British Journal of Radiology (2005) 78, 928-933
© 2005 British Institute of Radiology
doi: 10.1259/bjr/18119329
Tracing radiation induced genomic instability in vivo in the haemopoietic cells from fetus to adult mouse
P Uma Devi, PhD
and
M Satyamitra, PhD
Department of Research, Jawaharlal Nehru Cancer Hospital and Research Centre, Idgah Hills, Post Box No. 32, Bhopal 462 001, India
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Abstract
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The present experiment was aimed at studying the delayed expression of fetal irradiation induced genomic instability in the mouse haemopoietic cells in vivo. The abdominal area of 14 day pregnant Swiss albino mice was exposed to 0–1.5 Gy of gamma radiation. Chromosomal aberrations were studied in three passages of spleen colonies (short-term repopulating stem cells, STRSC) derived from 24 h post-irradiation fetal liver cells and in the 1–20 months postpartum bone marrow (long-term repopulating stem cells, LTRSC). Irradiation produced a significant and dose-dependent increase in the aberrant metaphases in the first passage spleen colony (CFU-S1) cells, which decreased in subsequent passages and reached normal levels by the third passage (CFU-S3). Bone marrow at 1–6 months postpartum showed similar chromosomal picture in the 0 Gy control and after 0.5–1.5 Gy, but there was a clear increase in aberrant cells from 9 months postpartum in the irradiated groups. Some mice in all irradiated groups showed a 2.5- to 5-fold increase in peripheral leukocyte counts. Bone marrow of these animals exhibited severe aneuploidy, the chromosome number ranging from less than 1n to 6n at 20 months of age. Our results indicate that unstable chromosome aberrations induced in the fetal haemopoietic STRSC are eliminated during subsequent cell divisions. However, genomic instability induced in the LTRSC persists and is expressed as chromosomal aberrations at advanced ages. Induction of chromosome aneuploidy could be an early step in the chain of events leading to adult leukaemia after prenatal irradiation.
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Introduction
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Radiation induced genomic instability can be expressed as delayed reproductive cell death [1], chromosomal aberrations [2, 3] or gene mutations [4] after many cell generations. Pampfer and Streffer [5] were the first to report that X-ray exposure of mouse zygotes increased the chromosomal aberrations in the fetal skin fibroblasts. More recently, we observed that exposure of Swiss albino mice to 0.25–1.5 Gy gamma rays during the fetal stage resulted in a dose-dependent increase in the aberrant metaphases, acentric fragments and polyploids in the bone marrow at 12 months of age [6]. But the bone marrow of 1–3 months old mice that were exposed to 1 Gy on day 14 of gestation did not show such anomalies [7]. The haemopoietic progenitor cell pool consists of two types of stem cells: short-term repopulating stem cells (STRSC) and long-term repopulating stem cells (LTRSC). The progeny of STRSC exhibit decreasing capacity for self-renewal and increasing probability of committing to different haemopoietic lineages, while the LTRSC consist of the most primitive stem cells and have the greatest capacity for self-renewal and long-term maintenance of haemopoiesis [8]. Measurements for STRSC are done up to about 90 days after irradiation and LTRSC are measured after 90 days post-irradiation. DNA strand breaks induced in the fetal haemopoietic cells that are unrepaired/misrepaired will be expressed as chromosomal aberrations in the subsequent cell generations. The cells carrying severe genomic damage will be eliminated by reproductive cell death, resulting in a decrease in the aberrant cells during successive cell cycles. Our earlier findings on the bone marrow chromosomes at 12 months of age [6] could reflect the delayed expression of genomic instability induced in the fetal haemopoietic LTRSC. Therefore, the present study was undertaken to trace the radiation induced genomic instability in the progenies of the fetal STRSC and LTRSC separately, by scoring unstable chromosomal aberrations.
