Biomedical subjects

Eric G Wright

Publications and source records attributed to Eric G Wright.

12 recordsLinked to original sources

PubMed2006

Untargeted effects of ionizing radiation: implications for radiation pathology.

The dogma that genetic alterations are restricted to directly irradiated cells has been challenged by observations in which effects of ionizing radiation, characteristically associated with the consequences of energy deposition in the cell nucleus, arise in non-irradiated cells. These, so called, untargeted effects are demonstrated in cells that have received damaging signals produced by irradiated cells (radiation-induced bystander effects) or that are the descendants of irradiated cells (radiation-induced genomic instability). Radiation-induced genomic instability is characterized by a number of delayed adverse responses including chromosomal abnormalities, gene mutations and cell death. Similar effects, as well as responses that may be regarded as protective, have been attributed to bystander mechanisms. Whilst the majority of studies to date have used in vitro systems, some adverse non-targeted effects have been demonstrated in vivo. However, at least for haemopoietic tissues, radiation-induced genomic instability in vivo may not necessarily be a reflection of genomically unstable cells. Rather the damage may reflect responses to ongoing production of damaging signals; i.e. bystander responses, but not in the sense used to describe the rapidly induced effects resulting from direct interaction of irradiated and non-irradiated cells. The findings are consistent with a delayed and long-lived tissue reaction to radiation injury characteristic of an inflammatory response with the potential for persisting bystander-mediated damage. An important implication of the findings is that contrary to conventional radiobiological dogma and interpretation of epidemiologically-based risk estimates, ionizing radiation may contribute to malignancy and particularly childhood leukaemia by promoting initiated cells rather than being the initiating agent. Untargeted mechanisms may also contribute to other pathological consequences.

Animals↗

PubMed2005

Chromosomal instability in unirradiated hemopoietic cells resulting from a delayed in vivo bystander effect of gamma radiation.

Untargeted effects of ionizing radiation (de novo effects in the unirradiated descendants or neighbors of irradiated cells) challenge widely held views about the mechanisms of radiation-induced DNA damage with implications for the health consequences of radiation exposures particularly in the context of the induction of malignancy. To investigate in vivo untargeted effects of sparsely ionizing (low linear energy transfer) radiation, a congenic sex-mismatch bone marrow transplantation protocol has been used to repopulate the hemopoietic system from a mixture of gamma-irradiated and nonirradiated hemopoietic stem cells such that host-, irradiated donor- and unirradiated donor-derived cells can be distinguished. Chromosomal instability in the progeny of irradiated hemopoietic stem cells accompanied by a reduction in their contribution to the repopulated hemopoietic system is consistent with a delayed genomic instability phenotype being expressed in vivo. However, chromosomal instability was also shown in the progeny of the nonirradiated hemopoietic stem cells implicating a bystander mechanism. Studies of the influence of irradiated recipient stromal microenvironment and experiments replacing irradiated cells with irradiated cell-conditioned medium reveal the source of the in vivo bystander effect to be the descendants of irradiated cells, rather than irradiated cell themselves. Thus, it is possible that a radiation-induced genomic instability phenotype in vivo need not necessarily be a reflection of intrinsically unstable cells but the responses to ongoing production of inflammatory-type damaging signals as a long-term unexpected consequence of the initial single radiation exposure.

Animals↗

PubMed2005

Genotype-dependent induction of transmissible chromosomal instability by gamma-radiation and the benzene metabolite hydroquinone.

Although it is well established that ionizing radiation and benzene are epidemiologically linked to acute myeloid leukemia (AML), the underlying mechanisms are not understood. We have shown that gamma-radiation can induce a persisting genomic instability in the clonal descendants of hemopoietic stem cells manifested as a high frequency of nonclonal chromosome and chromatid aberrations. A strikingly similar instability is shown after exposure to the benzene metabolite hydroquinone. The CBA/Ca but not the C57BL/6 genotype is susceptible to the induction of instability by both ionizing radiation and hydroquinone and exposure of CBA/Ca, but not C57BL/6, mice to either agent is known to be associated with the development of AML. The results are consistent with the proposal that chromosomal instability induced by either agent may contribute to AML development by increasing the number of genetic lesions in hemopoietic cells. Genotype-dependent chromosomal instability can be induced by hydroquinone doses that are not acutely stem cell toxic and this may have important implications for current assessment of safe levels of exposure to benzene as well as for mechanistic understanding of the hemotoxic and leukemogenic effects.

