Are Radiation-Induced Bystander Effects a Universal Phenomenon?
Studies on human cells fail to find low-LET radiation-induced damage in untargeted cells.
For years, radiation biologists have thought that human DNA is the primary target for energy deposition after exposure to ionizing radiation—such as that from X-rays and gamma rays. However, the discovery of non-targeted responses to radiation, such as the bystander response, has called this paradigm into question.
Ionizing radiation-induced bystander responses are effects occurring in cells that did not directly receive radiation doses but were induced by signals from nearby or neighboring irradiated cells. Bystander effects have been described in numerous in vitro cell culture systems. There is also evidence that they can occur in vivo in complex model systems and animals.
Results: In recent research on the effects of ionizing radiation on human cells, scientists have found that radiation induced bystander responses are not a universal phenomenon and they are dependent on the type of radiation used. In addition, there are likely many confounding factors influencing bystander responses reported in the literature.
The study discussed here represents a collaboration between scientists at Pacific Northwest National Laboratory, the University of Maryland, the University of Medicine and Dentistry of New Jersey and the University of Virginia. The results appear in the February 2010 International Journal of Radiation Biology.
Why it matters: According to PNNL scientist Dr. Marianne Sowa, the lead author of the study, "Bystander responses undoubtedly occur following exposure to alpha particles (those found in radionuclides). However, several papers have recently appeared that question the universality of bystander responses for other types of ionizing radiation. The interesting question is why are these responses occurring in some cases but not in others? We hypothesize it is based on the specific pattern of energy deposition produced by radiation as it interacts with the cell or tissue."
Unlike experiments with low doses of densely ionizing radiation—where some cells receive a high dose and the majority of cells receive no dose—the dose distribution for low-linear energy transfer (LET) or sparsely ionizing radiation is more homogeneous. This makes it difficult to separate the direct effects of the exposure from potential non-targeted responses. Previously, scientists at PNNL developed a unique electron microbeam capable of targeting single cells in a population. This device uses energetic electrons to simulate a low-LET source.
Methods: In this study, the researchers used medium-transfer experiments and targeted electron radiation to examine radiation-induced bystander effects in primary human fibroblast (skin) and human colon carcinoma cells. In medium-transfer experiments, medium from directly irradiated cells is placed on cells that have never been exposed to radiation. This type of experiment is often used for sparsely ionizing radiation because of the difficulties in performing targeted exposures with such a source.
The electron microbeam developed at PNNL offers an alternative method, as it provides targeted low-LET exposures. The research team found no low-LET radiation induced bystander effect. This result has led them to consider the role of ionization patterns produced by radiation in driving the bystander response. Future experiments designed specifically to test this hypothesis would be necessary to evaluate such suppositions.
The observation of non-targeted effects has implications for any individual who may be exposed to ionizing radiation because they suggest that the radiation response target might be greater than the volume actually irradiated. If bystander effects are detrimental, they would increase the target volume for radiation and, presumably, increase the risk to human health. However, the reverse may be possible if the bystander effect is beneficial.
What's next: It remains unclear how non-targeted effects might impact radiation risk. Current risk estimates are based on epidemiology, and as such, any bystander contribution to risk should already be included. Clearly, challenges remain for investigators to determine the robustness of medium-borne bystander effects, rigorously test whether changes in radiation quality can elicit the same changes in non-targeted bystander populations and determine if these effects have relevance to human health.
Acknowledgments: This work was supported by the U.S. Department of Energy Office of Biological and Environmental Research's Low Dose Radiation Research Program, the National Aeronautical and Space Administration and the National Cancer Institute. The research team includes Marianne Sowa and Bill Morgan, PNNL; Wilfried Goetz, Janet Baulch, Dinah Pyles and Susannah Yovino, University of Maryland; Jaroslaw Dziegielewski, University of Virginia; AR Snyder, Targonox, Boston, Mass.; and Sonia de Toledo and Edouard Azzam, UMDNJ.
References: Sowa MB, W Goetz, JE Baulch, DN Pyles, J Dziegielewski, S Yovino, AR Snyder, SM de Toledo, EI Azzam, and WF Morgan. 2010. "Lack of evidence for low-LET radiation induced bystander response in human fibroblast and colon carcinoma cells." International Journal of Radiation Biology 86(2):102-113. DOI: 10.3109/09553000903419957
Sowa MB, MK Murphy, JH Miller, JC McDonald, DJ Strom and GA Kimmel. 2005. A variable-energy electron microbeam: a unique modality for targeted low-LET radiation. Radiation Research 1645:695-700.