Differences in Phenotype and Cell Replicative Behavior of Hepatic Tumors Induced by Dichloroacetate (DCA) and Trichloroacetate (TCA)

Stauber, Anja J.; Bull, Richard J.

doi:10.1006/taap.1997.8159

Cited by 47 publications

(54 citation statements)

References 38 publications

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“…Our findings are also consistent with previous reports on the induction (by DCA and trichloroacetic acid) of in vivo hepatocyte replication, which is transient (Stauber and Bull, 1997) and occurs in the absence of detectable mitogenic activity in vitro (Walgren et al, 2005). Thus, after 12 wk of exposure to DCA, we measured increased liver weights in treated mice, although PCNA staining was negative.…”

Section: Discussionsupporting

confidence: 93%

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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Section: Discussionsupporting

confidence: 93%

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

Cai

Boor

Khan

et al. 2007

Journal of Immunotoxicology

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“…Small AHF (> 300 cells/AHF) were primarily eosinophilic, while the large AHF (> 1,000 cells/focus and corresponding to the LFCA) were primarily basophilic. The population of neoplastic lesions was found to have a significantly higher ratio of basophilic to eosinophilic lesions (Stauber and Bull 1997), which is similar to the findings in the present study. As seen in Tables 3 and 4, the number of basophilic and/or clear cell LFCA and ADs per animal was significantly different from controls at both low and high doses of DCA, and the development of basophilic and/or clear cell AHF, LFCA, and ADs was related to length of exposure and DCA dose.…”

Section: Discussionsupporting

confidence: 91%

“…The combined total of basophilic and/or clear cell LFCA and ADs was greater than the number of basophilic and/or clear cell AHF, indicating a faster growth rate of these AHF compared to eosinophilic AHF. This was consistent with the study of Stauber and Bull (1997), which treated male B6C3F 1 mice with 2 g/L DCA for 38 or 50 weeks before transferring groups to 0 to 2 g/L DCA for another 2 weeks. Small AHF (> 300 cells/AHF) were primarily eosinophilic, while the large AHF (> 1,000 cells/focus and corresponding to the LFCA) were primarily basophilic.…”

Section: Discussionsupporting

confidence: 90%

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A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

Carter

Deddens

et al. 2003

Environ Health Perspect

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Dichloroacetic acid (DCA) is carcinogenic to the B6C3F(1) mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in drinking water, reliable biologically based models to reduce the uncertainty of risk assessment for human exposure to DCA are needed. Development of such models requires identification and quantification of premalignant hepatic lesions, identification of the doses at which these lesions occur, and determination of the likelihood that these lesions will progress to cancer. In this study we determined the dose response of histopathologic changes occurring in the livers of mice exposed to DCA (0.05-3.5 g/L) for 26-100 weeks. Lesions were classified as foci of cellular alteration smaller than one liver lobule (altered hepatic foci; AHF), foci of cellular alteration larger than one liver lobule (large foci of cellular alteration; LFCA), adenomas (ADs), or carcinomas (CAs). Histopathologic analysis of 598 premalignant lesions revealed that (a)) each lesion class had a predominant phenotype; (b)) AHF, LFCA, and AD demonstrated neoplastic progression with time; and (c)) independent of DCA dose and length of exposure effects, some toxic/adaptive changes in non-involved liver were related to this neoplastic progression. A lesion sequence for carcinogenesis in male B6C3F(1) mouse liver has been proposed that will enable development of a biologically based mathematical model for DCA. Because all classes of premalignant lesions and CAs were found at both lower and higher doses, these data are consistent with the conclusion that nongenotoxic mechanisms, such as negative selection, are relevant to DCA carcinogenesis at lower doses where DCA genotoxicity has not been observed.

