Introduction

When ionizing radiation passes through biological tissue, it forms highly structured tracks as a consequence of the deposition of energy. Generally, a distinction can be made between sparsely and densely ionizing radiation on the basis of the average energy transferred per unit length of track (linear energy transfer, LET; Figure 1, courtesy of D Goodhead). A particular feature of tissue irradiation by low energy, high LET radiation, such as -particles, is that the entire insult is concentrated into a relatively small number of separate densely ionizing tracks of very limited range. At low doses, any individual cell in a tissue is likely to receive no dose, or if it happens to be in the path of a track, to receive a substantial dose (0.5 Gy) (Lorimore et al., 1993). For -particle emitters, therefore, the problem of whether low doses might produce biologically important effects reduces essentially to assessing the effectiveness of a single track, or a very small number of tracks, in producing appropriate damage in the relevant target cell. Alternatively, for low LET ionizing radiation, such as -rays or X-rays, the energy deposited is sparse and uniform, with every cell receiving a similar dose. Therefore, very low doses of low LET radiation still result in every cell receiving some irradiation, albeit of a reduced dose (Figure 1).

Figure 1.

Schematic representation of a cell nucleus irradiated with two electron tracks from -rays (low LET) or two -particle tracks (high LET) (courtesy of Professor Dudley Goodhead, MRC Harwell, UK; originally published in Goodhead (1988))

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Genomic instability describes a complex phenotype marked by an elevation in the rate of genetic change, and is observed during carcinogenic progression and in tumour cells. Genomic instability may also be induced in a fraction of clones surviving radiation exposure (reviewed in Morgan et al., 1996; Little, 2000; Morgan, 2003); some of the first descriptions of the manifestations of radiation-induced genomic instability were delayed, nonclonal chromosomal aberrations (Pampfer and Streffer, 1989; Kadhim et al., 1992; Sabatier et al., 1992; Holmberg et al., 1993; Marder and Morgan, 1993; Grosovsky et al., 1996), increased mutation rates (Chang and Little, 1992; Harper et al., 1997), delayed reproductive cell death (Gorgojo and Little, 1989), and lethal mutations (Seymour et al., 1986). These continue to be the most extensively studied end points of radiation-induced genomic instability (Morgan, 2003). Several factors may influence the expression of the instability phenotype, such as radiation quality and genotype (Limoli et al., 2000). The relationship between genetic predisposition and genomic instability has not been clearly defined and is an active area of investigation, especially in the light of recent advances in genomics and proteomics. Recent in vitro and in vivo evidence supports the contribution of genetics in predisposing to radiation-induced genomic instability.

Several human genetic disorders have been identified where genetic alterations are associated with the complex instability phenotype: Li–Fraumemi syndrome, Fanconi anemia, Nijmegen breakage syndrome, Ataxia telangiectasia, Cockayne's syndrome, and xeroderma pigmentosum (Vessey et al., 1999). Also, there have been several mouse studies suggesting a causal relationship between susceptibility to radiation-induced genomic instability and susceptibility to specific radiation-induced malignancies, such as acute myelogenous leukaemia (Major and Mole, 1978; Major, 1979; Bouffler et al., 1996; Di Majo et al., 1996; Ban et al., 2002), and mammary tumours (Ullrich et al., 1996; Ponnaiya et al., 1997). Through a series of murine backcrosses with CBA/H and C57BL/6 strains, Boulton et al. (2001) were able to demonstrate that sensitivity or resistance to radiation-induced chromosomal instability had a polygenic, heritable component (Boulton et al., 2001), supporting previous results demonstrating an association between loss of heterozygosity at a particular mouse chromosome and susceptibility to leukaemias (reviewed in Plumb et al., 1998). Genetic susceptibility might even arise from natural allelic variation, as has been demonstrated in the case of mouse mammary carcinogenesis (Yu et al., 2001). Recent studies have also described epigenetic mechanisms that might be responsible for the genomic instability phenotype (reviewed in Baverstock et al., 2003, unpublished data, Smith et al., 1998, 2001); however, these relationships are very complex and will be discussed in detail elsewhere in the current issue (Grosovsky, submitted).

