PITTSBURGH, Sept. 30 – The amount of smoke in just one or two puffs of a cigarette can cause breaks in DNA and defects to a cell's chromosomes, leading to irreversible changes in genetic information being passed to a newly divided cell, according to University of Pittsburgh researchers. Their findings, to be reported Tuesday, Oct. 5 at the 35th Annual Meeting of the Environmental Mutagen Society, are the first to show that cigarette smoke causes chromosome instability.
The meeting, "Genes, Mutations and Disease: The Environmental Connection," will be held Oct. 2 to 6 at the Pittsburgh Hilton and Towers.
While most research has focused on the changes in DNA sequence caused by cigarette smoke, little attention has been given to how smoke affects genomic stability of cells. In laboratory studies using human fibroblasts, common cells found in connective tissue, William S. Saunders, Ph.D., and colleagues discovered that exposure to even a small amount of cigarette smoke condensate – equal to about 1/25 of a cigarette – caused breaks to both strands of DNA and compromised the integrity of the cell's chromosomes.
Cigarette smoke contains some 5,000 organic compounds, including chemicals known to cause cancers. While the researchers did not expose cells to actual puffs of smoke, the cigarette smoke condensate they used was derived from burning real cigarettes and obtained from the R.J. Reynolds Tobacco Company. Containing mostly particulates, the extracted smoke was liquefied as part of a solvent mixture before it was exposed to the cells.
"Double-stranded breaks are considered the most mutagenic type of DNA damage because the broken ends can fuse to other chromosomes in the cell. Chromosome fusion is detrimental to normal chromosome segregation, which in turn leads to genetic imbalances," explained Dr. Saunders, associate professor of biological sciences, University of Pittsburgh School of Arts and Sciences, and a researcher with the Oral Cancer Center of Discovery at the University of Pittsburgh Cancer Institute.
Before a cell undergoes division, its DNA is replicated and compressed into identical copies of each chromosome inside the cell nucleus. The chromosomes are then segregated during cell division, so that each daughter nucleus receives a complete copy of the genetic material. The stage when chromosomes are segregated and become separated is called anaphase. Normally, each set of chromosomes is pulled with equal force in opposite directions so that each daughter cell receives the same number of chromosomes.
But when the researchers exposed cells in culture to cigarette smoke, they found that the fused chromosomes were being pulled simultaneously from both directions much like a piece of taffy, forming so-called anaphase bridges between its two ends. Eventually, these chromosomes either tear apart, leaving two broken pieces, or if they don't break apart, the abnormal, elongated chromosomes may persist after anaphase is completed. Either way, a major change in the structure of the chromosomes is the end result.
"Others have found the presence of anaphase bridges is correlated with chromosome instability in cancer cells. Because cigarette smoking is linked to oral, larynx, lung, bladder and esophageal cancers, our results showing that cigarette smoke can produce anaphase bridges and destabilize a cell's chromosomes have added significance," said Dr. Saunders.
"The failure of the cell to accurately repair the cigarette smoke condensate-induced double-stranded breaks probably leads to anaphase bridge formation and chromosomal instability," added Li Z. Luo, Ph.D., a graduate student in the department of biological sciences, who will present the data.
According to their results, which also are detailed in an upcoming article in the journal Mutation Research, the development of anaphase bridges and chromosome instability is most likely due to reactive oxygen species that form as the cell is exposed to the various chemicals in smoke. Treating the smoke-exposed cells with different antioxidants, agents that block formation of reactive oxygen species, prevented most occurrences of anaphase bridge formation and significantly reduced genomic imbalances.
"Unfortunately, no amount of scientific evidence arguing against smoking will get everyone to stop or not begin to smoke in the first place. So, perhaps one long-term goal should be to develop cigarettes that somehow prevent what we've seen happen to the cells in our lab," remarked Dr. Saunders.
In addition to Drs. Luo and Saunders, other authors of the abstract and paper are Kristen M. Werner, Ph.D., a former undergraduate student in the department of biological sciences; and Susanne M. Gollin, Ph.D., professor of human genetics at the University of Pittsburgh Graduate School of Public Health and co-investigator at the Oral Cancer Center of Discovery at the University of Pittsburgh Cancer Institute.
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