Environmental Mutagens Induced Transversions but not Transitions in Regulatory Region of Mitochondrial DNA

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 γ-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.

Michael A. Partridge and Sarah X. L. Huang have contributed equally to the studies presented in this article.

Grant support for this work was from NIH grants ES 05786 and ES 12888, Superfund grant P42 ES 10349, and Environmental Center grant ES 09089.