This review will focus on the influence that genetic variation may play in individual susceptibility to radiation-induced instability. For example, ataxia telangiectasia was originally identified in radiosensitive individuals (reviewed in Lavin and Shiloh, 1999), and recent murine studies demonstrate a predisposition to radiation-induced mammary carcinogenesis in ATM heterozygous mice (Weil et al., 2001), strengthening the link between genetic predisposition and radiation-induced genomic instability. Recent studies also suggest that various cancers are associated with predisposition for radiation-induced chromosomal instability (Papworth et al., 2001; Baria et al., 2002). Perhaps the strongest relationship between genetic predisposition and radiation response in human populations is the heterogeneous responses observed in occupationally and accidentally exposed populations (CBEIR, 1990; Chang et al., 1997; Salomaa et al., 1998; Lindholm et al., 1999; An and Kim, 2002; Salomaa et al., 2002; reviewed in Sankaranarayanan, 2001; Sankaranarayanan and Chakraborty, 2001), and in patients who are refractory to medical exposures to ionizing radiation (reviewed in Gudkov and Komarova, 2003).

Many of the mechanistic studies that have led to the characterization of the impact of altered genetic make-up on genetic stability have been investigated using mammalian cell lines. An extensive characterization of the positive correlation between reduced levels of normal TP53 and several instability end points has been demonstrated in human cell lines (Honma et al., 1997, 2000; Schwartz et al., 2001; Leger and Drobetsky, 2002). Further work using unstable clones from the human chromosome 4 hamster-hybrid system (GM10115) has shown that the radiosensitive phenotype was related to the efficiency of DNA repair (Limoli et al., 2001), supporting earlier results in GADD45 -/- mice. However, such studies are not always completely straightforward, even when concerning a single gene product, likely due to complex interactions (reviewed in Dent et al., 2003), and the choice of end points examined. Indeed, studies examining TP53 function and instability in human lymphoblastoid cells (Kadhim et al., 1996) and in immortalized murine haemopoietic stem cells (McIlrath et al., 2003) reported that expression of instability was independent of TP53 status (Kadhim et al., 1996; McIlrath et al., 2003). The complexity concerning the impact of genetic variation on instability has been further illuminated by microarray analyses of gene expression after ionizing radiation. Early studies in a myeloid tumour cell line demonstrated that very low doses of low LET ionizing radiation (0.02–0.5 Gy) are capable of initiating a demonstrable increase in the mRNA expression levels of damage response genes, such as GADD45 and CDKN1A (Amundson et al., 1999). Recently, a link has been reported between altered gene expression and low LET ionizing radiation exposure (0.5–4 Gy) in human peripheral blood lymphocytes from five donors (Kang et al., 2003), with four candidate genes being differentially expressed postirradiation (TRAIL receptor 2, FHL2, cyclin G, and cyclin protein gene). In this study, modest interindividual variation was observed in unirradiated and irradiated cells. These studies suggest that, in addition to interindividual variation, the contribution of genetics to radiation response may also vary between experimental systems.

Human studies with primary cells

Previous work with human bone marrow samples from haematologically normal individuals demonstrated interindividual variation in the expression of a radiation-induced instability phenotype, and suggested that genetic predisposition may play a role in differential susceptibility within the human population (Figure 2; Kadhim et al., 1994, 1995). Differences in genetic susceptibility to radiation-induced instability have also been observed in primary human fibroblasts (Kadhim et al., 1998). The interpretation of these results (Kadhim et al., 1994, 1995, 1998) was that the radiation-induced instability phenotype may be influenced by genetic factors. This interpretation was supported by a subsequent study of cells from three inbred mouse strains and their F₁ progeny (Figure 2; Watson et al., 1997). The human data from Figure 2 are consistent with there being several tiers of sensitivity to the induction of radiation-induced instability: highly sensitive, moderately sensitive, and slightly or nonsensitive. In the above studies, radiation-induced instability was assessed using delayed chromosomal aberrations. Recently, Mothersill et al. (1999) reported similar results in human urothelial cells when examining apoptosis and colony formation, and the authors proposed a similar sensitivity schema. These results indicate that radiation-induced genomic instability may have a genetic component, which may manifest irrespective of the end point studied. In summary, the interindividual variation that has been observed in radiation response in human populations supports a role for genetics in predisposing to radiation-induced instability.

