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Published on: February 23, 2020
Ki-ras activation in lung cells isolated from AC3F1 (A/J x C3H/HeJ) mice after treatment with aflatoxin B1
1Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Abstract:
Lung cells isolated from AC3F1 (A/J x C3H/HeJ) mice 7 wk after treatment with the carcinogenic mycotoxin aflatoxin B1 (AFB1) were examined for point mutations in the Ki-ras oncogene. Ki-ras mutant allele frequencies in fractions enriched with nonciliated bronchiolar epithelial (Clara) cells were consistently higher than in alveolar type II cell fractions. Mutant alleles were undetectable or minimal in macrophage- and polymorphonuclear leukocyte-enriched fractions. In cells from vehicle (dimethyl sulfoxide)-treated mice, small proportions of mutant Ki-ras alleles were found in the Clara cell-enriched fraction but not in other cell fractions. The results indicated that Clara cells are particularly susceptible to AFB1-induced Ki-ras mutation, an early event in AFB1-induced mouse lung tumorigenesis.
Insights
Carcinogenic aflatoxin B1 (AFB1) causes more Ki-ras mutations in mouse lung Clara cells than other cell types. This suggests Clara cells are particularly susceptible to AFB1-induced mutations, an early step in lung tumor development.
Area of Science:
- Toxicology
- Molecular Biology
- Oncology
Background:
- Aflatoxin B1 (AFB1) is a carcinogenic mycotoxin known to induce DNA mutations.
- The Ki-ras oncogene is frequently mutated in various cancers, including lung tumors.
- Understanding cell-specific susceptibility to carcinogens is crucial for identifying early events in tumorigenesis.
Purpose of the Study:
- To investigate the susceptibility of different lung cell types to AFB1-induced Ki-ras mutations.
- To determine if specific lung cell populations are preferentially targeted by AFB1 for oncogene mutation.
Main Methods:
- Lung cells were isolated from AC3F1 mice 7 weeks after treatment with AFB1 or vehicle (dimethyl sulfoxide).
- Fractions enriched for specific cell types (Clara cells, alveolar type II cells, macrophages, polymorphonuclear leukocytes) were analyzed.
- Point mutations in the Ki-ras oncogene were quantified using allele frequency analysis.
Main Results:
- Ki-ras mutant allele frequencies were significantly higher in Clara cell-enriched fractions compared to alveolar type II cell fractions.
- Mutant Ki-ras alleles were undetectable or minimal in macrophage- and polymorphonuclear leukocyte-enriched fractions.
- Vehicle-treated control mice showed minimal Ki-ras mutations, primarily in the Clara cell fraction.
Conclusions:
- Clara cells exhibit a particular susceptibility to AFB1-induced Ki-ras mutations.
- These mutations in Clara cells represent an early molecular event in AFB1-induced mouse lung tumorigenesis.
- The findings highlight Clara cells as a key target for AFB1 carcinogenicity in the lung.
