Immuno- and Hepato-Toxicity of Dichloroacetic Acid in MRL+/+ and B6C3F1 Mice

Abstract

Dichloroacetic acid (DCA) is a by-product of chlorination that occurs in drinking water disinfected with chlorine. Metabolism of trichloroethene (TCE) also generates DCA. TCE exposure is associated with the development of autoimmune diseases, which may be induced by TCE metabolites, such as DCA. Thus, it is important to understand immunotoxic responses to DCA. We chose 2 murine models, autoimmune-prone MRL+/+ and normal B6C3F1 mice. Both strains of mice were exposed to DCA for 12 weeks. Following DCA treatment, liver weights and liver-to-body weight ratios were significantly increased in both strains of mice when compared to their respective controls. The serum activity of alanine and aspartate aminotransferases was not significantly altered in either strain. In MRL+/+ mice, the serum concentrations of IgG and IgM were significantly increased, whereas in B6C3F1 mice, only serum IgG3 was increased. DCA treatment did not change the levels of inflammatory cytokines in the serum. However, independent of treatment, the concentrations of G-CSF in the serum were lower in MRL+/+ mice than in B6C3F1 mice, whereas IL-12 serum levels were higher in MRL+/+ mice. DCA treatment decreased IL-10 and KC chemokine concentrations in the livers of MRL+/+ mice, whereas T-helper cell cytokines (IL-4, IL-5, IL-10, IFNγ, and GM-CSF), pro-inflammatory cytokines (IL-6, IL-12, and G-CSF), and KC chemokine were increased in the livers of DCA-treated B6C3F1 mice. Stimulation of splenic T-lymphocytes with antibodies against CD3 and CD28 resulted in a marked difference in the secreted cytokines between the two strains of mice. T-lymphocytes from MRL+/+ mice secreted more IL-2, IL-4 and IL-10, but less IFNγ and GM-CSF, than did T-lymphocytes from B6C3F1 mice. Thus, the cytokine levels in serum and liver, and the cytokine secretion patterns from stimulated splenic T-lymphocytes suggested a higher propensity of inflammatory responses in B6C3F1 than in MRL+/+ mice. Treatment with DCA also affected lipid accumulation in the liver more severely in B6C3F1 than in MRL+/+ mice. Thus, these results indicate that DCA induced stronger inflammatory responses leading to more severe hepatotoxicity in B6C3F1 mice than in MRL+/+ mice, and more pronounced immune responses in the latter.