British Journal of Radiology (2003) 76, 366-372
© 2003 British Institute of Radiology
doi: 10.1259/bjr/42623440
Radiosensitivity of the developing haemopoietic system in mammals and its adult consequences: animal studies
P Uma Devi, MSc, 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 haemopoietic system in the developing mammal is very sensitive to the damaging effects of ionizing radiation. Epidemiological studies have established a strong association between obstetric exposure to diagnostic radiation and an increase in the incidence of childhood leukaemia and between low dose gamma irradiation during the early fetal period and mental retardation in children. It has been suggested that insufficient oxygen supply to the developing brain due to radiation induced damage to fetal haemopoietic tissue has a role in inducing the severe mental retardation observed in the Japanese children exposed to atom bomb radiation in utero. Experimental studies have shown that X- and gamma irradiation of pregnant mice with <1 Gy during the late organogenesis or fetal period caused chromosome damage and significant depletion in the fetal haemopoietic progenitor cells and led to haematological disorders in the adults. The present paper reviews the experimental findings on the effect of pre-natal irradiation on the fetal haemopoietic system and its long-term consequences.
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Introduction
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The embryonic haemopoietic system in mammals becomes functional in the yolk sac during the organogenesis period [1, 2]. Parallel to the yolk sac, another region of haemopoietic activity exists in the aorta, gonad and mesonephros (AGM) regions of mouse embryo, which remains active from days 9.5 to 11 post-conception (p.c.) [3]. However, its exact role in the haemopoietic chain of development is not clear. Later the function shifts to the fetal liver, then to spleen and finally, to the bone marrow. In the mouse embryo, the shift from the yolk sac to the liver occurs around day 11 p.c., which remains the major haemopoietic organ up to day 16 p.c. [2, 4]. The haemopoietic activity, especially erythropoiesis, in the fetal liver increases many-fold from day 12 to day 16 of gestation [5]. On day 14.5 p.c. of mouse development, liver contains more than 60% of the haemopoietically active cells [6, 7]. In humans, haemopoietic activity starts by 6 weeks of gestation in the liver [8] and continues until the first week post-partum. By day 15 p.c., the spleen also acquires haemopoietic activity and becomes the major site of haemopoiesis in the growing fetus. An in vivo spleen colony assay, developed by Till and McCulloch [9], is commonly used to evaluate the haemopoietic activity in the different organs. In this method, cells from the desired organ are injected into the tail vein of adult mice, after destroying the latter's bone marrow by an acute lethal whole body irradiation. The haemopoietic stem cells from the donor will settle in the spleen of the recipient and proliferate to form visible nodules (spleen colonies) in 1–2 weeks. The recipient's spleen is then dissected out and the colonies counted, which gives a measure of the progenitor cells (colony forming units, CFU-S). Colonies formed by the partially differentiated committed stem cells like the granulocyte-macrophage (GM) and erythroid (E) series will appear earlier (6–8 days after transfusion), than those formed of the more primitive pluripotent stem cells (10–12 days after transfusion). The total cellularity in spleen was found to increase 9 times from day 18 to day 20 p.c., while the progenitor cells (colony forming units) showed a more than 12-fold increase during this period in the Swiss albino mice [10].
Bone marrow starts functioning as a haemopoeitic organ towards the end of fetal period in mouse [2]. All the three sites, i.e. the liver, spleen and bone marrow, contribute to the late fetal haemopoiesis. The progenitor cells migrate from the blood islands of the yolk sac to the fetal liver and from there to the spleen and bone marrow (Figure 1
). Post-natally, the bone marrow becomes the main haemopoietic organ and continues so throughout life. Spleen still retains part of the function in the adult mice, along with thymus and other lymphoid tissues. However, in humans, the spleen ceases to be haemopoietic at birth [11]. Liver loses its haemopoietic function by the time of birth or within a short time thereafter, but there is some evidence to show that the adult liver can be stimulated to lymphopoiesis under certain conditions, like radiation damage, in lower vertebrates [12].
