Production Of Chromosomal Aberrations Research Articles

Amelioration of indole acetic acid-induced cytotoxicity in mice using zinc nanoparticles biosynthesized with Ochradenus arabicus leaf extract.

The diversity of natural phytochemicals represents an unlimited source for discovery and development of new drugs. Ochradenus arabicus, (family: Resedaceae) a notable medicinal plant displays a high content of flavonoid glycosides. This study investigates a possible preventative role of zinc nanoparticles biosynthesized by O. arabicus leaf extracts (OAZnO NPs) in limiting genotoxicity and cytotoxicity caused by indole acetic acid (IAA) in laboratory mice. ZnO NPs were synthesized using O. arabicus leaf extracts and characterized with UV–visible spectroscopy, scanning electron microscopy (SEM) and X-Ray diffraction (XRD). The mice were randomly distributed into the following six groups: control, OAZnO NPs treated (10 mg/kg BW), IAA treated (50 mg/kg BW); simultaneous treatment, pre-treatment, and post-treatment. Reactive oxygen species (ROS), DNA damage, chromosome aberration, and apoptosis were analyzed as toxicity endpoints. IAA exposure significantly induced production of ROS, DNA damage, apoptosis, chromosome aberrations, and micronuclei. Pre-, post-, and simultaneous treatment with OAZnO NPs ameliorated the damage caused by IAA exposure. Exposure to OAZnO NPs alone caused no toxicity for any endpoint based on comparison to controls. This study demonstrated that IAA-induced cytotoxic damage in mice could be ameliorated by treatment with OAZnO NPs. These findings require additional verification in mechanistic and in vitro studies.

Production and distribution of chromosome aberrations in human lymphocytes by particle beams with different LET

We investigated induction of chromosome aberrations (CA) in human lymphocytes when exposed to 150 MeV and spread out Bragg peak (SOBP) proton beams, and 199 MeV/u carbon beam which are currently widely used for cancer treatment and simultaneously are important components of cosmic radiation. For a comparison, the boron ions of much lower energy 22 MeV/u and a 60Co γ rays were used. Dose–effect curves as well as the distributions of CA were studied using Poisson and Neyman type A statistics. Systematics of experimentally determined parameters, their dependence on applied doses and irradiation quality are presented.

A Cytogenetic Profile of Radiation Damage

Most of the important biological effects associated with the exposure to ionizing radiations are mirrored at the chromosomal level. In all cases, changes in the levels of cytogenetic effects are associated with changes in absorbed dose, dose rate and radiation quality. Some of the complexities associated with the quantitative description of such changes in response can be circumvented by appealing to concepts embodied in what has been called the "mean inactivation dose". Additional metrics designed to provide LET-dependent "signatures" of damage have been employed with moderate degrees of success. These, along with some alternative approaches, are discussed in an effort to stimulate discussion, and to further work leading to a better understanding of mechanisms involved in the production and significance of chromosome aberrations after exposure to ionizing radiations.

Abstract ID: 37 The BIANCA biophysical model/MC code: calculations of radiation-induced cell damage in view of hadrontherapy treatments

A biophysical model and Monte Carlo code simulating cell death and chromosome damage by different ionizing radiations, including those used in hadrontherapy, will be presented. The model, called BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations [1] , [2] ), assumes that DNA “Cluster Lesions” (CLs) can produce chromosome aberrations (i.e., distance-dependent incorrect rearrangements of chromosome fragments), some of which can lead to cell death. The mean number of CLs per Gy and per cell is the first adjustable parameter; the second parameter is either the probability that a chromosome fragment remains unrejoined, or the characteristic distance governing chromosome-fragment rejoining, depending on which model version is used. Comparisons with experimental dose-response curves for cell survival and/or chromosome aberrations allowed tuning the model parameters for a radioresistant cell line (representative of tumour cell response) and a normal one (representative of the response of healthy tissues), thus producing a database of CL yields for different particle types and LET values. Since the CL yield for a given particle type showed a linear-quadratic increase with LET, a fit of such database allows performing full predictions of cell death and chromosome aberrations in principle for any LET value within the range covered by the experiments. Recently, the model was applied to calculate the dependence of cell death and chromosome damage on depth in tissue for SOBP profiles used in different centres, including the CATANA facility for eye melanoma treatment at INFN-LNS and the CNAO hadrontherapy centre in Pavia. In particular for protons, the biological effectiveness was found to increase in the distal region, and significant levels of damage beyond the distal dose fall-off were observed. In line with other studies, these results suggest that assuming a constant biological effectiveness along a proton SOBP may be sub-optimal.

