exposure to TCE has been linked to the development of autoimmune diseases, such as systemic lupus erythematosus (SLE), scleroderma, systemic sclerosis, and fasciitis (Lagakos et al., 1986, Byers et al., 1988, Kilburn and Warshaw, 1992, Waller et al., 1994, Reinl, 1957, Saihan et al., 1978, Phoon et al., 1984, Flindt-Hansen and Isager, 1987, Lockey et al., 1987, Brasington and Thorpe-Swenson, 1991, Goon et al., 2001, Brautbar, 2004).

An animal model, female autoimmune-prone MRL +/+ mice, to study the potential of TCE to induce/exacerbate autoimmunity was developed in our laboratory (Khan et al., 1995). We hypothesize that TCE reactive metabolites bind to self-proteins to form protein adducts, which then escape normal tolerance to self-proteins and act as neo-antigens, elicit autoreactive T cells resulting in B cell activation, induce autoimmune responses, and eventually lead to autoimmune diseases similar to SLE. This hypothesis is supported by our studies in MRL +/+ mice, which provided evidence that TCE induces or accelerates autoimmune responses (Khan et al., 1995), and that treatment with a reactive TCE metabolite, dichloroacetyl chloride (DCAC), increases serum levels of total IgG, DCAC-specific antibodies, and antinuclear antibodies, which is a measure of systemic autoimmunity (Khan et al., 1997, Cai et al., 2006). Protein-adducts of reactive metabolites of TCE also cause autoimmunity in MRL +/+ mice (Cai et al., 2007). However, very little is known about the effects of chronic exposure to TCE on autoimmune responses. Here, using our in vivo model, we show that TCE-accelerated autoimmunity in female MRL +/+ mice is associated with characteristics of SLE-like disease such as increased antinuclear antibodies, activated T cells, multi-organ infiltration of lymphocytes, and immunoglobulin deposits in kidney glomeruli.

Section snippets

Animal treatment

Five-week-old female MRL +/+ mice (body weight 23 to 26 g) were purchased from the Jackson Laboratory (Bar Harbor, ME) and acclimatized in the University of Texas Medical Branch's (UTMB) humidity- and temperature-controlled animal care facility, which is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International, for one week and provided lab chow and drinking water ad libitum. All experiments were performed in accordance with the guidelines of the

Water consumption

No statistically significant difference was observed in the consumption of water between untreated and TCE-treated MRL +/+ mice (data not shown).

Body weight gain

To determine if prolonged exposure to TCE via the drinking water affected the general health of MRL +/+ mice, body weight was recorded. After eleven weeks of TCE treatment, a statistically significant decrease in body weight gain (26% lower than age-matched, controls) was observed. For the remainder of the experimental exposure (total exposure time of

Discussion

In this report, we demonstrate that chronic TCE exposure may lead to SLE-like disease. The disease may be caused by reactive metabolites (intermediates) of TCE (Khan et al., 1997, Cai et al., 2006, Cai et al., 2007). TCE can be metabolized either oxidatively or through glutathione conjugation pathways. The glutathione-mediated metabolism is of minor significance in humans (Bloemen et al., 2001), and thus, we focused on the oxidative metabolic pathway. TCE can be oxidized to TCE-oxide, which can

Acknowledgments

This publication was made possible by grant ES11584 from the National Institute of Environmental Health Sciences (NIEHS), and its content are solely the responsibility of the authors and do not necessarily represent the views of the NIH or NIEHS. We gratefully acknowledge the Organic Synthesis Core at UTMB for the preparation of dichloroacetyl-albumin adducts supported by NIEHS center grant, P30ES06676.

References (41)

  • WhiteI.N. et al.

    Neoantigen formation and clastogenic action of HCFC-123 and perchloroethylene in human MCl-5 cells

    Toxicol. Lett.

    (2001)
  • BloemenL.T. et al.

    Study on the cytochrome P-450- and glutathione-dependent biotransformation of trichloroethylene in humans

    Int. Arch. Occup. Environ. Health

    (2001)
  • BoltH.M. et al.

    Irreversible binding of chlorinated ethylenes to macromolecules

    Environ. Health Persp.

    (1977)
  • BoltH.M. et al.

    Incubation of 14C-trichloroethylene vapor with rat liver microsomes. Uptake of radioactivity and covalent protein binding of metabolites

    Int. Arch. Occup. Environ. Health

    (1977)
  • BrasingtonR.D. et al.

    Systemic sclerosis associated with cutaneous exposure to solvent: case report and review of the literature

    Arthritis Rheum.

    (1991)
  • BrautbarN.

    Industrial solvents and kidney diseases

    Int. Occup. Environ. Health

    (2004)
  • ByersV.S. et al.

    Association between clinical symptoms and lymphocyte abnormalities in a population with chronic domestic exposure to industrial solvent contaminated domestic water supply and a high incidence of leukemia

    Cancer Immunol. Immunother.

    (1988)
  • CaiH. et al.

    Acylation of protein lysines by trichloroethylene oxide

    Chem. Res. Toxicol.

    (2000)
  • CaiH. et al.

    Mechanism of aqueous decomposition of trichloroethylene oxide

    J. Am. Chem. Soc.

    (1999)
  • ChristenU. et al.

    Identification of the dihydrolipoamide acetyltransferase subunit of the human pyruvate dehydrogenase complex as an autoantigen in halothane hepatitis: Molecular mimicry of trifluoroacetyl-lysine by lipoic acid

    Eur. J. Biochem.

    (1994)
  • Cited by (0)

    View full text