Biochemical, pathologic and morphometric alterations induced in male B6C3F1 mouse liver by short-term exposure to dichloroacetic acid

Carter, Julia H.; Carter, Harry W.; DeAngelo, Anthony B.

doi:10.1016/0378-4274(95)03409-9

Cited by 29 publications

(22 citation statements)

References 23 publications

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“…Enlargement of hepatocytes (cytomegaly) was found in 17.4% of the animals (Table 5). Consistent with previous short-term studies (Carter et al 1995a), cytomegaly was present in 90-100% of the livers of mice given 1.0-3.5 g/L DCA for 26 weeks. When DCA dose groups were combined over length of exposure, the incidence of cytomegaly was significantly different from controls in mice receiving 1.0, 2.0, and 3.5 g/L DCA (p ≤ 0.0001).…”

Section: Quantificationsupporting

confidence: 79%

“…Exposure of mice to DCA induces a multitude of toxic and adaptive hepatic responses including mitoinhibition, peroxisome proliferation, glycogen accumulation, and endocrine disruption (Carter et al 1995a;DeAngelo et al 1999;Kato-Weinstein et al 1998). Here we examined the relationship of some of these toxic and adaptive responses to DCA dose and length of exposure and to neoplastic progression.…”

Section: Discussionmentioning

confidence: 99%

“…These lesions have previously been referred to as hyperplastic nodules Carter et al 1995b;Richmond et al 1991Richmond et al , 1995Ward 1984). The present designation of these lesions as LFCA is to avoid confusion with non-neoplastic proliferative lesions termed "hepatocellular hyperplasia" that occur secondary to hepatic degeneration/necrosis or neoplasia (Harada et al 1999).…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemical techniques demonstrated that large foci of cellular alteration (LFCA; formerly called hyperplastic nodules) were putative preneoplastic lesions in the progression of DCA-induced hepatocarcinogenesis in both male B6C3F 1 mice and male F344 rats (Richmond et al 1991(Richmond et al , 1995. The presence of isolated, highly dysplasic hepatocytes in male B6C3F 1 mice chronically exposed to DCA suggested another direct neoplastic conversion pathway (Carter et al 1995a(Carter et al , 1995b. The relevance of these preneoplastic changes for DCA-induced carcinogenesis has not been tested by statistical methods.…”

mentioning

confidence: 99%

“…For example, DCA treatment induced significant effects during the first 30 days of exposure, before development of hepatic lesions. Effects of DCA treatment on B6C3F 1 mouse liver during the first 30 days of exposure to drinking water containing either 0.5 g/L or 5.0 g/L included induction of hypertrophy (Carter et al 1995a); alteration in nuclear size and ploidy (Carter et al 1995a); inhibition of hepatocyte proliferation (Carter et al 1995a;DeAngelo 2000a); and decreased apoptosis (Snyder et al 1995). Hepatocyte hypertrophy reflected accumulation of glycogen and peroxisome proliferation DeAngelo et al 1989).…”

mentioning

confidence: 99%

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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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Section: Quantificationsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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 induction of peroxisome proliferation in cultured hepatocytes

Everhart

Kurtz

McMillan

1998

J. Biochem. Mol. Toxicol.

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Trichloroethylene is a widespread industrial solvent and one of the most common environmental contaminants. Trichloroethylene causes hepatocarcinoma in the B6C3F1 mouse in a dose‐dependent manner. Trichloroethylene's hepatocarcinogenicity is thought to be mediated through its metabolites trichloroacetate and dichloroacetate. Although the mechanism of action is not well understood, hepatic tumors are thought to arise as a result of excessive peroxisome‐dependent active oxygen production or secondary to enhanced cell replication. The peroxisome proliferative activity of trichloroacetate has been replicated in cultured rodent hepatocytes, while that of dichloroacetate has not been demonstrated. The present experiments were designed to characterize the peroxisome proliferative response to dichloroacetate in hepatocyte cultures from male B6C3F1 mice and male Long Evans rats. The cultured hepatocytes were treated after attachment with 0.1, 0.5, 1.0, 2.0, or 4.0 mM dichloroacetate for 72 hours. Peroxisome proliferation was assessed by measuring palmitoyl‐CoA oxidation and by immunoquantitation of peroxisomal bifunctional enzyme. Palmitoyl CoA oxidation increased in a concentration‐dependent manner, with maximal induction of 5.5‐ and 5‐fold in mouse and rat hepatocytes, respectively, after treatment with 2.0 mM dichloroacetate. Peroxisomal bifunctional enzyme protein levels also increased in a concentration‐dependent manner in both rat and mouse hepatocytes in response to dichloroacetate exposure. These results indicate that the peroxisomal response observed in vivo in response to dichloroacetate administration can be reproduced in primary cultures of rat and mouse hepatocytes treated with dichloroacetate. Further studies using this model system will help elucidate mechanisms of dichloroacetate‐induced hepatocarcinogenesis. © 1998 John Wiley & Sons, Inc. J Biochem Mol Toxicol 12: 351–359, 1998

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Dichloressigsäure und ihre Salze [MAK Value Documentation in German language, 2010]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 49. Lieferung, Ausgabe 2010 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Aufnahme, Verteilung, Ausscheidung Metabolismus Erfahrungen beim Menschen Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Bewertung Anhang

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Biochemical, pathologic and morphometric alterations induced in male B6C3F1 mouse liver by short-term exposure to dichloroacetic acid

Cited by 29 publications

References 23 publications

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.

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.

Dichloroacetic acid induction of peroxisome proliferation in cultured hepatocytes

Dichloressigsäure und ihre Salze [MAK Value Documentation in German language, 2010]

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