Practical Considerations in the Conduct of Micronucleus Test

Genotoxicity is commonly evaluated during the chemical safety assessment together with other toxicological endpoints. The micronucleus test is always included in many genotoxicity test guidelines for long time in many classes of chemicals, e.g., pharmaceutical chemicals, agricultural chemicals, food additives. Although the trend of the safety assessment of chemicals faces to animal welfare and in vitro systems are more welcome than the in vivo systems, the in vivo test systems are paid more attention in the field of genotoxicity because of its weight of evidence. Chromosome defects are recognized as being the basis of a number of human genetic diseases. Chemicals can be tested in vitro for their ability to produce chromosome aberrations in cells with which they have direct contact in a static system. Chemicals may react differently in vivo, however, where metabolic systems other than liver cytochrome P448/P450 operate, and where the dynamic processes of absorption, metabolism and excretion are involved. Chemicals should therefore also be tested for chromosome damaging activity in vivo.Read more...

Towards Establishing Capacity for Biological Dosimetry at Ghana Atomic Energy Commission.

The aim of this study was not only to obtain basic technical prerequisites for the establishment of capacity of biological dosimetry at the Ghana Atomic Energy Commission (GAEC) but also to stimulate interest in biological dosimetry research in Ghana and Sub-Saharan Africa. Peripheral blood from four healthy donors was exposed to different doses (0–6 Gy) of gamma rays from a radiotherapy machine and lymphocytes were subsequently stimulated, cultured, and processed according to standard protocols for 48–50 h. Processed cells were analyzed for the frequencies of dicentric and centric ring chromosomes. Radiation dose delivered to the experimental model was verified using GafChromic® EBT films in parallel experiments. Basic technical prerequisites for the establishment of capacity of biological dosimetry in the GAEC have been realized and expertise in the dicentric chromosome assay consolidated. We successfully obtained preliminary cytogenetic data for a dose-response relationship of the irradiated blood lymphocytes. The data strongly indicate the existence of significant linear (α) and quadratic (β) components and are consistent with those published for the production of chromosome aberrations in comparable absorbed dose ranges.

Genetic Susceptibility

Genetic variation in the capacity to repair radiation damage is an important factor influencing both cellular and tissue radiosensitivity variation among individuals as well as dose rate effects associated with such damage. This paper consists of two parts. The first part reviews some of the available data relating to genetic components governing such variability among individuals in susceptibility to radiation damage relevant for radiation protection and discusses the possibility and extent to which these may also apply for space radiations. The second part focuses on the importance of dose rate effects and genetic-based variations that influence them. Very few dose rate effect studies have been carried out for the kinds of radiations encountered in space. The authors present here new data on the production of chromosomal aberrations in noncycling low passage human ATM+/+ or ATM+/- cells following irradiations with protons (50 MeV or 1 GeV), 1 GeV(-1) n iron ions and gamma rays, where doses were delivered at a high dose rate of 700 mGy(-1) min, or a lower dose rate of 5 mGy min(-1). Dose responses were essentially linear over the dose ranges tested and not significantly different for the two cell strains. Values of the dose rate effectiveness factor (DREF) were expressed as the ratio of the slopes of the dose-response curves for the high versus the lower (5 mGy min(-1)) dose rate exposures. The authors refer to this as the DREF5. For the gamma ray standard, DREF5 values of approximately two were observed. Similar dose rate effects were seen for both energies of protons (DREF5 ≈ 2.2 in both cases). For 1 GeV(-1) n iron ions [linear energy transfer (LET) ≈ 150 keV μ(-1)], the DREF5 was not 1 as might have been expected on the basis of LET alone but was approximately 1.3. From these results and conditions, the authors estimate that the relative biological effectiveness for 1 GeV(-1) n iron ions for high and low dose rates, respectively, were about 10 and 15 rather than around 20 for low dose rates, as has been assumed by most recommendations from radiation protection organizations for charged particles of this LET. The authors suggest that similar studies using appropriate animal models of carcinogenesis would be valuable.