Acute Disease↗

PubMed2005

Cell and tissue responses to genotoxic stress.

Cancers arise as a consequence of the accumulation of multiple genetic mutations in a susceptible cell, resulting in perturbation of regulatory networks that control proliferation, survival, and cellular function. Here, the sources of cellular stress that can cause oncogenic mutations and the responses of cells to DNA damage are reviewed. The role of different repair pathways and the potential for cell- and tissue-specific reliance on individual repair mechanisms are discussed. Evidence for cell- and tissue-specific activation of p53-mediated growth arrest and apoptosis after exposure to an individual genotoxin is assessed and some of the potential mediators of these different responses are provided. These cell- and tissue-specific responses to particular forms of DNA damage are likely to be key determinants of tissue-specific tumour susceptibility, and there is good evidence for genetic variations in these responses. The role that genotoxic agents play in altering the microenvironment to produce indirect effects on tumourigenesis through altered production of free radicals and cytokines that are characteristic of inflammatory-type processes is also evaluated. Changes to the microenvironment as direct or indirect effects of genotoxic stress can be involved in both tumour initiation and progression and may even be a prerequisite for tumourigenesis. Therefore, tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell-intrinsic responses of target cells and changes to the microenvironment. A fuller understanding of cell- and tissue-specific responses, alterations to the microenvironment, and genetic modifiers of these responses could lead to novel prevention and therapeutic strategies for common forms of human malignancy.

Animals↗

PubMed2005

A proteomic analysis of murine bone marrow and its response to ionizing radiation.

To characterize the mouse bone marrow tissue proteome and investigate the response to radiation damage we took bone marrow before and after 4-Gy gamma-irradiation from mouse strains (C57BL/6 and CBA/Ca) that differ in their short-term and long-term radiation responses and analyzed extracellular proteins by high-resolution 2-DE. Twenty proteins were identified from 71 protein spots in both C57BL/6 and CBA/Ca. We detected significant differences between control and irradiated bone marrow and between genotypes and identified many of the changed proteins by MS. In C57BL/6, 27 spots were significantly different between control and irradiated samples. In CBA/Ca, 18 spots showed significant changes following irradiation. Proteins such as serum albumin, apolipoprotein A-I, ferritin, haptoglobin (Hp) and alpha-1-antitrypsin were changed in irradiated bone marrow of both mouse strains, reflecting an ongoing acute-phase reaction. Several other proteins including serotransferrin, neutrophil collagenase, peroxiredoxin 2 and creatine kinase M chain were changed specifically in an individual mouse strain. The proteomic approach makes an important contribution to characterizing bone marrow proteome and investigating the tissue response of bone marrow to radiation, assists in identifying genotype-dependent responses and provides support for the importance of microenvironmental factors contributing to the overall response.

Amino Acid Sequence↗

PubMed2005

Radiation and the microenvironment - tumorigenesis and therapy.

Radiation rapidly and persistently alters the soluble and insoluble components of the tissue microenvironment. This affects the cell phenotype, tissue composition and the physical interactions and signalling between cells. These alterations in the microenvironment can contribute to carcinogenesis and alter the tissue response to anticancer therapy. Examples of these responses and their implications are discussed with a view to therapeutic intervention.

Animals↗

PubMed2004

Damaging and protective cell signalling in the untargeted effects of ionizing radiation.

