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Carcinogenic doses of methylnitrosourea induce dose response related delay in transit through S and G2 phases in
Abstract:
The cell kinetic, tumorigenic and carcinogenic effects of the short acting, alkylating carcinogen N-methyl-N-nitrosourea (MNU) on hairless mouse epidermis were investigated. The epidermal mitotic rate, the mitotic index, and the number of basal and suprabasal cells were scored in histological sections. Incorporation of [3H]thymidine and flow cytometric analysis of cellular DNA and protein content were performed on isolated basal cells at intervals for up to 10 days after a single application of either 1 or 10 mg MNU. The ensuing tumor rates and yields were observed for up to 48 weeks after 1 mg MNU and 30 weeks after 10 mg MNU. Generally, MNU induced an initial delay in epidermal cell cycle progression with an accumulation of cells in the S and G2 phases. Some days after treatment the delayed cells were released and entered mitosis. One milligram MNU caused a moderate delay of cells in S and G2, lasting for 2-3 days, and this was followed by a release leading to an increased number of suprabasal cells on day 7. The highest dose of MNU caused a more pronounced delay in transit through S and G2 and seemed to be followed by rapid regenerative proliferation. The subsequent tumor crop after 10 mg was significantly higher than that seen after the lowest dose. The present cell kinetic results are consistent with previous data from the study of other carcinogens, all showing a carcinogen-induced initial reduction in DNA synthesis after appropriate doses. A delay in transit through G2 phase was found as well, indicating that a general delay in cell cycle progression may follow the application of most (or all) carcinogens.
Insights
N-methyl-N-nitrosourea (MNU) carcinogen exposure initially delays hairless mouse epidermal cell cycle progression. Higher doses of MNU lead to more significant delays and increased tumor development, suggesting a general cell cycle delay mechanism for carcinogens.
Area of Science:
- Dermatology
- Toxicology
- Cell Biology
Background:
- N-methyl-N-nitrosourea (MNU) is a short-acting alkylating carcinogen.
- Understanding the cell kinetic, tumorigenic, and carcinogenic effects of MNU on mouse epidermis is crucial for carcinogen research.
Purpose of the Study:
- To investigate the cell kinetic, tumorigenic, and carcinogenic effects of MNU on hairless mouse epidermis.
- To analyze the impact of MNU on epidermal cell cycle progression, DNA synthesis, and tumor formation.
Main Methods:
- Histological analysis of epidermal mitotic rate, mitotic index, and cell counts.
- Measurement of [3H]thymidine incorporation in isolated basal cells.
- Flow cytometry for cellular DNA and protein content analysis.
- Long-term observation of tumor rates and yields after MNU application.
Main Results:
- MNU induced an initial delay in epidermal cell cycle progression, with cells accumulating in S and G2 phases.
- A moderate delay (2-3 days) was observed with 1 mg MNU, followed by an increase in suprabasal cells.
- The higher dose (10 mg MNU) caused a more pronounced delay and was followed by rapid regenerative proliferation and a significantly higher tumor yield.
- Carcinogen-induced reduction in DNA synthesis and G2 phase delay were consistent findings.
Conclusions:
- MNU causes dose-dependent delays in epidermal cell cycle progression.
- The observed cell kinetic changes are consistent with the effects of other carcinogens.
- A general delay in cell cycle progression may be a common response to carcinogen exposure.