Identification of genes regulating recombination of repetitive DNA

Transposons mold the genome by transposition and through subsequent recombination between the dispersed repeats. Recombination between Ty1 elements can produce chromosome aberrations in yeast. We previously developed a unique set of Retrotransposon Overdose (RO) strains which contain 3 to 10‐fold more Ty1 elements (Scheifele, PNAS 2009). We used RO strains to screen for genes controlling Ty1 recombination and identified DNA replication, repair, and cohesion genes that, when deleted, produce growth defects specific to RO strains. To confirm that these growth defects are due to increased recombination, we used a strain of yeast with a marked Ty1 element, individually deleted the genes identified in our screen, and measured the rate of marker loss; deletion of genes that control Ty1 recombination should increase loss of the genetic marker. Further, by comparing the frequency of marker loss, we can determine which genes have the greatest role in preventing recombination between Ty1 elements. While most of the gene deletions increased Ty1 recombination, the magnitude of their effects varied. In addition, we observed variation in the type(s) of recombination affected, with differential effects on recombination between transposons, between direct repeats, and between lys2 heteroalleles. This specificity suggests that there may be distinct mechanisms to regulate recombination between repetitive DNA sequences.

The Effectiveness of 20 MeV Protons at Nanosecond Pulse Lengths in Producing Chromosome Aberrations in Human-Hamster Hybrid Cells

Laser accelerated radiotherapy is a potential cancer treatment with proton and carbon-ion beams that is currently under development. Ultra-fast high-energy laser pulses will accelerate ion beams that deliver their dose to a patient in a "pulsed mode" that is expected to differ from conventional irradiation by increasing the dose delivery rate to a tissue voxel by approximately 8 orders of magnitude. In two independently performed experiments at the ion microprobe SNAKE of the 14 MV Munich tandem accelerator, A(L) cells were exposed either to protons with 1-ns pulse durations or to protons applied over 150 ms in continuous irradiation mode. A slightly but consistently lower aberration yield was observed for the pulsed compared to the continuous mode of proton irradiation. This difference was not statistically significant when each aberration type was analyzed separately (P values between 0.61 and 0.85 in experiment I and P values between 0.32 and 0.64 in experiment II). However, excluding the total aberrations, which were not analyzed as independent radiation-induced effects, the mean ratio of the yields of dicentrics, centric rings and excess acentrics scored together showed (with 95% CI) a significant difference of 0.90 (0.81; 0.98) between the pulsed and the continuous irradiation modes. A similar tendency was also determined for the corresponding RBE values relative to 70 kV X rays. Since the different findings for the comparisons of individual chromosome aberration types and combined comparisons could be explained by different sample sizes with the consequence that the individual comparisons had less statistical power to identify a difference, it can be concluded that 20 MeV protons may be slightly less effective in the pulsed mode.