The major adverse consequences of radiation exposures are attributed to DNA damage in irradiated cells that has not been correctly restored by metabolic repair processes. However, the dogma that genetic alterations are restricted to directly irradiated cells has been challenged by observations in which effects of ionizing radiation arise in non-irradiated cells. These, so called, untargeted effects are demonstrated in cells that are the descendants of irradiated cells either directly or via media transfer (radiation-induced genomic instability) or in cells that have communicated with irradiated cells (radiation-induced bystander effects). Radiation-induced genomic instability is characterized by a number of delayed responses including chromosomal abnormalities, gene mutations and cell death. Bystander effects include increases or decreases in damage-inducible and stress-related proteins, increases or decreases in reactive oxygen and nitrogen species, cell death or cell proliferation, cell differentiation, radioadaptation, induction of mutations and chromosome aberrations and chromosomal instability. The phenotypic expression of untargeted effects and the potential consequences of these effects in tissues reflect a balance between the type of bystander signals produced and the responses of cell populations to such signals, both of which may be significantly influenced by cell type and genotype. Thus, in addition to targeted effects of damage induced directly in cells by irradiation, a variety of untargeted effects may also make important short-term and long-term contributions to determining overall outcome after radiation exposures.

Animals↗

PubMed2004

Commentary on radiation-induced bystander effects.

The paradigm of genetic alterations being restricted to direct DNA damage after exposure to ionizing radiation has been challenged by observations in which effects of ionizing radiation arise in cells that in themselves receive no radiation exposure. These effects are demonstrated in cells that are the descendants of irradiated cells (radiation-induced genomic instability) or in cells that are in contact with irradiated cells or receive certain signals from irradiated cells (radiation-induced bystander effects). Bystander signals may be transmitted either by direct intercellular communication through gap junctions, or by diffusible factors, such as cytokines released from irradiated cells. In both phenomena, the untargeted effects of ionizing radiation appear to be associated with free radical-mediated processes. There is evidence that radiation-induced genomic instability may be a consequence of, and in some cell systems may also produce, bystander interactions involving intercellular signalling, production of cytokines and free radical generation. These processes are also features of inflammatory responses that are known to have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. Thus, radiation-induced genomic instability and untargeted bystander effects may reflect interrelated aspects of inflammatory type responses to radiation-induced stress and injury and contribute to the variety of the pathological consequences of radiation exposures.

Animals↗

PubMed2003

Radiation-induced genomic instability and bystander effects: inter-related nontargeted effects of exposure to ionizing radiation.

The paradigm of genetic alterations being restricted to direct DNA damage after exposure to ionizing radiation has been challenged by observations in which cells that are not exposed to ionizing radiation exhibit responses typically associated with direct radiation exposure. These effects are demonstrated in cells that are the descendants of irradiated cells (radiation-induced genomic instability) or in cells that are in contact with irradiated cells or receive certain signals from irradiated cells (radiation-induced bystander effects). There is accumulating evidence that radiation-induced genomic instability may be a consequence of, and in some cell systems may also produce, bystander interactions involving intercellular signalling, production of cytokines and free-radical generation. These processes are also features of inflammatory responses that are known to have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. Thus, radiation-induced genomic instability and untargeted bystander effects may reflect inter-related aspects of inflammatory-type responses to radiation-induced stress and injury and contribute to the variety of pathological consequences of radiation exposures.

Animals↗

PubMed2003

Tissue-specific p53 responses to ionizing radiation and their genetic modification: the key to tissue-specific tumour susceptibility?

