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Initiating carcinogen, triethylenemelamine, induces micronuclei in skin target cells
Abstract:
Keratinocytes from mouse skin were cultured for a short period in vitro following single or multiple treatments at low dose levels in vivo with the known chromosome-damaging agent triethylenemelamine (TEM). The chemical was applied to the skin of HRA/Skh hairless mice at concentrations corresponding to those reported to initiate cancer in initiation-promotion assays. A significant dose-related depression in keratinocyte cell recovery occurred over the dose range 0.3-1 mg TEM/mouse (single or multiple treatments). Under the same conditions, a dose-related induction of micronuclei was observed using the cytokinesis-block method with cytochalasin B. A similar frequency of micronuclei was detected in binucleate cells from mice treated with single or multiple applications of TEM. Mice held for 12-48 h post-treatment, before removal of skin for in vitro culture, yielded highest micronuclei frequencies. These results indicate that the same target cell population, skin keratinocytes, can be used to investigate both genotoxicity and carcinogenesis, and that micronucleus induction in these cells may be a sensitive signal of skin cancer initiation.
Insights
This study shows that triethylenemelamine (TEM) damages mouse skin cells, causing fewer cells to recover and more micronuclei, indicating potential skin cancer initiation. This suggests skin keratinocytes can signal genotoxicity and carcinogenesis.
Area of Science:
- Toxicology and Carcinogenesis
- Dermatology
- Genetics and Molecular Biology
Background:
- Skin keratinocytes are crucial for skin barrier function and are a target for environmental carcinogens.
- Assessing genotoxicity and carcinogenesis in skin cells is vital for understanding cancer initiation.
- Triethylenemelamine (TEM) is a known chromosome-damaging agent used in cancer research.
Purpose of the Study:
- To investigate the genotoxic effects of triethylenemelamine (TEM) on mouse skin keratinocytes in vivo and in vitro.
- To evaluate the potential of skin keratinocytes as a model for studying both genotoxicity and carcinogenesis.
- To determine if micronucleus induction in keratinocytes can serve as an early indicator of skin cancer initiation.
Main Methods:
- HRA/Skh hairless mice were treated topically with varying doses of TEM.
- Skin keratinocytes were cultured in vitro following TEM exposure.
- Cell recovery was assessed, and genotoxicity was measured by micronucleus induction using the cytokinesis-block method with cytochalasin B.
Main Results:
- A significant dose-related decrease in keratinocyte cell recovery was observed with TEM treatment (0.3-1 mg/mouse).
- TEM induced a dose-related increase in micronuclei in cultured skin keratinocytes.
- Peak micronuclei frequencies were detected in cells from mice treated 12-48 hours prior to skin harvesting.
Conclusions:
- Skin keratinocytes are a suitable target cell population for investigating both genotoxicity and carcinogenesis.
- Micronucleus induction in mouse skin keratinocytes is a sensitive biomarker for genotoxic events.
- This model system may predict skin cancer initiation following exposure to genotoxic agents like TEM.