The haemopoietic function in the developing mouse shifts from the yolk sac to liver, spleen and finally, to the fetal bone marrow by the end of gestation. The liver becomes functional around 11 days post coitus (p.c.) and remains the main haemopoietic organ up to 16 days p.c. [9]. The early fetal stage of day 14 p.c. was used for the experiments, because at this time the liver is the only major source of haemopoietic stem cells that seed the bone marrow [10, 11].
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Methods and materials
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Animals
8–10-week-old Swiss albino mice, weighing 30±3 g, from a randomly bred colony, were caged together from 8 to 10 a.m., 1 male: 2 females. Thereafter, the females were examined and those with vaginal plug were separated and marked as 0 day pregnant.
Irradiation
On day 14 p.c., the mice were anaesthetized by intraperitoneal (i.p.) injection of 50 mg kg–1 body weight of Ketamine (Themis Chemicals, Mumbai, India) and 0.5 mg mouse–1 of diazepam (Ranbaxy Fine Chemicals, Mumbai, India). The abdominal area was exposed to 0.0, 0.5 Gy, 1.0 Gy or 1.5 Gy of gamma radiation (60Co teletherapy unit, Siemens, Erlangen, Germany), at a dose rate of 1.0 Gy min–1, using 14 to 16 pregnant mice for each dose.
The effect on LTRSC can be studied by the spleen colony forming unit (CFU-S) assay, while LTRSC needs long-term follow-up. Genomic damage in the STRSC was assayed by chromosome aberration analysis through successive passages of spleen colony forming units (CFU-S) derived from the fetal liver. That in the LTRSC was followed up by chromosome analysis in the postpartum bone marrow.
Fetal haemopoietic studies
At 24 h after irradiation (day 15 p.c.) 4 mice from each group were killed by cervical dislocation. Liver from the fetuses was dissected out and single cell suspension was prepared in Eagle's minimum essential medium (MEM; Sigma Chemical Co., St Louis, MO). The cell suspensions from all fetuses of a mother were pooled. The nucleated cells were counted on a haemocytometer and a known number of cells was injected into the tail vein of adult recipient mice, whose bone marrow was ablated by 9.5 Gy whole body irradiation 6 h before the injection of fetal liver cells [12]. The recipients were observed for 11 days. On the 12th day, the animals were injected (i.p.) with 0.3 ml of 0.025% colchicine (Sigma) and killed 2 h later, the spleens then being removed. Visible nodules (macrocolonies) on the spleen surface (CFU-S1) were scooped out and single cell suspensions were prepared. The cell suspensions from all recipients of each donor were pooled. The cells were counted and a known number of cells were injected into a second set of donors and the 12-day spleen colonies (CFU-S2) were processed, as before. Similarly, a third passage of spleen colonies (CFU-S3) was developed from the CFU-S2 cells. In each passage, a part of the cell suspensions from the colonies was used for chromosome study. Cells from the third passage were injected into adult recipients, which were left for 20 days. On the 21st day, the animals were injected with colchicine and killed 2 h later. The femur marrow was flushed out with normal saline and processed for chromosome analysis.
Chromosome analysis
The cells were centrifuged, treated with hypotonic salt solution (0.56% KCl), fixed in methanol-acetic acid (3:1) and metaphase plates were prepared by the air drying method. Slides were stained with 3% Giemsa (Sigma) and aberrations were scored under a light microscope (60 x, AO Reichert, USA), as described earlier [13]. Percent aberrant metaphases and the number of different aberrations/metaphases were calculated.
Four pregnant mice were used for each dose. Five recipients were used for each donor and 500 metaphase plates were scored per donor. The means of data from 4 donors±standard error of the mean (SE) are presented.
Postnatal studies
The remaining animals (10–12 per group) were left to deliver their young. At 1, 3, 6, 9, and 12 months of age, 3–4 mice from control (0.0 Gy) and each irradiated group were injected with colchicine and chromosomal aberrations were scored in the femur marrow, as described above. Some animals showed very high peripheral leukocyte (WBC) counts at later ages. Chromosomal aberrations in the bone marrow were studied also at 20 months of age in the mice showing normal and high leukocyte counts.
