Metal-Induced Genomic Instability: Long-Term Effects of Chromium and Vanadium

Newswise — Human beings may be exposed to metals from the environment, industry or failing orthopedic joint replacements. Cells exposed briefly to soluble metal ions, specifically chromium or vanadium, can become chromosomally damaged. Without any further exposure to metal the daughters of these cells can experience further genetic damage, even onto the 30th generation, according to an international team led by Patrick Case of the Bristol Implant Research Centre at Bristol University in the UK. In a paper delivered at the American Society for Cell Biology's 43rd Annual Meeting in San Francisco, Case said these findings were an example of the phenomenon known as genomic instability.

Collaborating with Carmel Mothersill at the Dublin Institute of Technology and Judith Campisi and Miguel Rubio at the Lawrence Berkeley National Laboratory, the Bristol center exposed a cell line of human fibroblasts to soluble chromium or vanadium metal ions. Alloys of these metals are used in many modern prosthetic devices, because they are strong yet light. After a 24-hour metal ion bath, the fibroblasts soon showed signs of genetic damage— broken chromosomes, abnormal nuclei and decreased survival. These cells were then left in culture to grow with no further metal exposure for 30 division cycles. Researchers found that many daughter cells continued to experience genetic damage, even in the 30th generation, suggesting that exposure to the metal ion had heritably destabilized a pathway that normally maintains genome stability.

The researchers wondered if metal-induced genetic instability could be prevented by telomerase, an important enzyme that adds DNA to the ends of chromosomes ('telomeres'). By so doing, this enzyme counteracts the progressive loss of DNA that would otherwise occur each time cells replicate their DNA. As we age, our cells stop producing telomerase. Starting with the same strain of human fibroblasts, which do not express telomerase, researchers repeated their experiment but this time also infected the cells with a retrovirus engineered to express telomerase. This treatment is used widely in the laboratory to make cells telomerase-positive and thus immortal. The telomerase-protected fibroblasts were then given the same 24-hour metal ion treatment and emerged with similar chromosome damage. However this damage was not passed on. Thirty generations later, their cellular progeny showed no sign of genetic instability.

This work reinforces the group's earlier findings that soluble and particulate metal ions cause short-term chromosome damage in vivo (bone marrow and peripheral blood lymphocytes) and in tissue culture. At the moment its clinical significance, if any, is not clear, and Clark and his colleagues emphasize that orthopedic joint replacements provide important long-term benefits to patients. However in a cellular context, these findings offer a useful clue to possibly protecting human chromosomes from long-term damage after short-term exposure to toxic levels of metals.

Genomic Instability Caused by Metal Ions, A. Glaviano,1,2 C. Mothersill,1 J. Campisi,3 M. A. Rubio,3 V. Navak,2 A. Sood,2 C. P. Case2 ; 1 School of Physics, Dublin Institute of Technology, Dublin, Ireland, 2 Bristol Implant Research Centre, University of Bristol, Bristol, United Kingdom, 3 Lawrence Berkeley National Laboratory, Berkeley, CA.