Figure 2.

Differential induction of genomic instability following -particle irradiation. The unstable fraction (y-axis) describes the fraction of all cells examined that have chromosomal aberrations, and is corrected for background control values. Independent individual human primary bone marrow samples are labelled 'Human marrow 1–5'. Bone marrow was collected from healthy donors, irradiated with 0.5 Gy -particles, and nonclonal cytogenetic abnormalities were determined (as in Kadhim et al., 1994). Murine strain variation is shown as 'Mouse marrow', with strain shown parenthetically underneath. F₁ hybrids (Watson et al., 1997) are labelled 'F₁ marrow', with both parents involved in the cross shown parenthetically underneath, although strains are abbreviated for space. Femoral bone marrow was isolated from CBA/H, C57BL/6, and DBA/2 strains. CFU-A-derived colonies from cells surviving 0.5 Gy -particle irradiation were analysed for chromosomal instability (as in Kadhim et al., 1999)

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Mouse studies

Inbred mouse strains have frequently been used to assess the contribution of genetic background to radiation-induced instability. In a recent study using -particle irradiation, quantitative differences in the induction of chromosomal instability were observed in clonal descendants of haemopoietic stem cells obtained from three inbred mouse strains (Figure 2; Watson et al., 1997). The fractions of aberrant cells in the bone marrow colonies derived from the CBA/H and the DBA/2 inbred strains were significantly elevated compared with controls, and were not significantly different from each other, whereas the fraction of aberrant cells in the C57BL/6 colonies was not significantly elevated above controls. These data demonstrate genetically determined differences in susceptibility to the induction of chromosomal instability. It is important to note here that variability with respect to the induction of radiation-induced chromosomal instability has also been observed in stem cells derived from mice from the same inbred strains (Table 4 in Watson et al., 2001), suggesting that very subtle genetic differences, even in populations of mice that have lived in identical environments, might also affect susceptibility to radiation-induced genomic instability. To investigate further the proposed genetic contribution to chromosomal instability, C57BL/6 mice were crossed with both CBA/H and DBA/2 mice. The frequencies of aberrant cells in the colonies derived from the (C57BL/6 CBA/H) F₁ and the (C57BL/6 DBA/2) F₁ strains after -particle irradiation were not significantly elevated compared with C57BL/6 controls (Figure 2; Watson et al., 1997). Both F₁ hybrids showed a significantly lower fraction of aberrant cells than those observed for the CBA/H or DBA/2 strains, while not differing significantly from the fraction of aberrant cells observed in colonies derived from irradiated C57BL/6 bone marrow. The fraction of unstable cells in F₁ hybrids resembles the parental C57BL/6 value, suggesting that the sensitivity to the induction of genomic instability might be inherited in a recessive manner (Figure 2; Watson et al., 1997), an interpretation supported by previous work (Boulton et al., 2001). Additionally, elevated superoxide generation was observed in the sensitive CBA/H strain versus the resistant C57BL/6 strain, which is substantiated by previous data demonstrating increased oxidative stress in irradiated bone marrow derived from CBA/H mice (Clutton et al., 1996). Inflammatory processes that generate such oxygen stress have been hypothesized to contribute to the expression of genomic instability in haemopoietic cells (reviewed in Lorimore and Wright, 2003).

In addition to high LET irradiations, genotype-dependent expression of chromosomal instability has also been demonstrated for high doses (3–50 Gy) of low LET irradiation. Mammary epithelial cells from BALB/c mice were more sensitive to the induction of genomic instability than mammary epithelial cells from the C57BL/6 strain (Ponnaiya et al., 1997). The authors attribute this difference in susceptibility to significantly reduced DNA-PKcs expression and activity in BALB/c (Okayasu et al., 2000). This work is supported by a recent in vivo examination of the differences in genetic susceptibility between BALB/c and C57BL/6 mice used as sentinels for chromosomal damage in the radioactive environment of Chernobyl (Rodgers et al., 2001). Although the authors report a transient increase in the frequency of induced micronuclei at 10 days for both strains, the levels only remained persistently elevated in the BALB/c strain, consistent with the delayed instability phenotype. In a recent study using a high dose (>2 Gy) of low LET irradiation, Mothersill et al. (1999) found that apoptosis was higher in a C57BL/6 background than in the CBA/H background (Mothersill et al., 1999), and were able to attribute this difference to reduced or elevated bcl2 expression in the C57BL/6 or CBA/H strain, respectively. When taken with the earlier results of Watson et al. (1997), where the CBA/H and C57BL/6 strains were susceptible or resistant, respectively, to the induction of high LET radiation-induced chromosomal instability, the results of Mothersill et al. (1999) suggest an inverse relationship between apoptosis and chromosomal instability in these strains following high LET or high doses of low LET radiation.