Particulate hexavalent chromium is cytotoxic and genotoxic to the North Atlantic right whale (Eubalaena glacialis) lung and skin fibroblasts

Hexavalent chromium compounds are present in the atmosphere and oceans and are established mutagens and carcinogens in human and terrestrial mammals. However, the adverse effects of these toxicants in marine mammals are uncertain. Previously, we reported that North Atlantic right whales, one of the most endangered great whales, have tissue chromium levels that are high, levels that may pose a risk to the whale's health. Furthermore, the study suggested that inhalation may be an important exposure route. Exposure to chromium through inhalation is mainly because of particulate compounds. However, the toxicity of particulate chromium compounds in marine mammal cells is unknown. Accordingly, in this study, we tested the cytotoxic and genotoxic effects of particulate hexavalent chromium in primary cultured lung and skin fibroblasts from the endangered North Atlantic right whale. Cytotoxicity was measured by clonogenic survival assay, and genotoxicity was measured as production of chromosome aberrations. Particulate hexavalent chromium induced cytotoxicity and genotoxicity in a concentration-dependent manner in both right whale lung and skin fibroblasts. Lung fibroblasts were more resistant to chromium cytotoxicity, but presented with more chromosome damage than skin fibroblasts. These data further support the hypothesis that chromium may be a health concern for the endangered North Atlantic right whale.

Medaka ( Oryzias latipes) as a sentinel species for aquatic animals: Medaka cells exhibit a similar genotoxic response as North Atlantic right whale cells

Hexavalent chromium (Cr(VI)) is emerging as a major concern for aquatic environments, particularly marine environments. Medaka ( Oryzias latipes) has been used as a model species for human and aquatic health, including the marine environment, though few studies have directly compared toxicological responses in medaka to humans or other aquatic species. We used a medaka fin cell line to compare the genotoxic response of medaka to Cr(VI) to the response observed in North Atlantic right whale cells to see if responses in medaka were similar to those of other aquatic species, particularly aquatic mammals. We used the production of chromosomal aberrations as a measure of genotoxicity. We found that in medaka cells, concentrations of 1, 5 and 10 µM sodium chromate damaged 17, 32 and 43% of metaphases, respectively and these same concentrations 1, 2.5, 5 and 10 µM sodium chromate damaged 14, 24 and 49% of metaphases, respectively, in North Atlantic right whale lung cells and 11, 32 and 41% of metaphases, respectively, in North Atlantic right whale testes cells. These data show that genotoxic responses in medaka are comparable to those seen in North Atlantic right whale cells, consistent with the hypothesis that medaka are a useful model for other aquatic species.

Hexavalent chromium is cytotoxic and genotoxic to the North Atlantic right whale ( Eubalaena glacialis) lung and testes fibroblasts

Although hexavalent chromium is a known genotoxic agent in human and terrestrial mammals and is present in seawater and air, its effects on marine mammals including the endangered North Atlantic right whale are unknown and untested. The present study investigated the cytotoxic and genotoxic effects of hexavalent chromium in primary cultured North Atlantic right whale lung and testes fibroblasts and levels of total chromium in skin biopsies from North Atlantic right whales. Cytotoxicity was measured by clonogenic survival assay. Genotoxicity was measured as production of chromosome aberrations. Tissue chromium levels were determined from skin biopsies of healthy free-ranging whales in the Bay of Fundy using inductively coupled plasma optical emission spectroscopy. Hexavalent chromium-induced concentration-dependent increases in right whale lung and testes fibroblast cytotoxicity with the testes more sensitive to the cytotoxic effects. It also induced concentration-dependent increases in chromosomal aberrations in both cell types with no significant difference in sensitivity. Skin biopsy data indicate that North Atlantic right whales are exposed to chromium and accumulate a range of 4.9–10 μg Cr/g tissue with a mean of 7.1 μg/g. Hexavalent chromium is cytotoxic and genotoxic to North Atlantic right whale cells. The whales have tissue chromium levels that are concerning. These data support a hypothesis that chromium may be a concern for the health of the North Atlantic right whales. Considering these data with chromium chemistry, whale physiology and atmospheric chromium levels further suggest that inhalation may be an important exposure route.