The fetal period in mammals is a phase of active growth and evolution of all the organ systems. Two important systems, which evolve fully during this time, are the central nervous system and the haemopoietic system. In the central nervous system, the cortical development is the main event, when the cerebellum and the cerebral cortex acquire the adult architecture. During this period, the haemopoietic system also evolves, from the yolk sac in the early embryo to the adult organ, the bone marrow. There seems to be a close relation between these two systems and their radiation response to pre-natal irradiation. The two major effects recorded in the humans exposed during the early fetal period of gestation, i.e. severe mental retardation and leukaemia in children, concern these organs. The former has been extensively studied in animals as well as humans, especially in the Japanese children exposed to atom bomb radiation in utero [13–15], but the effect on the fetal haemopoietic system and its relationship to adult haematology has not received much attention. Epidemiological data on children from the Oxford Survey of Childhood Cancer (OSCC) in the UK [16–19], supplemented by studies in the USA [20–22], have demonstrated an increase in the incidence of leukaemia in the children who had been exposed to maternal irradiation during pre-natal development. But no such increase was found in the Japanese children exposed in utero to the atom bomb radiation [23]. One main reason could be that mental retardation is not fatal and therefore, it was possible to examine the affected children who grew up and went to school, while leukaemia would have resulted in the death of the children. Therefore, many of the childhood leukaemia cases may not have been detected under the conditions prevailing in Japan during the early post-war years. Mole [24] has suggested a role of radiation induced hypoxia (due to deficient blood supply during brain development) in the severe mental retardation of the Japanese children, who were exposed to atom bomb radiation in utero. However, there is no clear evidence to correlate the damage to fetal haemopoietic tissues and the haematological/neurological effects in the adults.
The mammalian haemopoietic system, in general, is very sensitive to radiation injury and pre-natal haemopoietic organs are especially so. Indirect evidence of damage to the developing haemopoietic cells due to irradiation of pregnant mothers comes from the study of the adult mammals that had been exposed during the pre-natal life. Haematological deficiency and disorders in the form of reduced blood cell counts, anaemia and reduced immunity have been reported in experimental animals after pre-natal exposure to X- and gamma rays [14, 25–30] and to internal emitters like tritium and plutonium-239 (239Pu) [31–33].
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Early effects on the fetal haemopoietic system
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Transient alterations in the counts of fetal primary blood elements have been reported following exposure of mouse fetuses to 50 R or 100 R of X-rays on day 15 p.c. [25]. Weinberg and co-workers observed a decrease in fetal haemopoietic function after gamma irradiation during the late organogenesis in the mouse [26, 28, 29]. From a study of the fetal haemopoiesis in HA/ICR mice exposed to 0.5–3 Gy of gamma radiation on day 10.5 p.c., Weinberg et al [26] concluded that fetal liver granulopoiesis is more sensitive to radiation injury than erythropoiesis and fetal liver has a greater potential for erythropoietic recovery. They also found that exposure of B6D2F1 mice to 2–3 Gy of gamma radiation on day 10.5 p.c. significantly reduced the fetal liver cellularity and haemopoietic progenitor cell concentrations on day 14.5 p.c. [28]. Pareek et al [34] reported a high sensitivity of 14.25-day fetal liver to radiation induced nuclear pyknosis and cell necrosis, even though they did not associate it with haemopoietic cell death.
Weinberg et al [27] examined the changes in haemopoietic functions of beagle dogs exposed to 0.9 Gy of cobalt-60 gamma radiation at mid-gestation, 33 days p.c. They observed a decrease in the nucleated cell counts in the peripheral blood between 44 days and 49 days, changes in the size and haemopoietic activity of the spleen, and an overall decrease in the haemopoietic functions of the fetal liver. Nold et al [30] reported that pre-natal irradiation of beagle dogs on day 35 p.c. with 1.5 Gy of gamma radiation produced progressively significant reduction in the CFU-GM (granulocyte/macrophage progenitor cells), accompanied by decreases in peripheral blood leukocytes up to 24 weeks of age. McFee et al [35] observed that chronic whole body irradiation of pregnant sows for 108 days of their gestation period, at 7 R/day, resulted in a moderate lymphocytopenia at birth, which rapidly disappeared. When rat fetuses were exposed to external gamma radiation at doses of 4 Gy and above on day 14 of gestation and examined on day 16 of gestation, the erythrocyte counts in liver was significantly reduced. However, the ratio of the large haematocyte count to the small haematocyte count significantly increased at doses of 
1 Gy, suggesting that gamma radiation doses of more than 1 Gy impaired normal migration of the stem cells from the yolk sac to the liver [36]. Joshima [37] observed that exposure of mice on day 15 p.c. with 1.89 Gy of gamma radiation depressed the fetal liver erythropoiesis. The studies of Yang et al [32] and Escribano et al [38] suggested that damage to the developing haemopoietic microenvironment (stroma) rather than the haemopoietic progenitor cells results in the cell death observed after fetal irradiation. It is difficult to compare these published data and draw a valid conclusion, as the investigators have used different gestation days, animal models/strains and exposure doses for their studies.
