Environmental mutagens induced transversions but not transitions in regulatory region of mitochondrial DNA

Our plain-English summary of Environmental mutagens induced transversions but not transitions in regulatory region of mitochondrial DNA, by M.A. Partridge, S.X. Huang, M.G. Kibriya, et al (Journal of Toxicology and Environmental Health. Part a, 2009).

The study

• Authors: M.A. Partridge, S.X. Huang, M.G. Kibriya, H. Ahsan, M.M. Davidson, T.K. Hei
• Journal: Journal of Toxicology and Environmental Health. Part a
• Published: 2009;72(5):301-4
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This study combined cultured-cell experiments with blood samples from arsenic-exposed people to ask whether agents known to damage DNA change single letters in mitochondrial DNA, the small separate DNA in cells' energy-producing structures. Hamster cells (CHO-K1) were exposed to arsenic, ultraviolet light or gamma radiation. Human small airway cells were exposed to crocidolite asbestos at 1, 2 or 4 micrograms per square centimetre for 3 days. Across more than 142,000 DNA letters, exposed cells showed no statistically significant difference from unexposed cells in the number of changes. This held for both common changes (transitions) and rarer ones (transversions). In blood-cell DNA from 47 arsenic-exposed people in Bangladesh, the authors found no association between arsenic exposure and these changes. Transversions were significantly more common in the 13 smokers (12 of 19 changes) than in the 34 non-smokers (12 of 49). The smokers were on average about 5 years older, and no age-adjusted analysis was done. The authors concluded that only changes in the number of rare transversions may indicate exposure to mutagens, at least in the regulatory region of mitochondrial DNA.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experiments on cultured cells exposed to known mutagens, plus DNA sequencing of blood lymphocyte samples from an arsenic-exposed human population
• Who was studied: Cultured CHO-K1 (hamster) cells and human small airway epithelial (SAE) cells. Also lymphocyte DNA from 47 people in Bangladesh exposed to arsenic in drinking water: 13 smokers and 34 non-smokers. Dates are not stated.
• Exposure: Crocidolite asbestos for 3 days at 1, 2 or 4 micrograms per square centimetre, in small airway epithelial cells. In CHO cells: arsenic at 1 microgram per ml for 5 days, 10 Gray of gamma radiation, or 10 J/m2 of UV-C light. In the human population: arsenic from drinking water.
• Main results:
  • In cultured cells, none of the agents tested produced a statistically significant difference (chi-squared tests) from unexposed controls in the number of base changes. This applied to both transitions and transversions. More than 142,000 base pairs were analyzed.
  • Small airway epithelial cells, base changes (transversions in parentheses): untreated, 10 (1) in 13,200 base pairs; asbestos 1 microgram/cm2, 13 (2) in 16,500; asbestos 2 micrograms/cm2, 6 (0) in 16,500; asbestos 4 micrograms/cm2, 11 (1) in 14,300.
  • In the arsenic-exposed Bangladesh population (47 individuals, 68 unique base changes), no association was found between arsenic exposure and point mutations. All but 3 of the 68 changes had been reported before.
  • Transversions, but not transitions, were significantly more common in smokers (12 of 19 base changes, 13 subjects) than in non-smokers (12 of 49 base changes, 34 subjects), with chi-squared p less than 0.001.
• The authors' conclusion: The authors concluded that only changes in the number of rare transversions may indicate exposure to mutagens, at least in the regulatory region of mitochondrial DNA. In their discussion they suggested that transversions, not total base changes, may be a reliable marker of increased mitochondrial point mutations in cancer.
• Limitations the authors state:
  • Smokers were on average 5 years older than non-smokers. Because of the small number of samples, no formal age-adjusted analysis was made.
  • Some types of DNA damage, such as double-strand breaks, would not be detected by the sequencing method used.
  • A high rate of spontaneous changes in mitochondrial DNA might hide any increase caused by the mutagens.

Topics

Medical terms in this study, explained in our Lexicon: Oxidative Stress, Carcinogenesis.

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