Although little is understood of the underlying mechanisms, there are tissue-specific responses to tumourigenic and therapeutic agents and these responses are influenced by genetic factors. Ionizing radiation is an important tumourigenic and therapeutic agent for which there is substantial evidence for such tissue-dependent and genotype-dependent responses. Because the p53 tumour suppressor protein is a major determinant of cellular responses to radiation, the present study has investigated whether modification of the p53 pathway contributes to tissue-dependent and genotype-dependent responses using inbred strains of mice. Comparison of responses in haemopoietic and epithelial cells in irradiated C57BL/6 and DBA/2 mice revealed significant differences in p53 and apoptotic responses in different cell types and in different cells of the same type, reflecting the complexity of damage responses operating in the whole organism. The data suggest that p53-mediated up-regulation of Bax is a major determinant of apoptosis in the spleen, but not in the intestine, whereas p53-mediated induction of p21(waf1) plays an anti-apoptotic role in the spleen, but not in the intestine. It is also shown that p53 stabilization and differential transactivational activities towards Bax or p21(waf1) are influenced by genetic factors that act in a tissue-specific manner. Analysis of ATM, a potential mediator of differential p53 activation, indicates that this key regulator of radiation responses is preferentially induced in epithelial cells, but is unlikely to account for genetic modification of p53 or apoptotic responses in the mouse strains studied. Polymorphisms in the p53 or DNA-PKcs genes are also unlikely to account for the genetic modifications that are reported here. There are numerous further potential modifiers of the p53 pathway, but analysis of backcross and inter-cross mice demonstrates that genes responsible for the complex modification of these in vivo responses can be identified by linkage analysis. This approach has the potential to reveal new or unexpected interactions involving the p53 pathway that determine both short-term and long-term effects of radiation exposure and the basis of tissue-specific responses and tumour susceptibility.

Animals↗

PubMedDate not supplied

Ionizing radiation and leukaemia: more questions than answers.

The mechanisms underlying the unequivocal association between ionizing radiation and the development of leukaemia remain unknown. Recent progress in defining sub-cellular events has contributed to our understanding of the production of genetic lesions in irradiated cells but the importance of tissue effects in response to radiation damage has attracted much less attention. Thus, genetic lesions induced by radiation are considered to result from the deposition of energy in the cell nucleus and the initiating lesion for radiation-induced transformation has been similarly attributed to direct DNA damage. Recently, however, there have been many reports of radiation effects, characteristically associated with the consequences of energy deposition in the cell nucleus, arising in non-irradiated cells as a consequence of communication with irradiated cells. These, so-called, non-targeted radiation effects pose major challenges to current views of the mechanisms of radiation-induced DNA damage and the mechanisms underlying radiogenic malignancies. Considered together with data obtained from laboratory model systems, a rather complex picture of radiation leukaemogenesis is emerging in which, additional to any damage induced directly in target stem cells, the haemopoietic microenvironment can be a source of damaging signals and cellular interactions make important genotype-dependent contributions to determining overall outcome after radiation exposures.

Bystander Effect↗

PubMedDate not supplied

Application of two-dimensional difference gel electrophoresis to studying bone marrow macrophages and their in vivo responses to ionizing radiation.

A flow cytometric protocol was developed to isolate primary bone marrow resident macrophages (CD11b((-)) Gr-1((-)) F4/80((+))) before and 24 h after 0.5 Gy gamma-irradiation from mouse strains (C57BL/6 and CBA/Ca) that exhibit significant differences in the response of their hematopoietic tissues to ionizing radiation. The proteins from these populations were analyzed using two-dimensional difference gel electrophoresis (2D DIGE) and mass spectrometry. We identified 36 macrophage proteins from 52 spots in both C57BL/6 and CBA/Ca. Thirty-three spots showed significant difference between genotypes and 16 of them corresponding to 11 proteins were identified. These included G-protein signaling 16, glucose-regulated protein 78, and lactoylglutathione lyase. We detected 16 and 18 spot changes following irradiation in C57BL/6 and CBA/Ca respectively, and in total 16 of them were identified. The identified proteins included calreticulin, lactoylglutathione lyase, regulator of G-protein signaling 16 and peroxiredoxin 5, mitochondrial precursor. The application of DIGE to primary bone marrow resident macrophages has allowed the first description of the proteome of these important components of the hematopoietic microenvironment and an analysis of their in vivo response to ionizing radiation which may shed light on the mechanism underlying the differential radiation-induced leukemogenesis exhibited within these mouse strains.

Animals↗