Recently, we investigated the effect of fetal irradiation with a range of gamma radiation doses from 0.1 Gy to 1.5 Gy on the fetal haemopoietic system and tried to trace the damage to the adult haematology and haemopoietic cells in the Swiss albino mice. The irradiation was given as a single dose, at a dose rate of 1 Gy min-1, to the abdominal area of the pregnant mice on day 14 or day 17 p.c., which will involve all the abdominal organs, including the entire uterus. Therefore, this can be taken as an acute whole body exposure of the fetuses.
Early effects of maternal irradiation were studied in the fetal liver (both gestation days) and spleen (17 day p.c.). Changes in the weight of fetal liver and spleen, total cellularity and progenitor cell survival (spleen colony forming units, CFU-S), were determined at 24 h and 72 h after irradiation and cytogenetic damage was studied by analysis of chromosomal aberrations and micronuclei at 24 h after exposure [10, 39].
At the early fetal stage, day 14 p.c., liver is the only major haemopoietic organ. The wet weight of the fetal liver showed a significant reduction at both 24 h (15 day p.c.) and 72 h (17 day p.c.) after exposure to doses from 0.25 Gy to 1.5 Gy. However, the liver weight/body weight ratio was not significantly affected, which suggests that low liver weight may be related to the general growth retarding effect of irradiation. The total cellularity of the fetal liver and the CFU-S12 (spleen colonies on day 12 after transfusion of progenitor cells, represent the primitive pluripotent stem cells) showed a dose-dependent decrease from control at both 24 h and 72 h after irradiation, significant at all doses from 0.25 Gy to 1.5 Gy. A similar dose-dependent decrease was observed in the CFU-S8 (spleen colonies on day 8 after transfusion of progenitor cells, represent the more mature committed stem cells) from fetal liver cells obtained at 72 h after exposure. When the fetal liver cells were taken at 24 h after irradiation, the CFU-S8 fell significantly below control only at the higher doses of 1.0 and 1.5 Gy. The cell survival data showed a linear-quadratic decrease with radiation dose, with the CFU-S8 values bending more sharply above 1 Gy [39].
On day 17 p.c., both spleen and liver function as haemopoietic organs in the fetus, the role of spleen increasing in significance as the fetal age increases. Bone marrow also starts the haemopoietic function around this time, although not fully evolved. Consequently, the liver becomes less important in haemopoiesis as the fetus advances in age. The spleen is growing very fast during the late fetal period and this is indicated in the weight gain of this organ. The spleen weight in the fetuses of Swiss albino mice increased by about 3 times, and cellularity by about 9 times, from day 18 to day 20 p.c., whereas the increase in liver weight and cellularity during the same period was only about 1.1–1.2 times in the control fetuses [10].
The 17 day fetuses showed a decrease in the radiosensitivity of liver haemopoietic cells, which were not significantly affected by gamma doses below 0.5 Gy. However, there was a significant reduction in the liver cellularity as well as in the CFU-S (both primitive and committed stem cells) at both 24 h as well as 72 h after exposure to 0.5 Gy to 1.5 Gy. In the case of spleen, a significant reduction in cellularity as well as progenitor cell survival was observed even after exposure to 0.25 Gy. The effect on cell survival was more pronounced for the CFU-S12 than for the CFU-S8 at doses below 1 Gy. The higher radiosensitivity of spleen cells of the late fetus compared with those of the liver indicates the increasing involvement of the former in the haemopoietic function of the fetus nearing term. The effect on the clonogenic cell survival in fetal spleen was more pronounced when the cell harvesting was delayed to 72 h after irradiation [10].