The study was conducted according to the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India. Statistical analysis was done by Student's t-test and one-way analysis of variance (ANOVA).
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Results
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Fetal haemopoietic studies
The first passage of spleen colonies (CFU-S1), derived directly from the 24 h post-irradiation fetal liver cells, showed significantly higher frequency of aberrant metaphases and aberrations per cell than in the 0.0 Gy controls. The effect increased with increase in radiation dose (Figure 1
). The main types of aberrations were chromatid and chromosome breaks and fragments and a few rings and dicentrics (Table 1). The aberrant metaphases and aberrations per cell decreased progressively in the subsequent passages of CFU-S (CFU-S2 and CFU-S3). No rings or dicentrics were observed in these later passages. The CFU-S1 cells also showed a high incidence of polyploidy, which increased with radiation dose. The frequency of polyploids dropped sharply in the next passage (CFU-S2) and none was detected in the CFU-S3 cells. The bone marrow of adult mice that had received cells from the CFU-S3 did not show any increase in chromosomal aberrations above control; neither were any polyploids detected (Table 1).
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Figure 1. Percentage of aberrant metaphases in three passages of fetal liver CFU-S and postnatal and adult bone marrow of mice exposed to gamma rays on day 14 p.c. ap<0.05; bp<0.01; cp<0.001, compared with 0.0 Gy. Other explanations as in Table 1 .
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Postnatal studies
The postnatal bone marrow of the irradiated mice at 1, 3 and 6 months of age did not show any increase in chromosome abnormalities above control, but there was a notable increase in the aberrant metaphases from 9 months, which increased further with age (Figure 1). The main types of aberrations at all ages were chromatid breaks and fragments. A few chromosome breaks appeared at 6 months in the irradiated groups and their incidence increased at 12 months, which was not radiation dose-dependent. Polyploids were observed at 9 months, and further increased at 12 months in the 1.0 Gy and 1.5 Gy groups. Control animals also showed some chromosome breaks at 9 months and 12 months and a few polyploids at 12 months of age, but their frequency was lower than in the irradiated groups (Table 2).
In general, peripheral blood counts were significantly lower than in control in the adult mice that had been exposed on day 14 p.c. at all doses (data not shown). However, some animals in all irradiated groups (5–12% at 0.5–1.5 Gy), but not control, showed very high WBC counts at the later ages, and in these mice the counts went up to 2.5–5 fold the normal. Bone marrow chromosome analysis in these animals at 20 months of age showed very high levels of aneuploidy compared with the animals with normal leukocyte counts, the chromosome number ranging from less than 1n (lowest chromosome number=16) to 6n, while no hypoploids were detected in their normal WBC counterparts (Table 3).
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Discussion
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The present results indicate that a single exposure to gamma radiation in the range of 0.5–1.5 Gy at the early fetal stage of mice can induce DNA damage in the fetal haemopoietic cells. This is evident from the significant and dose-dependent increase in aberrant metaphases and aberrations per cell in the spleen colonies formed from the fetal liver cells (CFU-S1), which represent the short-term re-populating stem cells [8]. The cells bearing severe chromosome damage will undergo reproductive death and will be removed from the proliferating stem cell pool. The continuous elimination of the damaged stem cells through further cell cycles can explain the progressive decrease in aberrant cells and aberrations per cell through the successive passages of spleen colonies. The bone marrow of the mice receiving the CFU-S3 cells or of the 1-month-old pups that had been irradiated on day 14 p.c. did not show any increase in chromosomal anomalies above spontaneous occurrence. This could be due to elimination by death of the fetal haemopoietic cells with DNA damage, thus preventing them from seeding the bone marrow. Rosemann et al [14] also reported a low frequency of chromosomal aberrations in the bone marrow of newborn mice following 239Pu contamination on day 14 p.c. They explained this as due to failure of the stem cells bearing aberrations in seeding the bone marrow and their subsequent elimination. Apart from cell death, loss through differentiation also may contribute to the decrease in aberrant cells in the postnatal bone marrow. The bone marrow of the 3 month and 6 month old mice that had been exposed at the fetal stage presented a normal chromosome picture. However, both structural aberrations and polyploids showed a clear increase at the later ages.
