A new mechanism of DNA damage by nanoparticles?
According to the results of the study published on November 5 in the online version of the journal Nature Nanotechnology in the article "Nanoparticles can cause DNA damage across a cellular barrier", nanoparticles can damage DNA even without direct contact. These data raise new questions about the safety of nanomaterials used in clinical practice.
DNA damage associated with nanoparticles has been described for many varieties of nanoparticles, but all types of damage known so far occur when nanoparticles come into direct contact with DNA. The authors described for the first time the mechanism of the mediated destructive effect of nanoparticles on DNA.
Scientists use modern nanotechnology in the development of systems for the delivery of drugs and imaging agents to various organs and tissues, but the results of some studies indicate the toxicity of such particles. For example, the relationship between the inhalation of nanoparticles or nanotubes and the development of cardiorespiratory pathology has already been proven. In addition, it is known that cobalt-chromium alloy (CoCr) nanoparticles, which can be released by metal joint prostheses, damage human cells in culture.
For a more detailed study of the toxicity of cobalt-chromium nanoparticles, scientists from the University of Bristol (UK), working under the leadership of Charles Patrick Case, analyzed the state of human fibroblasts exposed to nanoparticles directly in culture or through a barrier of living cells (in a living organism, such a barrier may be the placenta or pulmonary epithelium). They created the barrier by culturing a thick layer of the BeWo human cell line, often used to create barriers in various experimental models, on a porous plastic insert, which was subsequently placed on a fibroblast culture. After 24 hours of exposure to nanoparticles, the authors assessed the level of DNA damage in fibroblasts. They revealed a significant amount of DNA damage in all cells, both directly exposed to nanoparticles and protected by a barrier of BeWo cells. Similar results were obtained in parallel experiments using microparticles.
When planning the experiments, the researchers counted on the effectiveness of the BeWo barrier, so they were very surprised that the level of DNA damage in the cells protected by it was as high as in cells directly exposed to nanoparticles.
Analysis of the culture medium under the plastic insert did not reveal the presence of nanoparticles. This suggests that the BeWo barrier, whose thickness reached four layers of cells, effectively detained nanoparticles.
When using only a plastic insert and significantly larger cobalt-chromium microparticles that do not penetrate through its pores, the DNA of fibroblasts was damaged much less than with additional insulation in the form of a barrier of BeWo cells. According to this unexpected observation, the BeWo barrier itself somehow mediates or enhances the processes of DNA damage.
The researchers suggested that exposure to particles causes changes in the cells of the outer layer of the barrier. This effect is somehow transmitted to the underlying cells and eventually causes the observed DNA damage.
Blocking intercellular slit-like contacts between fibroblasts with the help of various chemical compounds, disrupting chemical interactions between cells, reduced the level of DNA damage. This fact supports the assumption that the damaging effect is transmitted to cells that are not directly exposed to nanoparticles using chemical signals. The results of further verification showed that at one of the stages of this process, ATP, which is an extracellular signaling molecule, is released.
According to Stephan Stern, who did not participate in the work of a toxicologist from the Nanotechnology Characterization Lab, part of the US National Cancer Institute, so far he has not seen a single mediated mechanism of action of nanoparticles, except for immune reactions mediated by cytokines and secondary messengers. Apparently, these particles are able to exert influence through a system of secondary messengers, without directly affecting the target cells.
The authors emphasize that the experimental system they created is very different from real conditions in vivo. Firstly, it uses a much higher concentration of cobalt-chromium nanoparticles than can presumably be in the body. Secondly, the BeWo barrier is not equivalent to natural cellular barriers such as the placenta. Thus, the results of the study demonstrate a possible mechanism by which nanoparticles can influence cells, but so far there is no evidence that this will actually happen in the body. As a useful illustrative example, Stern cites nanoparticles made of titanium dioxide, which, according to experimental data, have a destructive effect on DNA in vitro, but in the conditions of the body suppress carcinogenesis.
In addition, the authors studied the effect of only one type of nanoparticles and demonstrated that the effect of larger microparticles has a similar effect. They emphasize that the data obtained do not apply to all types of nanoparticles, and the revealed phenomenon is not their exclusive property. However, the results of the study indicate a possible indirect effect of nanoparticles on DNA, which must be taken into account when developing various nanotechnologies.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of The Scientist: New mechanism for nano damage?
09.11.2009