Adaptive response and human benefit: Part I. A microdosimetry dose-dependent model

Purpose: It is important to evaluate how adaptive response may be of human benefit from the risks of ionizing radiation. The purpose of this work is to develop and apply a microdosimetric dose response model capable of explicitly determining, for broad beam exposures, the threshold and progressive activation of natural spontaneous and radiation damage protective mechanisms associated with adaptive response and other cellular negative response behavior.Materials and methods: A biophysical model was developed quantifying the accumulation of Poisson distributed microdose specific energy hits to cell critical nucleus volumes. The model was applied to the adaptive response data of Wiencke et al., Redpath et al., Azzam et al. and Pohl-Ruling et al. The model was also applied to non-adaptive response data showing dose response reductions below the zero dose natural spontaneous level and to data exhibiting mid-range non-monotonic dose response plateaus.Results: We find good fits of the model to all data. For adaptive response, a significant result is, that only one or two specific energy hits of low linear energy transfer (LET) radiation in the cell nucleus activates the protective mechanisms for both the natural spontaneous and radiation damage. Several data support a dose plateau for radon progeny alpha production of chromosome aberrations in human lymphocytes. Using the model, a bystander factor of about 30 is obtained with the model for high dose rate, in vitro alpha particle data. For low dose rate in vivo, the bystander effect is minimal suggesting for alphas that the bystander effect may be dose rate dependent. There is no evidence of bystander effects in the low LET adaptive response data analysis.Conclusions: The microdosimetry model allows concise determinations of specific energy hits within the cell critical nucleus volume to activate both protective and damage mechanisms. One or two low LET hits can result in reduction of both zero dose natural spontaneous and radiation-induced, carcinogenic causing damage. The model should be useful in comparing in vitro and in vivo broad beam to single track microbeam exposure data. The model is capable of determining, to an accuracy of ± one specific energy hit, the minimum threshold for induction of radioprotective mechanisms – crucial to assessing the potential human benefit of adaptive response and other negative dose response behavior.

Evidence That Oxymorphone-Induced Increases in Micronuclei Occur Secondary to Hyperthermia

Oxymorphone is a potent opioid analgesic. Oral administration of oxymorphone to rats at doses >or= 20 mg/kg and mice at 500 mg/kg produced an increase in micronucleated polychromatic erythrocytes (MPCEs). Oxymorphone does not produce chromosome aberrations in vitro, suggesting that the increased MPCEs in vivo may involve indirect mechanisms. Opioids are known to affect thermoregulatory mechanisms. Changes in body temperature can increase the incidence of MPCEs in rodents. Studies were conducted to examine the relationship between increased MPCEs in rats given oxymorphone and changes in body temperature. Single oral doses of oxymorphone associated with increased MPCEs (20 and 40 mg/kg) also produced a marked, rapid increase in body temperature. When animals were pretreated with sodium salicylate, peak body temperature was lower and returned to baseline more quickly than when oxymorphone was given alone. MPCEs were evaluated in rats after administration of oxymorphone (40 mg/kg) alone or following pretreatment with an oral dose of sodium salicylate. Oxymorphone alone produced a statistically significant increase in the incidence of MPCEs (3.6 per 1000 polychromatic erythrocytes vs. 0.4 in controls). The number of MPCEs in animals pretreated with sodium salicylate was similar to controls. Sodium salicylate alone had no effect on the number of MPCEs. Systemic oxymorphone exposure was not affected by sodium salicylate pretreatment; maximum plasma concentration (C(max)) and area-under-the-curve values were similar after administration of oxymorphone alone or following pretreatment with sodium salicylate. These results indicate that the increased incidence of MPCEs following oxymorphone administration is directly related to increased body temperature.

Studies on chromosome aberration induction: What can they tell us about DNA repair?