In the 14 day mouse fetus, liver is the only major haemopoietic organ and is the source of the stem cells that seed the future bone marrow. Therefore, any genomic instability induced in these cells can be transmitted to the postnatal bone marrow through migration of the affected cells from the fetal liver. The genomic instability may persist in the adults, leading to a delayed induction of chromosomal instability [11]. Thus, the high incidence of chromosomal abnormalities observed in the adult bone marrow of the mice irradiated on day 14 p.c. would reflect the delayed expression of genomic instability induced in the fetal cells. The cells, which populate the adult bone marrow, represent the long-term re-populating cells, with the capacity for long-term maintenance of haemopoiesis and include the most primitive stem cells, which exhibit significant resistance to proliferation and differentiation stimuli [8]. The de novo appearance of aberrations in the bone marrow at the advanced ages, while they are not detected at the young ages, after prenatal irradiation indicates a non-clonal origin of chromosomal instability in these cells. Kronenberg [15] suggested that a large fraction of cells surviving radiation exposure develop genomic instability or delayed chromosomal instability, observed as de novo aberrations many cell cycles after the treatment. Watson et al [16] have also demonstrated the occurrence of unstable chromosomal aberrations in the bone marrow up to 24 months after irradiation of young mice.
According to Morgan et al [17], several radiation induced cellular events such as double strand breaks, signal transduction cascades, gene induction and/or modification of gene expression, may initiate genomic instability. The non-clonal effects in the haemopoietic cells may be due to de novo DNA damage arising via transmission of instability from the irradiated stem cells to their progeny. Yang et al [18] proposed that damage to the stromal cells contributes to the induction of chromosomal instability in the haemopoietic cells after prenatal irradiation. Clutton et al [19] suggested a role of epigenetic factors (e.g. aberrant oxy-radical metabolism) in the persistent occurrence of genomic instability. They demonstrated an association of radiation-induced chromosomal instability with increased intracellular reactive oxygen species (ROS), oxidative DNA base damage and vulnerability to free radical-induced membrane damage in haemopoietic cells. Limoli et al [20] have shown that unstable clones possessed higher levels of ROS than their stable counterparts.
The control animals also showed an increase in the spontaneous chromosomal aberrations and polyploids at advanced ages, suggesting that these changes may be part of the natural ageing process. But the increase in these anomalies was much more pronounced and occurred earlier (9 months) in the irradiated animals compared with controls (12 months). This indicates that irradiation at the prenatal stage must have accelerated the changes associated with ageing and consequently, resulted in the early expression of genomic instability. Wolff et al [21] have demonstrated that response to mild oxidative stress can accelerate the ageing process in fibroblasts. Plumb et al [22] have suggested that ionizing radiation advanced the onset of sporadic Y-chromosome instability associated with age.
Watson et al [23] have reported that when irradiated bone marrow was transplanted into the recipient, de novo appearing unstable aberrations were detected up to 1 year post-irradiation. Uma Devi and Hossain [6] also observed that exposure to 0.25–1.5 Gy of gamma rays at the fetal stage of mice increased the frequency of acentric fragments and polyploids in the bone marrow at 12 months postpartum and this effect increased with increase in radiation dose. The present data show that the structural aberrations and chromosome aneuploidy in the adult bone marrow increased with age. The absence of any such increase at the early postnatal and young adult stages suggests that there is a latent period between the induction of genomic instability and its expression in the chromosome morphology.
