Trichloroethylene Does Not Accelerate Autoimmune Diabetes in NOD Mice

Abstract

Pre-existing or contributing risk factors, including genetic predisposition and environmental influences, are largely thought to play a crucial (though ill-elucidated) role in the development of autoimmunity. Trichloroethylene (TCE) is a widely used organic solvent, which has been suspected of increasing the prevalence of autoimmune diseases, e.g., lupus, following environmental contamination. Although few epidemiological data are available, several studies reported an accelerated and more severe disease in TCEexposed autoimmunity-prone MRL +/+ mice. To test whether TCE can exert similar deleterious effects on organ-specific autoimmune diseases, non obese diabetic (NOD) mice were given 5 mg/ml TCE via the drinking water for 12 weeks. TCE administration induced a decrease in CD44 + splenic T-cells and CD45RB high , CD54 + blood and splenic T-cells. Conversely, the number of CD45RB low splenocytes was increased. Interestingly, the progressive increase in serum TNF-α and IFN-γ levels normally seen with age in these mice was inhibited by TCE. There was also a relative lower incidence of histological changes in the pancreas of TCE-exposed NOD mice than in unexposed mice. Contrary to what has been found in systemic models of autoimmunity, TCE did not accelerate the diabetes of NOD mice and may have a protective effect. This finding suggests that comparative studies using different genetically related autoimmune-prone models are needed to investigate the role of xenobiotics in the precipitation of autoimmunity, particularly in sensitive populations.

Toxicogenomic Analysis Reveals Profibrogenic Effects of Trichloroethylene in Autoimmune-Mediated Cholangitis in Mice

“…A previous study found that TCE exposure did not exacerbate autoimmunity in NOD.ShiLtJ mice (Ravel et al, 2005). In agreement, exposure to TCE had no effect on profibrogenic gene expression or hepatic collagen deposition in NOD.ShiLtJ mice, suggesting that exposure to this environmental contaminant selec-tively modifies the progression of liver disease only in the context of autoimmunity.…”

“…Early fibrosis was reported to occur in only a small number of NOD.c3c4 mice (Irie et al, 2006), rendering the observation that TCE exacerbates this feature of disease quite exciting. Of importance, TCE exposure did not cause fibrosis in livers of NOD.ShiLtJ mice, in which TCE has been shown to not increase autoimmunity (Ravel et al, 2005). Taken together, the results in NOD.c3c4 mice suggest that TCE has the potential to act as a disease modifier in the presence of concurrent hepatic autoimmunity.…”

Immune assessments in developmental and juvenile toxicology: Practical considerations for the regulatory safety testing of pharmaceuticals

“…At the present time, there is little scope to screen for xenobiotics which promote hypersensitivity and/or autoimmunity. A few animal models of autoimmune diseases have been developed, such as the non-obese diabetic (NOD) mouse (Atkinson and Leiter, 1999;Ravel et al, 2004) or the Bio-Breeding (BB) rat (Kroemer et al, 1992) for type 1 diabetes, and the (NZB £ NZW) F 1 mouse (Burnett et al, 2004;Ravel et al, 2002), for systemic lupus erythematosus. Their use in developmental or juvenile studies would be extremely problematic, owing to the compromised reproductive capacity of the animal strains used.…”

Trichloroethylene exposure reduces liver injury in a mouse model of primary biliary cholangitis

“…Rather, this highlights a model-specific response and the importance of defining the impact of TCE on autoimmunity across multiple models. Interestingly, in nonobese diabetic (NOD) mice, which also develop autoimmunity, TCE exposure did not accelerate autoimmunity and the mice did not develop autoimmune hepatitis (Ravel et al, 2005). In NOD mice, TCE exposure reduced lymphocyte proliferation and cytokine production, suggesting a protective effect (Ravel et al, 2005).…”