Contents lists available at ScienceDirect DNA Repair journal homepage: www.elsevier.com/locate/dnarepair Proximity effects in chromosome aberration induction by low-LET ionizing radiation John James Tello Cajiao a,b,c , Mario Pietro Carante a,b , Mario Antonio Bernal Rodriguez c , Francesca Ballarini a,b, ⁎ a University of Pavia, Physics Department, via Bassi 6, I-27100 Pavia, Italy b INFN-Sezione di Pavia, via Bassi 6, I-27100 Pavia, Italy c Universidade Estadual de Campinas. Cidade Universitária Zeferino Vaz, Campinas, SP, Brazil ARTICLE INFO Keywords: Chromosome aberrations Ionizing radiation Biophysical modelling Proximity effects DNA damage Monte carlo simulation ABSTRACT Although chromosome aberrations are known to derive from distance-dependent mis-rejoining of chromosome fragments, evaluating whether a certain model describes such “proximity effects” better than another one is complicated by the fact that different approaches have often been tested under different conditions. Herein, a biophysical model (“BIANCA”, i.e. BIophysical ANalysis of Cell death and chromosome Aberrations) was up- graded, implementing explicit chromosome-arm domains and two new models for the dependence of the re- joining probability on the fragment initial distance, r. Such probability was described either by an exponential function like exp(-r/r 0 ), or by a Gaussian function like exp(-r 2 /2σ 2 ), where r 0 and σ were adjustable para- meters. The second, and last, parameters was the yield of “Cluster Lesions” (CL), where “Cluster Lesion” defines a critical DNA damage producing two independent chromosome fragments. The model was applied to low-LET- irradiated lymphocytes (doses: 1–4 Gy) and fibroblasts (1–6.1 Gy). Good agreement with experimental yields of dicentrics and centric rings, and thus their ratio (“F-ratio”), was found by both the exponential model (with r 0 = 0.8 μm for lymphocytes and 0.7 μm for fibroblasts) and the Gaussian model (with σ = 1.1 μm for lym- phocytes and 1.3 μm for fibroblasts). While the former also allowed reproducing dose-responses for excess acentric fragments, the latter substantially underestimated the experimental curves. Both models provided G- ratios (ratio of acentric to centric rings) higher than those expected from randomness, although the values calculated by the Gaussian model were lower than those calculated by the exponential one. For lymphocytes the calculated G-ratios were in good agreement with the experimental ones, whereas for fibroblasts both models substantially underestimated the experimental results, which deserves further investigation. This work suggested that, although both models performed better than a step model (which previously allowed reproducing the F- ratio but underestimated the G-ratio), an exponential function describes proximity effects better than a Gaussian one. 1. Introduction Living cells exposed to ionizing radiation during the G0/G1 phase of the cell cycle can show chromosome aberrations following chromosome breakage and large-scale rearrangement of the fragments, mainly due to Non-Homologous End Joining (e.g. [1,2]). Two chromosome breaks induced in two distinct chromosomes can give rise to a “dicentric”, visible in metaphase as a chromosome with two centromeres accom- panied by an acentric fragment, or a “reciprocal translocation”, where both chromosomes have one centromere. On the contrary if both breaks were induced in the same chromosome, they can produce a “ring” (“centric” or “acentric” depending on the presence of the centromere) or an “inversion” (“pericentric” or “paracentric”, respectively). A single, un-rejoined chromosome break will give rise to a “terminal de- letion”, whereas the expression “interstitial deletion” is used to indicate a small acentric fragment deriving from two chromosome breaks on the same chromosome arm; many, if not most, interstitial deletions are indeed small (acentric) rings. All patterns involving at least three chromosome breaks and two chromosomes are called “complex ex- changes”. A more detailed classification of the various aberration types can be found in [3]. Besides providing information on the initial DNA damage, the http://dx.doi.org/10.1016/j.dnarep.2017.08.007 Received 5 May 2017; Received in revised form 21 July 2017; Accepted 14 August 2017 ⁎ Corresponding author at: University of Pavia, Physics Department, via Bassi 6, I-27100 Pavia, Italy. E-mail addresses: fisk2190@gmail.com (J.J. Tello Cajiao), mariopietro.carante01@universitadipavia.it (M.P. Carante), mbernalrod@gmail.com (M.A. Bernal Rodriguez), francesca.ballarini@unipv.it (F. Ballarini). DNA Repair 58 (2017) 38–46 Available online 24 August 2017 1568-7864/ © 2017 Elsevier B.V. All rights reserved. MARK