Lack of direct mitogenic activity of dichloroacetate and trichloroacetate in cultured rat hepatocytes

Walgren, Jennie; Kurtz, David T.; McMillan, Jo Ellyn

doi:10.1016/j.tox.2005.03.009

Cited by 11 publications

(5 citation statements)

References 60 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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“…Moreover, in contrast to Wy-14,643, DEHP only transiently increases DNA synthesis and at higher doses than required for carcinogenesis (Conway et al 1989; David et al 1999; Marsman et al 1988) (Table 1). Only short-term increases in rat liver DNA synthesis are seen with many other PPAR-α agonists, including clofibrate [ethyl 2-(4-chlorophenoxy)-2-methylpropanoate] (Tanaka et al 1992), clofibric acid [2-( p -chlorophenoxy)-2-methylpropionic acid] (Barrass et al 1993; Marsman et al 1992), nafenopin (2-methyl-2[ p -(1,2,3,4-tetrahydro-1-naphthyl)phenoxy]-propionic acid) (Eacho et al 1991; Lake et al 1993), ciprofibrate (2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid) (Yeldandi et al 1989), and trichloroacetic acid (TCA) (Walgren et al 2005). A causal mechanistic link between transient increases in DNA synthesis and rodent hepatocarcinogenesis remains to be established (Melnick et al 1993).…”

Section: Do Ppar-α Activation and Its Sequelae In Hepatocytes Cause Cmentioning

confidence: 99%

A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

Guyton

Chiu

Bateson

et al. 2009

Environ Health Perspect

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BackgroundDiverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator–activated receptor-α (PPAR-α) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-α agonists is irrelevant to human carcinogenic risk.Data synthesisHerein, we review recent studies that experimentally challenge the PPAR-α activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-α–null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-α activation in a transgenic mouse model. We further examine whether relative potency for PPAR-α activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-α agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis.ConclusionsOur review and analyses raise questions about the hypothesized PPAR-α activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-α agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-α. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation.

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“…However, as anticipated, there were no large decreases in serum insulin concentrations during this study, or any changes in PDK4 expression. Despite the potential action of DCA on peroxisome proliferator-activated receptor-α (PPARα) – via changes in expression [22] and trans-activation [23] – there was no change in the mRNA content of PPARα and PPARδ in DCA or CON. However, the PPAR co-activator-1α, PGC1α, did increase significantly in CON, but not in DCA-treated subjects.…”

Section: Discussionmentioning

confidence: 99%

Skeletal Muscle Metabolic Gene Expression Is Not Affected by Dichloroacetate-Mediated Modulation of Substrate Utilisation

Tisdale¹,

Seevaratnam²,

Macdonald³

et al. 2011

Ann Nutr Metab

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Aim: This study investigated whether changing fuel use, by increasing pyruvate dehydrogenase complex (PDC) flux, independently of plasma substrate availability and insulin signalling, would alter metabolic gene expression. Methods: The PDC activator, dichloroacetate (DCA), was administered as an intravenous infusion in healthy male subjects at a rate of 50 mg kg^–1 min^–1, for 90 min. Saline was infused as a control (CON) on a separate occasion in a randomised sequence. Muscle biopsies were taken from the vastus lateralis at 0 and 30 min into the infusion and 90 min after infusion. Gene expression was quantified using RT-qPCR, and immunoblotting was used to confirm that there were no changes in insulin signalling via the PI3K/Akt pathway. Results: Blood glucose concentrations fell during both trials but 3 h after the start of the infusion they were lower in DCA (p < 0.05) than CON. Blood lactate concentrations also declined in both trials (p < 0.01), however, this decrease was also more pronounced in DCA than CON (p < 0.001). Carbohydrate oxidation was increased by DCA, 0.037 ± 0.017 g min^–1 (p < 0.05) at 3 h with no change observed in CON. UCP3 and PGC1α mRNA expression were induced in CON (as a response to continued fasting) but this was attenuated by DCA. Akt phosphorylation and the expression of other metabolic genes and transcription factors were unchanged throughout the intervention. Conclusion: It is concluded that PDC flux can be increased independently of plasma substrate availability, without causing downstream alterations to metabolic gene expression in the short term.

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Lack of direct mitogenic activity of dichloroacetate and trichloroacetate in cultured rat hepatocytes

Cited by 11 publications

References 60 publications

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

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

A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

Skeletal Muscle Metabolic Gene Expression Is Not Affected by Dichloroacetate-Mediated Modulation of Substrate Utilisation

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Lack of direct mitogenic activity of dichloroacetate and trichloroacetate in cultured rat hepatocytes

Cited by 11 publications

References 60 publications

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

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

A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

Skeletal Muscle Metabolic Gene Expression Is Not Affected by Dichloroacetate-Mediated Modulation of Substrate Utilisation

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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