Contribution of Dichloroacetate and Trichloroacetate to Liver Tumor Induction in Mice by Trichloroethylene

Bull, Richard J.; Orner, Gayle A.; Cheng, Rita; Stillwell, Lisa C.; Stauber, Anja J.; Sasser, L. B.; Lingohr, Melissa K.; Thrall, Brian D.

doi:10.1006/taap.2002.9427

Cited by 67 publications

(58 citation statements)

References 42 publications

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“…Thus, TCE exposure and metabolism yield several metabolites, including chloral, CH, dichloroacetic acid, trichloroacetic acid, trichloroethanol, and dichloroacetyl chloride. Although the assignment of a TCE metabolite to a specific toxic effect and/or to a specific tissue hast proven to be a complex issue, it has been proposed that trichloroacetic acid is associated with hepatotoxicity (Buben and O'Flaherty, 1985), trichloroacetic acid and dichloroacetic acid with hepatocarcinogenicity (Bull et al, 2002), and S-(1,2-dichlorovinyl)-L-cysteine with nephrotoxicity (Dekant et al, 1990;Bruning and Bolt, 2000).…”

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confidence: 99%

Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

Forkert

Millen²,

Lash³

et al. 2005

J Pharmacol Exp Ther

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This study was undertaken to test the hypothesis that bronchiolar damage induced by trichloroethylene (TCE) is associated with bioactivation within the Clara cells with the involvement of CYP2E1 and CYP2F2. Histopathology confirmed dose-dependent Clara cell injury and disintegration of the bronchiolar epithelium in CD-1 mice treated with TCE doses of 500 to 1000 mg/kg i.p. Immunohistochemical studies, using an antibody that recognizes dichloroacetyl lysine adducts, revealed dose-dependent formation of adducts in the bronchiolar epithelium. Localization of dichloroacetyl adducts in the Clara cells coincided with damage to this cell type in TCE-treated mice. Pretreatment of CD-1 mice with diallyl sulfone, an inhibitor of CYP2E1 and CYP2F2, abrogated the formation of the dichloroacetyl adducts and protected against TCE-induced bronchiolar cytotoxicity. Treatment of wild-type and CYP2E1-null mice with TCE (750 mg/kg i.p.) also elicited bronchiolar damage that correlated with the formation of adducts in the Clara cells. Immunoblotting, using lung microsomes from TCE-treated CD-1 mice, showed dose-dependent production of dichloroacetyl adducts that comigrated with CYP2E1 and CYP2F2. However, TCE treatment resulted in a loss of immunoreactive CYP2E1 and CYP2F2 proteins and p-nitrophenol hydroxylation, a catalytic activity associated with both cytochrome P450 enzymes. The TCE metabolite, chloral hydrate, was formed in incubations of TCE with lung microsomes from CD-1, wild-type, and CYP2E1-null mice. The levels were higher in CD-1 than in either wild-type or CYP2E1-null mice, although levels were higher in CYP2E1-null than in wild-type mice. These findings supported the contention that TCE bioactivation within the Clara cells, predominantly involving CYP2F2, correlated with bronchiolar cytotoxicity in mice.

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confidence: 99%

Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

Forkert

Millen²,

Lash³

et al. 2005

J Pharmacol Exp Ther

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“…The metabolism of TCE progresses through hydrolysis of its reactive intermediate DCAC to the stable metabolite DCA (Lash et al, 2000). While several studies have been conducted to determine the effects of TCE (Khan et al, 1995;Griffin et al, 2000a and b;Gilbert et al, 2004) or DCAC (Khan et al, 1997;Cai et al, 2006) on autoimmune responses in susceptible MRL +/+ mice, animal studies with DCA have focused on hepatocarcinogenicity (Bull et al, 1990(Bull et al, , 2002(Bull et al, , 2004. Here, we evaluated the potential for immunotoxicity and hepatotoxicity of DCA in MRL +/+ mice and in the normal strain B 6 C 3 F 1 .…”

Section: Discussionmentioning

confidence: 99%

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

Cai

Boor

Khan

et al. 2007

Journal of Immunotoxicology

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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

