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Environmental mutagens induced transversions but not transitions in regulatory region of mitochondrial DNA
Michael A Partridge1, Sarah X L Huang, Muhammad G Kibriya
1Center for Radiological Research, Columbia University, New York, NY 10032, USA.
Abstract:
One of the long-term objectives of the research in our laboratory was to determine whether mitochondrial DNA (mtDNA) mutations were generated in cell lines exposed to a variety of known mutagens. Many of these mutagens are known to increase oxidative stress in the cell, and one potential outcome of this would be an increased incidence of point mutations in mtDNA. Recently, there has been some controversy regarding the validity of point mutations in the regulatory region of mtDNA as a predictive or causative marker for carcinogenesis. Studies were undertaken to assess whether nuclear mutagens such as arsenic (As), asbestos, and ultraviolet (UV) and gamma-radiation, induced both heteroplasmic and homoplasmic point mutations in mtDNA. A direct sequencing approach was used to reduce the occurrence of experimental errors and cross-checked all base changes with databases of known polymorphisms. Our results showed that, while base changes did occur, there was no marked difference between the number of changes in treated and untreated cells. Furthermore, in human lymphocyte samples from subjects exposed to As, most of these base changes were previously reported. Interestingly, there was an increase in the number of transversions (purine ( pyrimidine) in smokers from a human population study, but as with the findings in cell culture samples, there was no difference in the total number of base changes. Data suggest that only a change in the number of rare transversions would be indicative of an increase in point mutations in mtDNA after exposure to mutagens.
Insights
Exposure to mutagens like arsenic and UV radiation did not significantly increase mitochondrial DNA (mtDNA) point mutations in cell lines. Only rare transversion changes in mtDNA may indicate mutagen exposure.
Area of Science:
- Molecular Biology
- Genetics
- Toxicology
Background:
- Mitochondrial DNA (mtDNA) mutations are linked to oxidative stress and carcinogenesis.
- Controversy exists regarding mtDNA regulatory region mutations as cancer markers.
- Investigating mutagen-induced mtDNA mutations is crucial for understanding cellular damage.
Purpose of the Study:
- To determine if known mutagens induce point mutations in mitochondrial DNA (mtDNA).
- To assess the role of nuclear mutagens (arsenic, asbestos, UV, gamma-radiation) in mtDNA mutation generation.
- To evaluate mtDNA mutations as potential biomarkers for mutagen exposure and carcinogenesis.
Main Methods:
- Cell lines were exposed to various mutagens (arsenic, asbestos, UV, gamma-radiation).
- Mitochondrial DNA (mtDNA) was analyzed for heteroplasmic and homoplasmic point mutations using direct sequencing.
- Human lymphocyte samples from arsenic-exposed individuals and population studies (smokers) were analyzed.
- Sequencing data were cross-checked with polymorphism databases to identify novel changes.
Main Results:
- No significant difference in mtDNA base changes was observed between mutagen-treated and untreated cell lines.
- Most base changes in human lymphocytes from arsenic-exposed subjects were previously reported polymorphisms.
- Smokers showed an increased number of transversions in mtDNA, but total base changes did not differ significantly.
- Mutagen exposure did not markedly increase overall mtDNA point mutations in cell cultures.
Conclusions:
- Nuclear mutagens tested do not appear to significantly increase point mutations in mitochondrial DNA (mtDNA).
- Observed base changes in exposed humans were largely known polymorphisms, not novel mutations.
- A specific increase in rare transversions might be a more sensitive indicator of mtDNA mutation induction by mutagens.
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