Many, if not the majority of spontaneous or induced mutations in somatic mammalian cells associated with cancer are large chromosome level changes. For exposure to carcinogenic agents, certain specific chromosomal aberrations are likely to lie early along the pathway leading from initial molecular damage to cancer. The kinds of aberrations that occur, and the positions of breakpoints involved in their formation, can reveal not only genes and controlling elements whose expression or suppression underlie the molecular nature of the initiation of malignant transformation, but also how structural and functional features of chromatin can affect processes involved in repair or mis-repair of initial DNA damage. Thus, cytogenetics can provide information in ways that are not readily appreciated in studies requiring disruption of chromatin organization as it exists in the cell and its tissue context, and where DNA repair assays measure effects averaged over the entire genome. Examples include the fact that in contrast to a more efficient repair of single strand or base damage in transcriptionally active chromatin, after ionizing radiation exposure, the preponderance of translocation breakpoints indicating mis-repair occur in transcriptionally active or potentially active chromatin. Cytogenetic studies have led to the recognition that processing of DNA ends – both ends resulting from breaks along chromosomes and natural chromosomal termini, or telomeres – share very interesting similarities and differences. Further, direct observation of chromatin in cells during interphase can speak directly to early stages of aberration formation where processes occur within the context of intact cells, and to the role (or lack thereof) of cell cycle checkpoint responses that often accompany DNA damage. The superior resolution of many of the current molecular cytogenetics approaches, combined with immunocytochemical detection of proteins involved in DNA damage processing, and the availability of repair deficient mutants or knockdown strategies such as RNA interference, suggest that cytogenetics may still provide useful information and set certain restrictions important for rational interpretation of studies of DNA repair and associated protein interactions that can only be carried out in vitro. The intent of this paper is to focus on contributions of studies on the production of chromosomal aberrations following ionizing radiation exposure regarding important insights on associated DNA repair processes involved, and further, on guidelines or constraints they provide for the interpretation of in vitro DNA repair studies that would have been difficult to appreciate without the cytogenetics. We will first briefly summarize some early studies that serve as a reminder of the background on which current studies are based, and then carry forward to the present day certain interesting facets of these studies.

Intrachromosomal exchange aberrations predicted on the basis of the globular interphase chromosome model.

One of the key questions in understanding mechanisms of chromosome aberration production is how does interphase chromosome structure affect aberration formation. To explore this a modelling approach is presented which combines Monte Carlo simulation of both alpha particle track and interphase chromosome structure. The structural state of interphase chromosome influences a dose-effect relationship for intrachromosomal exchange aberrations (intrachanges). It is shown that intrachanges are induced frequently by both X rays and alpha particles if the chromosome is in the condensed globular but not in the decondensed coiled state. Truly simple intra-arm intrachanges induced by X rays are dose squared in coiled chromosomes, but exhibit linear dose dependence in globular chromosomes. Experimental data on interarm intrachanges obtained by dual arm chromosome painting are analysed by means of the technique presented. Results of analysis support the conclusion about the arms proximity of chromosome 1 in human lymphocytes.

Computer analysis of mFISH chromosome aberration data uncovers an excess of very complicated metaphases

Purpose : To analyse spectra of chromosome aberrations induced in vitro by low LET radiation, in order to characterize radiation damage mechanisms quantitatively. Methods : Multiplex fluorescence in situ hybridization (mFISH) allows the simultaneous identification of each homologous chromosome pair by its own colour. mFISH data, specifying number distributions for colour junctions in metaphases of human peripheral blood lymphocytes 72 hours after exposure in vitro to a 3 Gy γ-ray dose, were combined with similar, previously published results. Monte Carlo computer implementations of radiobiological models for chromosome aberration production guided quantitative analyses, which took into account distribution of cells among different metaphases and lethal effects or preferential elimination of some aberrations at cell division. Results and Conclusions : Standard models of DNA damage induction/repair/misrepair explain the main trends of the data as regards the fraction of metaphases having a particular number of colours involved in colour junctions. However, all standard models systematically under-predict the observed fraction of metaphases where a large number of different chromosomes participate in aberrations. An early appearance of chromosomal instability could explain most of the discrepancies.