Once initiated, the genomic instability can be perpetuated by enhanced and persistent oxidative stress in the progeny of the irradiated cells, which initiates signal cascades contributing to the delayed chromosome instability [17]. The decrease in cellular defence, and the consequent increase in oxidative stress at advanced ages, would increase the DNA damage, especially in the cells carrying unstable genome, resulting in the observed elevation in chromosomal aberrations in the in utero exposed adult mice. The rate of production of superoxide anions and hydrogen peroxide in mitochondria was shown to increase with age [24]. Atamna et al [25] have reported a decline in the levels of cellular antioxidants, particularly glutathione, with increasing age, resulting in an increase in the susceptibility to oxidative stress-induced DNA damage. Prenatal irradiation may not induce any new type of changes, but can significantly enhance and accelerate the changes associated with normal ageing so that there is a temporal advancement in the manifestation of these changes. This could cause an earlier manifestation of chromosomal instability in the irradiated mice. A significant decrease in the maze learning ability of young adult (6 months p.p.) mice exposed to 1 Gy gamma radiation on day 14 p.c. has been demonstrated, which was comparable with that exhibited by unirradiated mice at 18 months of age, suggesting an accelerated induction of senile changes by fetal irradiation [26]. Irradiation on day 14 p.c. was also found to significantly reduce the mean age (by 4–5 months) at which solid tumours develop in these animals [27].
A noteworthy finding of the present study is the clear association between severe chromosome loss in the bone marrow stem cells and the high peripheral leukocyte counts in the prenatally irradiated offspring, while such a phenomenon was not detected in the unirradiated controls. The number of aneuploids and the severity of hypoploidy increased with increase in leukocyte counts. This suggests that the stem cells carrying genomic instabilities undergo clonal expansion, resulting in the perpetuation and magnification of chromosomal instability in their progeny. Limoli et al [28] have reported that chromosomally unstable clones showed a significantly higher amplification frequency than stable clones. They suggested that radiation initiates a series of events that can mediate the persistent destabilization of chromosomes. In vitro studies on mouse bone marrow cells exposed to alpha particles suggested that non-clonal chromosomal aberrations may be important for radiation induced leukaemia [2]. The mouse strain used in the present study is not known to develop leukaemia. However, most solid tumours in the prenatally irradiated adult mice developed around the age (
9 months [6]), when the aberrant metaphases in the bone marrow also showed an elevation above control. The occurrence of severe chromosome aneuploidy in the bone marrow with high peripheral leukocyte counts suggests a possible association between chromosome instability in the haemopoietic stem cells and development of leukaemia after fetal irradiation. Plumb et al [22] observed that progression of X-ray induced acute myeloid leukaemia in the CBA/H mouse was associated with an increasing instability of the Y-chromosome.
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Conclusions
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From the present study it can be concluded that radiation induced genomic instability in the fetal haemopoietic progenitor cells is transmitted to the postnatal bone marrow and may remain latent until triggered by stimulating factors, for example, increased oxidative stress. At advanced ages, when there is a decrease in cellular defense and consequent increase in susceptibility to oxidative stress, the genomic instability may become manifest in the form of increased chromosomal aberrations. According to Selvanayagam et al [29], genomic instability is the earliest event in the multi-step sequence leading to radiation-induced cancer. Duesberg et al [30] believe that chromosome aneuploidy is the basic event leading to the development of cancer. Our results suggest that chromosome aneuploidy observed in the adult mice after fetal irradiation is the delayed cellular expression of the genomic instability induced in the fetal cells, and this could be an early step in the multi-step events leading to leukaemia development after prenatal irradiation.
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Acknowledgments
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This work was supported by a Senior Research Fellowship (MS) from the Council of Scientific and Industrial Research, Government of India. Thanks are also due to the Dean, Kasturba Medical College, Manipal, India, for kindly providing the research facilities.
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Footnotes
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Current address for Dr M Satyamitra, Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland MD 20892, USA. 
Received for publication September 13, 2004.
Revision received March 24, 2005.
Accepted for publication May 9, 2005.
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Abstract
Introduction
