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Alternariol induces abnormal nuclear morphology and cell cycle arrest in murine RAW 264.7 macrophages
A Solhaug1, J A Holme, K Haglund
1Norwegian Veterinary Institute, Oslo, Norway. Anita.Solhaug@vetinst.no
Abstract:
The mycotoxin alternariol (AOH), a frequent contaminant in fruit and cereal products, is known to induce DNA damage with subsequent cell cycle arrest. Here we elucidated the effects of AOH on stages of cell cycle progression using the RAW 264.7 macrophage model. AOH resulted in an accumulation of cells in the G2/M-phase (4N). Most cells exhibited a large G2 nucleus whereas numbers of true mitotic cells were reduced relative to control. Both cyclin B1 and p-cdc2 levels increased, while cyclin B1 remained in the cytoplasm; suggesting arrest in the G2/M transition point. Remarkably, after exposure to AOH for 24h, most of the cells exhibited abnormally shaped nuclei, as evidenced by partly divided nuclei, nuclear blebs, polyploidy and micronuclei (MN). AOH treatment also induced abnormal Aurora B bridges, suggesting that cytokinesis was interfered within cells undergoing karyokinesis. A minor part of the resultant G1 tetraploid (4N) cells re-entered the S-phase and progressed to 8N cells.
Insights
The mycotoxin alternariol (AOH) causes DNA damage, leading to cell cycle arrest in macrophages. AOH disrupts mitosis and cytokinesis, resulting in abnormal cell nuclei and polyploidy.
Area of Science:
- Toxicology
- Cell Biology
- Molecular Biology
Background:
- Mycotoxins like alternariol (AOH) are common food contaminants.
- AOH is known to cause DNA damage and cell cycle arrest.
Purpose of the Study:
- To investigate the effects of AOH on cell cycle progression in RAW 264.7 macrophages.
- To elucidate the specific mechanisms of AOH-induced cell cycle disruption.
Main Methods:
- Exposure of RAW 264.7 macrophages to AOH.
- Analysis of cell cycle distribution using flow cytometry.
- Assessment of nuclear morphology and mitotic abnormalities.
- Evaluation of key cell cycle regulatory proteins (cyclin B1, p-cdc2).
Main Results:
- AOH induced G2/M phase cell cycle arrest with large G2 nuclei and reduced mitotic figures.
- Increased cyclin B1 and p-cdc2 levels, with cyclin B1 cytoplasmic localization, indicated G2/M transition arrest.
- Significant nuclear abnormalities including polyploidy, micronuclei, and abnormal Aurora B bridges were observed.
- A minor population of tetraploid cells re-entered S-phase, progressing to 8N cells.
Conclusions:
- AOH disrupts cell cycle progression at the G2/M transition in macrophages.
- AOH interferes with both karyokinesis and cytokinesis, leading to multinucleated and polyploid cells.
- The observed abnormalities suggest a potential for genotoxicity and aneuploidy induction by AOH.
