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Biological effects in unirradiated human tissue induced by radiation damage up to 1 mm away
Oleg V. Belyakov *,,
Stephen A. Mitchell *,
Gerhard Randers-Pehrson *,
Stephen A. Marino *,
Sally A. Amundson *,
Charles R. Geard *, and
David J. Brenner *,
*Center for Radiological Research, Columbia University, New York, NY 10032; Radiation Biology Laboratory, Research and Environmental Surveillance, Radiation and Nuclear Safety Authority, P.O. Box 14, FIN-00881, Helsinki, Finland; and Stuyvesant High School, New York, NY 10282
Edited by Richard B. Setlow, Brookhaven National Laboratory, Upton, NY
Accepted for publication August 3, 2005.
Received for publication June 16, 2005.
A central tenet in understanding the biological effects of ionizingradiation has been that the initially affected cells were directlydamaged by the radiation. By contrast, evidence has emergedconcerning "bystander" responses involving damage to nearbycells that were not themselves directly traversed by the radiation.These long-range effects are of interest both mechanisticallyand for assessing risks from low-dose exposures, where onlya small proportion of cells are directly hit. Bystander effectshave been observed largely by using single-cell in vitro systemsthat do not have realistic multicellular morphology; no studieshave as yet been reported in three-dimensional, normal humantissue. Given that the bystander phenomenon must involve cell-to-cellinteractions, the relevance of such single-cell in vitro studiesis questionable, and thus the significance of bystander responsesfor human health has remained unclear. Here, we describe bystanderresponses in a three-dimensional, normal human-tissue system.Endpoints were induction of micronucleated and apoptotic cells.A charged-particle microbeam was used, allowing irradiationof cells in defined locations in the tissue yet guaranteeingthat no cells located more than a few micrometers away receiveany radiation exposure. Unirradiated cells up to 1 mm distantfrom irradiated cells showed a significant enhancement in effectover background, with an average increase in effect of 1.7-foldfor micronuclei and 2.8-fold for apoptosis. The surprisinglylong range of bystander signals in human tissue suggests thatbystander responses may be important in extrapolating radiationrisk estimates from epidemiologically accessible doses downto very low doses where nonhit bystander cells will predominate.
Key Words: bystander normal human tissue radiological risk
Author contributions: O.V.B., G.R.-P., S.A.A., C.R.G., and D.J.B.designed research; O.V.B., S. A. Mitchell, D.P., and S. A. Marinoperformed research; G.R.-P. contributed new reagents/analytictools; O.V.B., S.A.A., and D.J.B. analyzed data; and O.V.B.,S.A.A., C.R.G., and D.J.B. wrote the paper.
This paper was submitted directly (Track II) to the PNAS office.
Freely available online through the PNAS open access option.
microRNAome changes in bystander three-dimensional human tissue models suggest priming of apoptotic pathways.
O. Kovalchuk, F. J. Zemp, J. N. Filkowski, A. M. Altamirano, J. S. Dickey, G. Jenkins-Baker, S. A. Marino, D. J. Brenner, W. M. Bonner, and O. A. Sedelnikova (2010)
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Inducible response required for repair of low-dose radiation damage in human fibroblasts.