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“…Exposure to DCA produces an initial mitogenic response in mouse hepatocytes that is suppressed by continued treatment (Stauber and Bull 1997). The interaction between Ras and Raf is a focal point for cross-talk between growth factor-and cAMP-dependent signaling pathways.…”

Section: Structural Bases Of Selectivitymentioning

confidence: 99%

Science to Support DOE Site Cleanup: The Pacific Northwest National Laboratory Environmental Management Science Program Awards-Fiscal Year 1999 Mid-Year Progress Report

Peurrung¹

1999

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Over three-hundred underground storage tanks containing about 350,000 cubic meters (92 million gallons) of mixed chemical and radioactive waste are located at the Hanford Site (Washington), Oak Ridge Reservation (Tennessee), Savannah River Site (South Carolina), Idaho National Engineering and Environmental Laboratory (Idaho), and West Valley Site (New York). The liquids, sludges; saltcake, and calcined solids (at Idaho) in these tanks contain about 70% (720 million curies) of the man-made radioactivity existing in the DOE complex. Remediation of this tank waste is one of the most technically complex, scientifically challenging, and potentially expensive problems facing DOE.Hanford contains 60% of the waste volume and 30% of the radioactivity for all DOE highlevel waste tanks. At Hanford there are 177 underground storage tanks containing 210,000 cubic meters (55 million gallons) ofhigh-level waste. The current baseline approach to remediating this tank waste involves retrieving the waste followed by a solid-liquid separation. The liquid, low-activity stream will have cesium (Cs) and other radionuclides removed and then be immobilized as low-level radioactive and chemical waste. The solid, high-activity stream will be pretreated to reduce its volume (mainly through the removal of non-radioactive inorganic components such as chromium, phorphous, and aluminum) and then immobilized as high-level radioactive waste.The presence of sub-micron, colloidal particles in the waste complicates nearly every aspect of waste processing. They make the separation of solid and liquid waste streams difficult by forming colloidal suspensions, which may take months to settle, if at all. These suspensions can also form sediments or gels, clogging pipes and interrupting waste transfer operations.lll Colloidal particles can also contaminate the liquid waste, complicating downstream processing. Radionuclides can adsorb to the particles' surface and radioactively contaminate the low-level liquid waste stream, forcing it to be treated as high-activity waste, thereby increasing treatment costs. In other cases, the presence of colloidal particles interferes with separations processes; for example, plugging ion exchange columns causing schedule delays and increased costs.The EMSP project Colloidal Agglomerates in Tank Sludge: Impact on Waste Processing (Page 1) is conducting experiments to understand and identify the chemical conditions which control the formation and agglomeration of colloidal particles. In this way, the impact that agglomerate structures have on the rheology and sedimentation properties of the waste can be quantified, and methods for manipulating agglomerate structures to optimize tank waste transfer and processing conditions can be developed. It is important to note that the new knowledge and data generated by this project will also be of benefit to the cleanup ofN-Basin liquids at Hanford, and of the tank wastes at the Oak Ridge Reservation and the Savannah River Site.The removal of radionuclides to prepare the liquid wast...

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Differences in Phenotype and Cell Replicative Behavior of Hepatic Tumors Induced by Dichloroacetate (DCA) and Trichloroacetate (TCA)

Cited by 47 publications

References 38 publications

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

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

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

Science to Support DOE Site Cleanup: The Pacific Northwest National Laboratory Environmental Management Science Program Awards-Fiscal Year 1999 Mid-Year Progress Report

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Differences in Phenotype and Cell Replicative Behavior of Hepatic Tumors Induced by Dichloroacetate (DCA) and Trichloroacetate (TCA)

Cited by 47 publications

References 38 publications

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

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

A 2-year dose-response study of lesion sequences during hepatocellular carcinogenesis in the male B6C3F(1) mouse given the drinking water chemical dichloroacetic acid.

Science to Support DOE Site Cleanup: The Pacific Northwest National Laboratory Environmental Management Science Program Awards-Fiscal Year 1999 Mid-Year Progress Report

Contact Info

Product

Resources

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

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