Immuno- and Hepato-Toxicity of Dichloroacetic Acid in MRL^+/+and B₆C₃F₁Mice

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 B 6 C 3 F 1 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 B 6 C 3 F 1 mice, only serum IgG 3 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 B 6 C 3 F 1 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 B 6 C 3 F 1 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 B 6 C 3 F 1 mice. Thus, the cytokine levels in serum and liver, and the cytokine secretion patterns from stimulated splenic T-lymphocytes suggested

Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger

“…Not surprisingly, approaches using such metabolic targeting therapies are rapidly gathering momentum as promising novel treatments for cancer (reviewed in Michelakis et al, 2008;Ralph and Neuzil, 2009). Unfortunately, DCA is not specific for tumor PDH and similar doses inhibiting the tumor enzyme also decrease other metabolic pathways causing toxicity to the normal tissues as well (Cai et al, 2007).…”

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

“…In a number of in vitro studies, DCA is reported to enhance reactive oxygen generation (ROS) generation and oxidative stress leading to cell death (Ayyanathan et al 2012;Hassoun and Ray 2003;Wong et al 2008). In exposed in vivo models, mainly rodents, DCA is reported to cause developmental- (Smith et al 1992), spermato- (Linder et al 1997), immuno-, and hepatotoxicity (Cai et al 2007;Hassoun and Dey 2008). However, concern about DCA adversity underlies on the data generated in rodents after their exposure to this chemical at doses (up to~4,000 mg/kg) thousands of times higher than those to which humans are usually exposed (Stacpoole et al 1998).…”

Suppression of immunity by some pesticides, xenobiotics, and industrial chemicals. <i>In vitro</i> model

“…Increased hepatocellular carcinomas were observed in male mice given DCA in drinking water [14][15][16]. The hepato-and immunotoxicity of DCA are described in [17]. Immunotoxicity was characterized as a pronounced response in this investigation.…”