Mutagenesis Advance Access originally published online on September 5, 2008
Mutagenesis 2009 24(1):25-33; doi:10.1093/mutage/gen048
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Effects of hTERT on genomic instability caused by either metal or radiation or combined exposure
1Radiation and Environmental Science Centre, Focas Institute, Dublin Institute of Technology, Dublin, Ireland 2Bristol Implant Research Centre, University of Bristol, Bristol, UK 3Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Canada 4The Netherlands Cancer Institute, Amsterdam, The Netherlands 5National Heart and Lung Institute, Imperial College London, London, UK
Genomic instability is considered to be an important component in carcinogenesis. It can be caused by low-dose exposure to agents, which appear to act through induction of stress–response pathways related to oxidative stress. These agents have been studied mostly in the radiation field but evidence is accumulating that chemicals, especially heavy metals such as Cr (VI), can also act in the same manner. Previous work showed that metal ions could initiate long-term genomic instability in human primary fibroblasts and this phenomenon was regulated by telomerase. The aim of this study was to examine the difference in clonogenic survival and cytogenetic damage after exposure to Cr (VI) and radiation both singly and in combination in normal human fibroblasts (hTERT– cells) and engineered human fibroblasts, infected with a retrovirus carrying a cDNA encoding hTERT, which rendered these cells telomerase positive and replicatively immortal (hTERT+ cells). Cr (VI) induced genomic instability in hTERT– cells but not in hTERT+ cells, whereas radiation induced genomic instability in hTERT+ cells and to a lesser extent in hTERT– cells. Combined exposure caused genomic instability in both types of cells. However, this genomic instability was more pronounced in hTERT– cells after radiation followed by Cr (VI) and more pronounced in hTERT+ cells after Cr (VI) followed by radiation. Moreover, the biological effects provoked by combined exposure of Cr (VI) and radiation also led to a synergistic action in both types of cells, compared to either Cr (VI) treatment only or radiation exposure only. This study suggests that telomerase can prevent genomic instability caused by Cr (VI), but not by radiation. Furthermore, genomic instability may be prevented by telomerase when cells are exposed to radiation and then Cr (VI) but not after exposure to Cr (VI) and then radiation.
* To whom correspondence should be addressed. Tel: +35318968475; Email: a.glaviano{at}libero.it or a.glaviano{at}tcd.ie
Received on April 15, 2008; revised on July 10, 2008; accepted on August 4, 2008.