The higher survival of CFU-S8 than CFU-S12 at 24 h post-irradiation at doses below 1 Gy indicates that the committed stem cells are more resistant than the more primitive progenitor cells to radiation lethality. The higher reduction in the CFU-S8 from liver at 72 h after exposure, however, suggests that the effect increased with time after exposure. This additional effect may result from an indirect effect owing to damage to the microenvironment, which, in turn, will result in cell death and depletion of the stem cell pool. Damage to the stromal cells has been implicated in the depletion of post-natal haemopoietic progenitor cells by pre-natal irradiation with internal emitters [32, 40] gamma radiation [33] and X-rays [38]. Lord et al [40], using the internal emitter 239Pu, have shown that the actinide preferentially affected the haemopoietic microenvironment at the fetal stage of development. Yang et al [33], based on their study of post-natal bone marrow stem cell survival after pre-natal irradiation, concluded that irradiation at mid term gestation damages the developing regulatory microenvironment, but not the haemopoietic stem cell population. This may limit the rate of growth of CFU-S, stimulating a compensatory response [41]. Escribano et al [38] have demonstrated enhanced levels of CFU-S and committed progenitors, indicating hyperproliferative response after irradiation at 13 day p.c., but not at 4 day p.c. Such an effect on the fetal haemopoietic cells may also contribute to the higher CFU-S8 (committed) observed at 24 h after exposure on day 14 p.c. in the author's study [39]. However, this does not seem to be the main cause of the decrease in the haemopoietic stem cell survival, as was suggested by Escribano et al [38].
The chromosome damage at 24 h after irradiation was obvious even at the low dose of 0.1 Gy on day 17 p.c. The yield of aberrant cells and micronucleated cells fitted a linear-quadratic dose–response model, with the increase becoming very highly significant at doses above 0.25 Gy [39]. The chromosome damage showed a significant increase from control (both aberrant metaphases and cells with micronuclei) even after a dose of 0.1 Gy, spleen showing a more pronounced increase from control compared with liver. While the percentage of aberrant metaphases in liver increased linearly with radiation dose, that in the spleen showed a linear quadratic dose response. However, cells with micronuclei in both the organs showed a good linear dose response [10]. The radiation-induced micronuclei are formed mainly from acentric fragments [42]. The fragments in the fetal haemopoietic cells increased with radiation dose, as was observed for the micronuclei [10, 39]. The chromosomal damage at doses below 0.25 Gy, however, does not seem to cause cell death, as the stem cell survival was not significantly affected at these doses.
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Late effects of fetal irradiation
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During the development of the haemopoietic organs in the fetus, the progenitor cells migrate from the liver to the spleen and to the fetal and post-natal bone marrow. Therefore, the damage sustained at the fetal stage can be carried forward and expressed in the adult in the form of haematological deficiencies and disorders like leukaemia. Haematological deficiency in adult rodents following pre-natal radiation exposure [26, 28, 30, and others mentioned earlier], and leukaemia in children exposed to maternal diagnostic X-rays during pregnancy [16, 17, 21] have been reported. A direct link between the radiation induced damage in the fetal haemopoietic cells and the adult haematological/haemopoietic disorders has not been established. Our studies have demonstrated that mice that received a single dose of gamma radiation during the early (day 14 p.c.) or late (day 17 p.c.) fetal period had lower than normal post-natal blood counts. This deficit continued throughout the adult life, without recovery, in the animals exposed to doses of 0.5–1.5 Gy. The total white blood cell counts in the peripheral blood were 15–20% lower and the peripheral lymphocyte counts were lower by 14% to 22% from control at 12 months of age in mice exposed at the fetal period [43]. Grande and Bueren [4] also found that days 13 and 17 of mouse gestation are sensitive to induction of adult haematological deficiency by radiation. They reported that a single dose of 0.5 Gy of X-rays on day 13 p.c. produced long-term deterministic effects in the mouse haemopoietic system. The bone marrow from the pre-natally exposed 12 month old mice showed a higher incidence of chromosomal aberrations and a dose dependent increase in the frequency of aberrant metaphases. The effect was detected in all groups of adult mice that had received irradiation, irrespective of whether the radiation was given at the early (14 day p.c.) or late (17 day p.c.) fetal stage [44]. This indicates that the changes induced by irradiation in the fetal haemopoietic cells can lead to long-lasting chromosomal abnormalities in the haemopoietic stem cells and haematological effects in the adult animals. However, it is of no great consequence whether the liver, the spleen or the bone marrow is the haemopoietic organ at the time of exposure. It is to be ascertained whether it is the persistent chromosomal lesions which are expressed at a later age or the radiation induced increase in the susceptibility of the chromosomes to later insults which lead to the development of these aberrations in response to some environmental or senility factors.
