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DICHLOROACETIC ACID (DCA) INHIBITS PROLIFERATION AND APOPTOSIS IN NORMAL HEPATOCYTES OF MALE F344 RATS
Citation:
Carter, J. H., E. R. Hugo, L. E. Douglass, R. E. Richmond, A B. DeAngelo, AND S Nesnow. DICHLOROACETIC ACID (DCA) INHIBITS PROLIFERATION AND APOPTOSIS IN NORMAL HEPATOCYTES OF MALE F344 RATS. Presented at American Association of Cancer Research, New Orleans, LA, March 24-28, 2001.
Description:
Dichloroacetic acid (DCA} inhibits proliferation and apoptosis in nonnal hepatocytes of
male F344 rats.
Large segments of the population are chronically exposed to dichloroacetic acid (DCA}: DCA is a by product of the chlorine disinfection of drinking water, a metabolite of several industrial solvents, and a compound used therapeutically, DCA is carcinogenic in the livers of male and female B6C3F1 mice and male F344 rats. Assessment of the risks of chronic human exposure to DCA is incomplete because the carcinogenic mechanism(s} and mode(s) of action of the chemical in rodent bioassays are uncertain. The purpose of this study was to determine if alterations in cell proliferation and cell death were relevant to DCA carcinogenesis in the male F344 rat. DeAngelo, et.aJ reported that the multiplicity and prevalence of neoplasia and proliferative lesions were significantly increased relative to controls in F344 male rats receiving drinking water containing 0.5 g/L DCA (Toxicology 114:207, 1996). In this study, animals were given 0.05 or 0.5 g/L DCA in the drinking water for up to two years. Control animals were given 1.5 g/L acetic acid (HAc), 2,0 g/1 NaC1 or water. Groups of animals were sacrificed quarterly. Cell proliferation was quantified by PCNA labeling and apoptosis by TUNEL in histologic sections of routinely processed livers. Altered foci were identified in H & E stained sections by focal cellular changes in staining characteristics or phenotype or in sections stained immunohistochemically for expression of glutathione-S- transferase P (GSTP). We found that during the first year of treatment, DCA inhibits both cell proliferation and apoptosis in normal hepatocytes relative to HAc controls. However, the number of both phenotypically and GSTP altered foci/cm2 found after two years was similar to controls in DCA treated rats. Taken together these data suggest that DCA may. by inhibiting apoptosis, permit survival of genetically damaged cells that are resistant to the mitoinhibitory action of the chemical. Consistent with this, we have found increased PCNA labeling in GSTP+ foci in DCA treated rats.
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