458 RADIATION RESEARCH 170, 458–466 (2008) 0033-7587/ 08 $15.00  2008 by Radiation Research Society. All rights of reproduction in any form reserved. Chromosome Inter- and Intrachanges Detected by Arm-Specific DNA Probes in the Progeny of Human Lymphocytes Exposed to Energetic Heavy Ions D. Pignalosa, a,d A. Bertucci, a,b G. Gialanella, a,c G. Grossi, a,c L. Manti, a,c M. Pugliese, a,c P. Scampoli a,c and M. Durante a,c,d,1 a Dipartimento di Scienze Fisiche, Universita ` Federico II, Monte S. Angelo, 80126 Napoli, Italy; b Center for Radiological Research, Columbia University, New York, New York; c INFN, Sezione di Napoli, Napoli, Italy; and d GSI, Biophysics Department, 64291 Darmstadt, Germany Pignalosa, D., Bertucci, A., Gialanella, G., Grossi, G., Man- ti, L., Pugliese, M., Scampoli, P. and Durante, M. Chromo- some Inter- and Intrachanges Detected by Arm-Specific DNA Probes in the Progeny of Human Lymphocytes Exposed to Energetic Heavy Ions. Radiat. Res. 170, 458–466 (2008). We measured residual cytogenetic damage in the progeny of human peripheral blood lymphocytes exposed to 1 GeV/ nucleon iron ions or  rays. Arm-specific DNA probes for chromosome 1 were used to detect aberrations as a function of dose in cells harvested 144 h after exposure. In addition, arm-specific mFISH was applied to samples exposed to a sin- gle dose of 2 Gy. These methods allowed the detection of in- terarm intrachanges (pericentric inversions) in addition to in- terchanges. The ratio of these types of aberrations (F ratio) has been proposed as a fingerprint of exposure to densely ion- izing radiation. The fractions of aberrant cells in the progeny of cells exposed to iron ions were similar to those in the pop- ulation exposed to  rays, possibly because many rearrange- ments induced by heavy ions ultimately lead to cell death. Simple inter- and intrachanges were also similar, but more complex rearrangements were found in cells that survived af- ter exposure to iron ions. We did not find a significant differ- ence in the ratio of simple interchanges to simple intrachanges for the two radiation types. However, iron ions induced a much higher frequency of events involving both inter- and intrachanges. We conclude that these complex rearrange- ments represent a hallmark of exposure to heavy ions and may be responsible of the decrease of the F ratio with increas- ing LET reported in the literature in some in vitro and in vivo experiments.  2008 by Radiation Research Society INTRODUCTION Cancer is a major health concern for exploratory-class space missions, because crew members will be exposed to high-energy and charge (HZE) ions from galactic cosmic radiation, whose oncogenic potential is largely unknown (1). Chromosomal aberrations are recognized as a biomark- er of cancer risk in humans (2, 3), and heavy ions are sig- 1 Address for correspondence: GSI, Biophysics Department, 64291 Darmstadt, Germany; e-mail: M.Durante@gsi.de. nificantly more effective than sparsely ionizing radiation in the induction of chromosomal rearrangements in human cells [e.g. ref. (4)]. The possibility of using particular ab- erration classes as indicators of the quality of radiation ex- posures has been long debated (5–8). Such a parameter could be helpful in determining the quality of radiation ab- sorbed by persons accidentally exposed to unknown sourc- es or to mixed fields and in elucidating the basic mecha- nisms underlying the greater efficiency of densely ionizing radiation in promoting cancer. Among the parameters proposed, the ratio between inter- and intrachromosomal exchanges, also known as the F ratio (5, 9), is one of the most discussed. Because of the energy deposition patterns characteristic of sparsely and densely ionizing radiation, it is expected that heavy-ion tracks will produce more double-strand breaks (DSBs) along the same chromosome than sparsely ionizing radiation at the same dose. Aberration formation is influenced by the ‘‘proximity effect’’ (10), so illegitimate reunion of these closely asso- ciated DNA free ends and consequent formation of intra- chromosomal aberrations (both symmetrical and asymmet- rical) should be more likely after densely than sparsely ion- izing radiation exposure. Since this parameter can be cal- culated from both unstable (dicentrics/rings) and stable (translocations/inversions) chromosomal aberrations, it can be used in retrospective biodosimetry (11, 12). Some in vitro and in vivo studies have shown LET dependence for the F ratio (11–15), while others failed to detect significant differences (16–22). The low resolution of the methods used (e.g. for Giemsa staining) and the low statistical power of the studies (e.g. for multicolor FISH probes) are the main problems affecting the experiments mentioned above. In this paper, we studied the residual cytogenetic damage in human lymphocytes exposed in vitro to iron ions or  rays using arm-specific probes for chromosome 1. Such probes, besides detecting simple and complex interchanges, also allow for the detection of interarm intrachanges (peri- centric inversions), which are normally undetectable by whole-chromosome painting probes. To further increase the resolution power of our study, we used a new technique, human arm-specific mFISH (X a Cyte, MetaSystems, Ger-