Fetal irradiation has also been found to result in malignant changes in the adult mice. Solid tumours, especially of the ovary, were found to increase after a dose of 0.25 Gy [45]. Some animals which had received a single dose of 0.5 Gy to 1.5 Gy on day 14 or 17 of gestation, with or without solid tumours, showed abnormally high peripheral leukocyte counts along with splenomegaly (author's unpublished observation). The bone marrow from these animals showed a higher frequency of aberrant metaphases, with a very high incidence of polyploid cells (2–8 times the normal chromosome number). The increase in the percentage of aberrant metaphases in the bone marrow at 12 months of age in these animals was significant compared with the similarly irradiated apparently healthy counterparts [44].
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Induction of genomic instability by fetal irradiation and its possible role in leukaemogenesis
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There are strong indications that some of the early molecular/cellular changes occurred at the fetal stage, at least in the case of childhood acute leukaemia [46, 47]. Edwards [48] suggested that in utero irradiation of the early fetus might induce genomic instability, leading to aberrations in the haemopoietic cells, which migrate to the bone marrow. Persistent genomic instability is indicated to significantly influence the development of leukaemia in the atom bomb exposed persons [49]. Leukaemia induction in children after a single diagnostic X-ray exposure at the pre-natal stage [16, 17] implies that the radiation induced genomic instability in the fetal haemopoietic progenitor cells is transmitted to the post-natal bone marrow by migration of the affected cells, and persist in the adults. This genomic instability can be expressed in the form of chromosomal aberrations in the adult bone marrow, as demonstrated by Uma Devi and Hossain [44]. Marder and Morgan [50] have shown that genomic instability increases with the number of cell divisions after radiation exposure. In vitro studies on the haemopoietic stem cells of the CBA/H mice have demonstrated that after X-irradiation the descendants of irradiated cells frequently developed unstable aberrations. This chromosomal instability is transmitted over several cell divisions, leading to overt aberrations [51]. Rosemann et al [52] found that, following X-irradiation or injection of the pregnant mice with 239Pu, the haemopoietic cells from the fetal liver showed a significant increase in unstable chromosomal aberrations. The aberration frequency increased with the increase in time between X-irradiation and cell sampling. They also noticed a higher than control incidence of chromatid breaks in the 22 day and 55 day old offspring that had received 239Pu at the fetal stage. When irradiated bone marrow was transplanted into a recipient, de novo appearing unstable aberrations have been detected up to 1 year post-irradiation [53]. This is supported by the findings of Uma Devi and Hossain [44] who observed that chromatid breaks and fragments increased at 1 year of age in the bone marrow cells of mice exposed to gamma radiation at the fetal stage. There was also a noticeable increase in polyploid cells in the bone marrow, which was more pronounced in the animals with abnormal leukocyte counts. Our attempt to trace the chromosomal abnormalities from fetus to the adult stage has shown that the cells with explicit aberrations are eliminated during the early post-natal stage [54]. This indicates that the aberrations as such are not carried forward. The increase in the aberrations at 12 months of age [44], but not at juvenile or young adult stages [54], suggests that pre-natal irradiation makes the chromosomes more sensitive to degenerative changes associated with the normal ageing process, leading to accelerated and increased manifestation of such changes. The high increase in the incidence of polyploid cells in the bone marrow of mice with abnormal leukocyte counts points to a possible association between development of polyploidy in the haemopoietic cells and induction of haematological disorders like leukaemia, although studies so far have not shown any leukaemogenic effect of pre-natal irradiation in mice. The increase in the incidence of solid tumours in the adult mice [45, 55] suggests that induction of chromosomal instability by fetal irradiation may not be limited to the haemopoietic cells, but can also affect other organs that are undergoing active proliferation and differentiation at the time of exposure. Pampfer and Streffer [56] have reported an increase in the frequency of chromosomal aberrations in the fetal skin fibroblasts from mice irradiated at the zygote stage. Abramsson-Zetterberg et al [57] did not find any delayed effects in terms of an increase in micronucleated erythrocytes of post-natal mice after exposure to gamma radiation on day 16 of gestation. They concluded that gamma irradiation of mice during pre-natal stage did not induce damage in erythroid stem cells that can be detected as persistent or delayed chromosome aberrations. Kozlowski et al [58] also reported that unstable aberrations, represented by chromatid breaks, did not show any increase at 2–8 weeks after birth in mice exposed to 0.5 Gy of X-rays on day 7 or 14 p.c. These results in no way contradict the author's findings, which also did not show any increase in the aberrations at 1 or 3 months of post-natal life [54], the effect being manifest at a much later age, i.e. 12 months post-partum [44].
