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Reversibility of promoter induced hepatic focal lesion growth in mice
K L Kolaja1, D E Stevenson, E F Walborg
1Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis 46202, USA.
Abstract:
The effect of cessation of phenobarbital and dieldren treatment on hepatic focal lesion growth in male B6C3F1 mice was investigated. Following induction of lesions by diethylnitrosamine, mice were placed on control NIH-07 diet (control diet) or NIH-07 diet containing either dieldrin (10.0 mg/kg diet) or phenobarbital (500 mg/kg diet). Mice were sacrificed after 30 and 60 days of dietary treatment. Two additional groups of mice were fed either the dieldren- or phenobarbital-containing diet for 30 days followed by feeding of NIH-07-only diet for an additional 30 days. The effect of treatment and removal of dieldrin or phenobarbital on lesion growth was examined by measuring both the number of focal lesions per liver and the relative volume of focal lesions. In addition, the rate of cell proliferation and programmed cell death in focal lesion growth was investigated by examining DNA synthesis and apoptosis in the focal lesions. Dietary dieldrin or phenobarbital increased the number of focal lesions and the focal lesion volume. In both dieldrin- and phenobarbital-treated mice, an increased number of eosinophilic lesions were seen. The focal lesion volume was increased in both eosinophilic and basophilic lesions. Dieldrin and phenobarbital treatment also increased the DNA synthetic labeling index in both eosinophilic and basophilic lesions. Removal of dieldrin or phenobarbital from the diet after 30 days of promoter treatment decreased the total number and volume of hepatic focal lesions. The labeling index of the focal lesions was also decreased in these mice. At the terminal sacrifice, the percentage of apoptotic cells in focal lesions was higher in mice fed dieldrin- or phenobarbital-containing diets for the entire 60 days than in mice returned to control diet for the last 30 days. Eosinophilic lesions were more dependent on the presence of a promoting stimulus than the basophilic lesions. These data indicate that induction and maintenance of the growth of some preneoplastic lesions in the mouse may be dependent upon continuous tumor promoter treatment.
Insights
Removing tumor promoters like dieldrin and phenobarbital from the diet reduced hepatic focal lesion growth in mice. Continuous exposure to these promoters is necessary for maintaining preneoplastic lesion development.
Area of Science:
- Hepatology
- Toxicology
- Carcinogenesis
Background:
- Phenobarbital and dieldrin are known tumor promoters.
- Preneoplastic hepatic lesions can be induced by diethylnitrosamine.
Purpose of the Study:
- To investigate the effect of phenobarbital and dieldrin cessation on hepatic focal lesion growth.
- To determine the role of continuous promoter exposure in lesion maintenance.
Main Methods:
- Mice were treated with diethylnitrosamine, followed by diets containing dieldrin or phenobarbital.
- Lesion number, volume, cell proliferation (DNA synthesis), and apoptosis were quantified.
- Groups included continuous treatment and cessation of treatment after 30 days.
Main Results:
- Dieldrin and phenobarbital increased hepatic focal lesion number, volume, and cell proliferation.
- Cessation of promoter treatment after 30 days decreased lesion growth and proliferation.
- Apoptosis rates were higher with continuous promoter exposure.
Conclusions:
- Continuous exposure to tumor promoters like dieldrin and phenobarbital is required for the maintenance of preneoplastic hepatic lesions.
- Eosinophilic lesions showed greater dependence on continuous promoter stimulus than basophilic lesions.