The above observations reinforce the supposition that genetic factors affect instability; however, all have been performed in systems using either high LET or high doses of low LET radiation. Ongoing investigations in our lab using low doses of low LET radiation suggest that a more complex relationship may exist under such conditions. Femoral bone marrow cells from CBA/H and C57BL/6 were irradiated in vitro with 0.1 and 1 Gy X-rays, and the levels of delayed chromosomal instability and apoptosis were determined. The percentage of cells with aberrations was elevated over controls with both doses from either strain (Figure 3), but the relationship between dose and percentage of cells with aberrations was inverse between the strains (Figure 3). A profound elevation in the percentage of cells with apoptosis was observed with increasing dose in the C57BL/6 strain; however, the response decreased with increasing dose in the CBA/H strain (Figure 3). These results are substantiated by two further studies of in vitro chromosomal instability at 0.1 and 3 Gy (Table 1), and in vivo apoptosis at 0.1 and 3 Gy (Table 2). When taken together, a trend becomes evident: while both strains demonstrate an inverse relationship between chromosomal instability and apoptosis at high doses (1 and 3 Gy), there is no such clear relationship at the lowest dose (0.1 Gy), and the levels of both chromosomal instability and apoptosis are very similar between the strains. These results indicate that in these strains, a genetic component, likely associated with cellular apoptotic response to ionizing radiation, is responsible for the differences observed between the strains at high LET and high doses of low LET. However, at low doses of low LET, the same genetic component may not be sufficiently active or activated.

Figure 3.

Delayed low LET-induced chromosomal aberrations and apoptosis in CBA and C57BL/6 mice. Femoral bone marrow was isolated from CBA/H and C57BL/6 strains. Bulk cultures containing cells surviving varying doses of 250 keV X-irradiation were analysed for chromosome damage (as in Kadhim et al., 1999) and apoptosis (as in Green et al., 2001). The first three data sets along the x-axis are CBA/H, the second three are C57BL/6. See text for detailed discussion

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Table 1 - Low doses of low LET irradiation induce chromosomal instability in CBA and C57BL/6.

Full table

Table 2 - Summary of the differences in genetic predisposition to radiation-induced apoptosis at high and low doses of low LET irradiation.

Full table

Conclusions

There is a large body of work using high LET and high doses of low LET irradiations, which provides evidence that genetic background may alter sensitivity to the induction of radiation-induced instability. These studies also support the mechanistic model of an inverse relationship between apoptosis and delayed chromosomal instability. This relationship may explain the current evidence that radiation-induced genomic instability is a nonthreshold dose response. Chromosomal instability is thought to be maintained at low levels due to the removal of heavily damaged cells via activation of apoptosis following high LET or high doses of low LET irradiation. However, at low doses of low LET radiation, the results presented here suggest that the relationship between genetic predisposition and radiation-induced instability is rather complex, especially with regard to the balance between apoptosis and chromosomal instability. This implies that under low dose, low LET conditions, more of the population may be at risk than previously recognized, which may have important implications for human health and radiation risk assessment.

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Acknowledgements

I am grateful to the following people: Stephen R Moore, Dudley T Goodhead, Edwin Goodwin, and Keith Baverstock for valuable contribution and comments; Denise Macdonald, Debbie Bowler, Gwyneth Watson (RAGSU, MRC, Harwell, UK) for assistance in experimental studies on radiation-induced chromosomal instability; Lora Green (Loma Linda University Medical Center, Loma Linda, CA, USA) for analysis of apoptosis; and David Papworth (RAGSU, MRC, Harwell, UK) for statistical analysis. This work was supported by the Medical Research Council (UK) and the National Aeronautics and Space Administration (NASA, USA).