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Possible effect on brain development
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Mole [24] suggested that radiation damage to fetal erythropoietic tissue and the resulting impairment of oxygen transport to the developing brain may have an important role in inducing the severe mental retardation observed in the Japanese children exposed in utero to the atom bomb radiation. Exposure of mice at the late fetal stage (day 17 p.c.), to 0.3–1.5 Gy of gamma radiation, produced significant impairment in the locomotor activity, dark-bright arena performance, and deficits in the shock avoidance and maze learning ability at 6 months of age [59]. A similar effect on the locomotor performance [60, 61], as well as learning and memory [62], was observed in the adult mice that had received gamma radiation below 1 Gy at the early fetal day 14 p.c., with permanent alterations in the normal activity at doses of 0.5 Gy to 1.5 Gy. Day 14 p.c. in mouse is a period of very high erythropoietic activity in the fetal liver [63]; on day 17 both spleen and bone marrow are active as haemopoietic organs. Migration of progenitor cells from fetal liver to spleen and bone marrow, and between spleen and bone marrow are occurring during this period [2]. Radiation has been shown to impair the normal migration of embryonic haemopoietic stem cells in rat [36]. Day 13 to 17 p.c. in mouse is also a period when developmental activity is at a peak in the fetal brain, characterized by intense cell proliferation, differentiation and migration [64]. Irradiation at this stage, therefore, will have a direct effect in causing cell death in the neuronal population and thereby, impairing the normal developmental process of the fetal brain. Damage to the blood forming cells can further enhance this effect of irradiation by reducing the blood supply and consequently, curtailing the availability of oxygen and nutrients to the developing brain. Exposure of rats to X-ray doses of 
1 Gy during the early fetal period has been shown to produce significant decrease in the thickness of the cerebral cortex and increase in neuronal cell death, as well as significant changes in the post-natal behaviour [65]. Hossain [66] has demonstrated that fetal exposure to gamma radiation below 1 Gy caused subnormal brain weight and significant reduction in the hippocampal neurons in the adult mice.
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Conclusions
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Thus, the experimental data on in utero exposure demonstrates the high sensitivity of the fetal haemopoietic system of mouse to radiation induced cell death and chromosomal damage. Radiation induced genotoxicity appears to have a very low or no threshold. However, at doses below 0.25 Gy the chromosomal aberrations do not seem to contribute significantly to stem cell death. The changes induced in the fetal haemopoietic cells can lead to long-term effects in the form of haemocytopenia, abnormal leukocyte counts and possibly, leukaemia in the adult. Radiation induced genomic instability in the fetal haemopoietic cells is transferred through cell migration to the post-natal bone marrow, which, in turn, can lead to chromosomal abnormalities in the adult bone marrow cells. Induction of significant long-term haematological effects by fetal irradiation appears to have a threshold between 0.25 Gy and 0.5 Gy. Development of polyploidy in the bone marrow seems to be associated with the induction of haematological disorders in the adult mice after fetal irradiation. It is also likely that the deficient oxygen supply to the developing brain, resulting from damage to the fetal haemopoietic system, can contribute to the detrimental effect of pre-natal irradiation on the normal brain growth and function, leading to behavioural deficits. These points need to be taken into account while estimating the risk from low dose radiation exposures during pre-natal development. However, the available data do not imply any cause for serious concern about permanent haemopoietic damage from acute fetal irradiation at doses below 0.2 Gy.
Received for publication July 23, 2002.
Revision received December 4, 2002.
Accepted for publication February 26, 2003.
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P Uma Devi and M Satyamitra
Tracing radiation induced genomic instability in vivo in the haemopoietic cells from fetus to adult mouse
Br. J. Radiol.,
October 1, 2005;
78(934):
928 - 933.
[Abstract]
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Abstract
Introduction
