[en] α-particles, which are ionising radiation of high linear-energy-transfer emitted, for example, from radon or plutonium, pass through tissue as highly structured tracks. Single target cells in the path of the tracks might be damaged by even low-dose α-irradiation. We found non-clonal cytogenetic aberrations, characterised by a high frequency of chromatid aberrations with chromosome aberrations, in clonal descendants of haemopoietic stem cells after exposure to α-particles of bone marrow cells from two of four haematologically normal individuals (up to 25% abnormal metaphases). The data are consistent with a transmissible genetic instability induced in a stem cell resulting in a diversity of aberrations in its clonal progeny many cell divisions later. (author)

[en] When investigating the biological effects of ionizing radiation on the haemopoietic system, a confounding problem lies in possible differences between the biological effects of sparsely ionizing, low linear energy transfer radiation such as X-, β- or γ-rays, and densely ionizing, high linear energy transfer radiation such as α-particles. To address this problem we have developed novel techniques for studying haemopoietic cells irradiated with environmentally relevant doses of α-particles from a plutonium-238 source. Using a clonogenic culture system, cytogenetic aberrations in individual colonies of haemopoietic cells derived from irradiated stem cells have been studied. Exposure to α-particles (but not X-rays) produced a high frequency of non-clonal aberrations in the clonal descendants, compatible with α-emitters inducing lesions in stem cells that result in the transmission of chromosomal instability to their progeny. Such unexpected instability may have important implications for radiation leukaemogenesis. (author)

[en] Full text: The contribution of genetic factors to the initiation of radiation-induced genomic instability remains poorly understood. Studies with high LET α-particles and very high doses of low LET radiation have described several common mouse strains that differ in their sensitivity to the induction of genomic instability and apoptosis. The aim here was to investigate whether low doses of low LET radiation would elucidate a similar genetic predisposition. To assess the influence of genetic factors on the initiation of genomic instability by low doses of low LET radiation, we irradiated stem cells from two mouse strains known to differ in susceptibility to radiation-induced delayed chromosomal instability. The frequency of delayed chromosomal aberrations was measured in bone marrow cells from CBA/H and C57BL/6 mice after exposure to 0.1 - 2 Gy of 250 kV X-rays. The yield of both chromosomal and chromatid-type aberrations were assessed 13-15 cell divisions post-irradiation in the clonal descendents of surviving stem cells. The apoptotic index of these surviving clones was scored as morphological changes by electron microscopy. At low doses, the frequency of cells with aberrations increased significantly in both strains, contrary to the strain differences observed with high LET α-particles in earlier studies (Watson et al. 1997). The percentage of apoptotic cells was similar between the strains at low doses, with both showing comparable levels of cells with aberrations and apoptotic cells. However, at higher doses, strain differences became evident: CBA/H cells had a substantially higher fraction of cells with aberrations to apoptotic cells, while the converse was true for C57/Bl/6. This data indicates that low doses may be insufficient to initiate the apoptotic pathway, while still resulting in significant induction of delayed chromosomal instability. Overall, these observations have important implications for low dose low LET radiation risk assessment and human health

[en] The target theory of radiation-induced effects has been challenged by numerous studies, which indicate that in addition to biological effects resulting from direct DNA damage within the cell, a variety of non-DNA targeted effects (NTE) may make important contributions to the overall outcome. Ionising radiation induces complex, global cellular responses, such as genomic instability (GI) in both irradiated and never-irradiated 'bystander' cells that receive molecular signals produced by irradiated cells. GI is a well-known feature of many cancers, increasing the probability of cells to acquire the 'hallmarks of cancer' during the development of tumours. Although epidemiological data include contributions of both direct and NTE, they lack (i) statistical power at low dose where differences in dose response for NTE and direct effects are likely to be more important and (ii) heterogeneity of non-targeted responses due to genetic variability between individuals. In this article, NTE focussing on GI and bystander effects were critically examined, the specific principles of NTE were discussed and the potential influence on human health risk assessment from low-dose radiation was considered. (authors)

[en] Complete text of publication follows. Genomic instability has been demonstrated in the progeny of irradiated cells and unirradiated bystander cells. Bystander responses are thought to depend on the activation of cellular communication processes. In this study we examine one such mediator of cellular communication, the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) TNF-α is known to increase in expression following ionizing radiation (IR) exposure. Upon binding to its cellular receptors, TNF-α initiates a signaling cascade mediated by reactive oxygen species (ROS) that can activate sequestered NF-κB, thus initiating a pro-inflammatory and antiapoptotic pathway. NF-κB can in turn upregulate TNF-α expression, which when secreted can induce subsequent autocrine and paracrine stimulation of TNF-α and NF-κB. We speculate that this increase in TNF-α signaling and concomitant ROS generation has a mechanistic role in the initiation of genomic instability and a potential involvement in producing bystander responses. Genomic instability is induced by IR in a non-dose-dependent manner. Previous investigation by our group using primary human vascular endothelial cells has shown that both low (0.1 Gy) and high (2 Gy) doses of IR raise levels of secreted TNF-α in a non-linear manner, that both immediate genetic damage and delayed chromosomal instability can be induced at similar levels following treatment with either 0.1-10 ng/mL TNF-α or 0.1 or 2 Gy IR, and that this immediate damage was abrogated by pre-incubation with antioxidants. The current study is therefore focused on the mechanism responsible for this TNF-α-induced instability, and whether TNF-α is a signaling mediator of bystander-induced responses. TNF-α suppressors are added to either directly irradiated or bystander cell cultures exposed to low or high doses of low-LET radiation, and the results are compared to cells pre-treated with antioxidants. Cellular damage is assessed by cell survival, the comet assay, formation of damage-induced foci, and presence of delayed chromosomal instability. Preliminary results indicate that: 1) suppressing TNF-a prevents immediate genetic damage in directly irradiated cells, similar to antioxidant treatment, 2) antioxidants but not TNF-a suppression can abrogate delayed chromosomal instability in directly irradiated cells, and 3) the suppression of either TNF-α or nitric oxide in bystander cells increases survival and protects against immediate genetic damage after exposure to medium from cells irradiated with 2 Gy.