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“…For the DCA-or TCA-exposed animals, the experiment was limited by low statistical power (i.e., a maximum of 20 animals were used per exposure group), a relatively short duration of exposure (i.e., 52 weeks), loss of ability to determine specific lesion prevalence and multiplicity (i.e., grouping of hyperplastic nodules, adenomas, and carcinomas together and reporting them as ''tumors''), and incomplete histopathology determinations (i.e., random selection of gross lesions for histopathology examination and differentiation as either nodules, adenomas, or carcinomas). Bull et al [2002] report variability between experiments for the carcinogenic potency for DCA and TCA that could be a reflection of the above design limitations of the experiment. Pereira [1996], and Pereira and Phelps [1996] have also reported results for tumor induction at 51 and 81 weeks using similar exposure concentrations of DCA and TCA as Bull et al [2002].…”

Section: Introductionmentioning

confidence: 89%

“…Bull et al [2002] report variability between experiments for the carcinogenic potency for DCA and TCA that could be a reflection of the above design limitations of the experiment. Pereira [1996], and Pereira and Phelps [1996] have also reported results for tumor induction at 51 and 81 weeks using similar exposure concentrations of DCA and TCA as Bull et al [2002]. Table I shows that a 52-week exposure duration has consistently produced a tumor response for these chemicals, but with greater lesion incidence and multiplicity at 82 versus 52 weeks.…”

Section: Introductionmentioning

confidence: 89%

“…Thus, to determine the effects of coexposure it is important to determine the response for the individual chemicals being tested and to use a robust paradigm with the ability to detect the effects of coexposure. Given the earlier limitations, Bull et al [2002] report consistent liver tumor induction by exposures of TCA (0.5 or 2 g/L) or DCA (0.1, 0.5, or 2 g/L) in drinking water for 52 weeks, and by exposure to TCE (1 g/kg/day) for 79 weeks via gavage. Each chemical is effective as a carcinogen at exposure levels that do not produce observed cytotoxicity in B6C3F1 mice [Bull et al, 1990;Anna et al, 1994;DeAngelo et al, 1999;Bull et al, 2002;Carter et al, 2003].…”

Section: Introductionmentioning

confidence: 91%

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Difficulty of mode of action determination for trichloroethylene: An example of complex interactions of metabolites and other chemical exposures

Caldwell

Keshava

Evans

2007

Environ and Mol Mutagen

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The mode(s) of action (MOA) of a pollutant for adverse health effects may be dependent on the mixture of metabolites resulting from exposure to a single agent and may also be affected by coexposure to pollutants that have similar targets or affected pathways. Trichloroethylene (TCE) can be an useful example for illustration of the complexity coexposure can present to elucidation of the MOA of an agent. TCE exposure has been associated with increased risk of liver and kidney cancer in both laboratory animal and epidemiologic studies. There are a number of TCE metabolites that could play a role in the induction of these effects. Coexposures of other chemicals with TCE typically occurs as a result of environmental cocontamination that include its own metabolites, such as trichloroacetic acid, dichloroacetic acid, and other pollutants with similar metabolites such as perchloroethylene. Behaviors such as alcohol consumption can also potentially modify TCE toxicity through similar MOAs. The U.S. Environmental Protection Agency (EPA)'s 2001 draft TCE risk assessment, Trichloroethylene (TCE) Health Risk Assessment: Synthesis and Characterization, concluded that it was difficult to determine which of the metabolites of TCE may be responsible for these effects, what key events in their hypothesized MOAs are involved, and the relevance of some of the hypothesized MOAs to humans. Since the publication of U.S. EPA's draft TCE assessment, several studies have been conducted to understand the effects of coexposures to TCE. They cover both pharmacodynamic and pharmacokinetic considerations. This article highlights some of the recently published scientific literature on toxicological interactions between TCE, its metabolites, and other coexposures, including solvents, haloacetates, and ethanol. These studies give insight into both the potential MOAs of TCE exposure itself and putative modulators of TCE toxicity, and illustrate the difficulties encountered in determining the MOAs and modulators of toxicity for pollutants with such complex metabolism and coexposures.

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Contribution of Dichloroacetate and Trichloroacetate to Liver Tumor Induction in Mice by Trichloroethylene

Cited by 67 publications

References 42 publications

Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

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

Difficulty of mode of action determination for trichloroethylene: An example of complex interactions of metabolites and other chemical exposures

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Contribution of Dichloroacetate and Trichloroacetate to Liver Tumor Induction in Mice by Trichloroethylene

Cited by 67 publications

References 42 publications

Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

Pulmonary Bronchiolar Cytotoxicity and Formation of Dichloroacetyl Lysine Protein Adducts in Mice Treated with Trichloroethylene

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

Difficulty of mode of action determination for trichloroethylene: An example of complex interactions of metabolites and other chemical exposures

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