Radiobiological effects of a low-energy ion beam on wheat.

The radiobiological effects of a low-energy nitrogen ion (N+) beam on wheat were studied, particularly with regard to the induction of chromosome aberrations. The results demonstrated that the three test varieties showed different sensitivities to ion implantation, and a higher dose of ion implantation had a marked effect on the germination and survival rate of the seeds exposed. The germination rate and survival rate curve basically followed a similar trend in the same variety. Cytological analysis indicated that ion beams were effective in producing chromosome aberrations. The frequencies of mitotic or meiotic cells with chromosome aberrations increased linearly with increasing doses. The aberration types included, for example, acentric fragments, chromosome deletions, lagging chromosomes, chromosome bridges and micronuclei. In the root tip cells, aberrations chiefly consisted of acentric fragments and deletions. Chromosome bridges and lagging chromosomes were the main aberration phenomena observed in the pollen mother cells. The highest frequencies of root tip cells and pollen mother cells with chromosome aberrations were 15.2% and 39.8%, respectively. Changes in morphology and mutant were also observed in the plants derived from exposed seeds.

Underprediction of visibly complex chromosome aberrations by a recombinational-repair ('one-hit') model

Purpose : Published low-LET FISH data were used to test two models of chromosome aberration production based on breakage-and-reunion or recombinational repair. Materials and methods : Randomness of DNA double strand break induction and misrejoining is analyzed comprehensively and adopted as a working hypothesis. Proximity effects are approximated by using interaction sites. Model results are calculated using CAS (chromosome aberration simulator) Monte Carlo computer software with two adjustable parameters. CAS can emulate the specifics of any experimental painting protocol, allowing very detailed tests of the models. Results : To reasonable approximation, breakage-and-reunion model predictions are consistent with low-LET FISH results, including two large, elaborate, one-paint data sets. An explicitly specified version of the recombinational-repair model severely underpredicts the frequency of the visibly complex aberration patterns most commonly observed with one-paint FISH, and is inconsistent with some observed multi-paint patterns. When high-dose effects (distortion and saturation) are taken into account quantitatively, a dose-response relation for apparently simple interchanges slightly favours the breakage-and-reunion model over the recombinational-repair model, despite being approximately linear over the dose range 2-6Gy. Conclusions : The random breakage-and-reunion model gives comprehensive baseline predictions that are sufficiently accurate for the organization of experimental results. The data speak against complex aberrations being formed by the random recombinational repair pathway discussed here.

Random breakage and reunion chromosome aberration formation model; an interaction–distance version based on chromatin geometry

. Purpose : Using published FISH data for chromosome aberration production in human fibroblasts by hard X-rays to test a breakage-and-reunion model. Methods : The model assumed pairwise misrejoining, random apart from proximity e ffects, of DNA double-strand break (DSB) free ends. CAS (chromosome aberration simulator) Monte Carlo computer software implementing the model was modified to use a distance algorithm for misrejoining instead of using DSB interaction sites. The modification (called CAS2) allowed a somewhat more realistic approach to large-scale chromatin geometry, chromosome territories and proximity effects. It required adding a third adjustable parameter, the chromosome territory intersection factor, quantifying the amount of intertwining among different chromosomes. Results : CAS2 gave somewhat better results than CAS. A reasonable fit with a few discrepancies was obtained for the frequencies at three different radiation doses of many different aberration types and of aberrations involving various specific chromosomes in a large data set using one-paint FISH scoring. The optimal average chromosome territory intersection factor was ~1.1, indicating that, for an arbitrarily chosen location in the nucleus, on average slightly more than two chromosomes have very nearby loci. Without changing the three parameter values, a fit was also obtained for a corresponding, smaller, two-paint data set. Conclusions : A random breakage-and-reunion model incorporating proximity effects by using a distance algorithm gave acceptable approximations for many details of hard X-ray aberration patterns. However, enough discrepancies were found that the possibility of an additional or alternate formation mechanism remains.