Instability In Bone Marrow Cells Research Articles

Predator odor induces genome instability in the mouse bone marrow cells

Background. Long coevolution of prey and predator species of mammals creates specific mechanisms of their interaction, e. g. preys innate behavior aversive to the predator odor. However, little is known about genetic responses in the prey organism. We assessed genome instability of the bone marrow cells in mice affected by the cats odor influence, and proposed pathway of such action.
 Materials and methods. CBA mouse males were exposed to volatiles from adult cat urine for 2 or 24 hours. To estimate the genetic effect, ana-telophase method of chromosome aberration analysis and comet assay were used. The level of corticosterone was also measured after the exposure for 30 or 60 minutes.
 Results. The exposure to cats urine volatiles for 2 hours induced damage of DNA in bone marrow cells of the mouse males as was shown by the DNA comet analysis. The exposure for 24 hours elevated the frequency of chromosome aberrations in mitotically dividing cells at ana-telophase stage. No significant changes were found in the level of corticosterone in the peripheral blood.
 Conclusion. We have shown that volatile chemosignals from predators urine induce genomic instability in bone marrow cells of a prey. The hormonal pathway of such influence is still unknown. Intraorganismic paths leading to genome damage are discussed as well as far consequences of discovered effects.

Response to Baverstock, K. Comments on Rithidech, K.N.; et al. Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation. Int. J. Environ. Res. Public Health 2013, 10, 1356–1377.

We thank Dr. Baverstock [1] for his interest in reading our article and his time in writing his comments for our work [2]. We, however, respectfully disagree with his statement that we made "two category errors" associated with the assessment of the occurrence of "genomic instability" by determining the frequencies of delayed- or late-occurring chromosomal damage. Our disagreement is based upon the well-known fact that radiation-induced genomic instability (or delayed/late-occurring damage) can be manifested in many ways. These include late-occurring chromosomal damage, or mutations, or gene expression, or gene amplifications, or transformation, or microsatellite instability, or cell killing [3-9]. Such phenomena have been detected many cell generations after irradiation. We agree that genomic instability may well be the consequence of epigenetic changes. Another mechanism mentioned by Dr. Bavertock as being probably unlikely is the reversibility of damage. This potential may not be discarded off-hand, as Dr. Baverstock prefers to do. There is much reproducible evidence of adaptive protection that depending on absorbed dose precisely may reverse early damage, and damage appearing late may be due to some form of residual damage letting the cell become genetically unstable. In other words, the argument by Dr. Baverstock regarding upward or downward causation appears to be rather speculative and far from being settled.

Comments on Rithidech, K.N.; et al. Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation. Int. J. Environ. Res. Public Health 2013, 10, 1356–1377

I would like to take issue with Rithidech et al., authors of the paper entitled "Lack of genomic instability in mice at low doses" [1] who claim to have shown that their results on the measurement of late occurring chromosome aberrations after irradiation of SCID mice with X-rays show that lower doses (0.05 Gy) do not induce genomic instability. Their earlier work at higher doses (0.1 and 1.0 Gy) on the same strain of mouse indicated that de novo chromosome aberrations were detected at 6 months post-irradiation. This was taken, almost certainly correctly, to be an indication of the presence of genomic instability: late appearing chromosome damage, as the authors note, seems to be a reliable indicator of the process. The lack of de novo chromosome aberrations at 6 months post-irradiation, however, cannot be taken as evidence of the absence of genomic instability. In drawing their conclusion of a "lack of genomic instability …." the authors have committed two category errors.

Effects of 100 MeV protons delivered at 0.5 or 1 cGy/min on the in vivo induction of early and delayed chromosomal damage

Little is known about in vivo cytogenetic effects of protons delivered at the dose and dose rates encountered in space. We determined the effects of 100MeV protons, one of the most abundant type of protons produced during solar particle events (SPE), on the induction of chromosome aberrations (CAs) in bone marrow (BM) cells collected at early (3 and 24h) and late (6 months) time-points from groups of BALB/cJ mice (a known radiosensitive strain) exposed whole-body to 0 (sham-controls), 0.5, or 1.0Gy of 100MeV protons, delivered at 0.5 or 1.0cGy/min. These doses and dose-rates are comparable to those produced during SPE events. Additionally, groups of mice were exposed to 0 or 1Gy of 137Cs γ rays (delivered at 1cGy/min) as a reference radiation. The kinetics of formation/reduction of gamma-histone 2-AX (γH2AX) were determined in BM cells collected at 1.5, 3, and 24h post-irradiation to assess the early-response. There were five mice per treatment-group per harvest-time. Our data indicated that the kinetics of γH2AX formation/reduction differed, depending on the dose and dose rate of protons. Highly significant numbers of abnormal cells and chromatid breaks (p<0.01), related to those in sham-control groups, were detected in BM cells collected at each time-point, regardless of dose or dose-rate. The finding of significant increases in the frequencies of delayed non-clonal and clonal CAs in BM cells collected at a late time-point from exposed mice suggested that 0.5 or 1Gy of 100MeV protons is capable of inducing genomic instability in BM cells. However, the extent of effects induced by these two low dose rates was comparable. Further, the results showed that the in vivo cytogenetic effects induced by 1Gy of 100MeV protons or 137Cs γ rays (delivered at 1cGy/min) were similar.

Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation

It is clear that high-dose radiation is harmful. However, despite extensive research, assessment of potential health-risks associated with exposure to low-dose radiation (at doses below or equal to 0.1 Gy) is still challenging. Recently, we reported that 0.05 Gy of 137Cs gamma rays (the existing limit for radiation-exposure in the workplace) was incapable of inducing significant in vivo genomic instability (measured by the presence of late-occurring chromosomal damage at 6 months post-irradiation) in bone marrow (BM) cells of two mouse strains, one with constitutively high and one with intermediate levels of the repair enzyme DNA-dependent protein-kinase catalytic-subunit (DNA-PKcs). In this study, we present evidence for a lack of genomic instability in BM cells of the severely combined-immunodeficiency (SCID/J) mouse (which has an extremely low-level of DNA-PKcs activity) exposed whole-body to low-dose radiation (0.05 Gy). Together with our previous report, the data indicate that low-dose radiation (0.05 Gy) is incapable of inducing genomic instability in vivo (regardless of the levels of DNA-PKcs activity of the exposed mice), yet higher doses of radiation (0.1 and 1 Gy) do induce genomic instability in mice with intermediate and extremely low-levels of DNA-PKcs activity (indicating an important role of DNA-PKcs in DNA repair).

Cytogenetic consequences of chronic irradiation in rodent populations inhabiting the Eastern Ural Radioactive Trace zone

Chromosome instability in bone-marrow cells and 90Sr accumulation in the bone tissue are studied in rodents (Apodemus (Sylvaemus) uralensis Pall., 1811 and Apodemus agrarius Pall., 1771)* inhabiting the Eastern Ural Radioactive Trace (EURT) zone (Kyshtym radiation accident 1957) and adjacent areas of the Urals. Intensive mutagenic process in both species from impact plots (soil pollution by 90Sr, 2322–16690 kBq/m2) is found. Significant positive correlation of the frequency of aberrant cells and the concentration of 90Sr is shown. Possible causes of the lack of resistance to long-term mutagenic factors (over 100 generations in the 50 years since the accident), such as migration of animals and the specific configuration of the EURT zone (an extended narrow territory with a sharply falling gradient of radionuclide pollution), which considerably decrease the probability that certain changes will be fixed and inherited in a series of generations of rodents, are discussed.

Niacin status and treatment-related leukemogenesis

Chemotherapy often causes damage to hematopoietic tissues, leading to acute bone marrow suppression and the long term development of leukemias. Niacin deficiency, which is common in cancer patients, causes dramatic genomic instability in bone marrow cells in an in vivo rat model. From a mechanistic perspective, niacin deficiency delays excision repair and causes double strand break accumulation, which in turn favors chromosome breaks and translocations. Niacin deficiency also impairs cell cycle arrest and apoptosis in response to DNA damage, which combine to encourage the survival of cells with leukemogenic potential. Conversely, pharmacological supplementation of rats with niacin increases bone marrow poly(ADP-ribose) formation and apoptosis. Improvement of niacin status in rats significantly decreased nitrosourea-induced leukemia incidence. The data from our rat model suggest that niacin supplementation of cancer patients may decrease the severity of short- and long-term side effects of chemotherapy, and could improve tumor cell killing through activation of poly(ADP-ribose)-dependent apoptosis pathways.

DNA instability in low-risk myelodysplastic syndromes: refractory anemia with or without ring sideroblasts

We tested genomic instability in patients with myelodysplastic syndrome (MDS) by the comet assay and verified the suitability of this approach as a tool for analysis of ineffective hematopoiesis in refractory anemia (RA) and RA with ring sideroblasts (RARS). Erythroid and myeloid cell populations from bone marrow aspirates of 20 RA, 14 RARS and 15 control subjects were separated by differential expression of glycophorin A and subjected to comet assay. The extent of DNA migration was measured in single cells (200 cells/bone marrow fraction/subject). The results were in agreement with the concept of increased apoptosis in low-risk MDS subtypes. The RA samples had a significantly higher DNA instability than controls in glycophorin A positive cells, and the extent of DNA breakage correlated with the degree of cytopenia. Although RARS had an even higher rate of genomic instability in bone marrow cells than RA, there was no clear relationship to peripheral cytopenia. This suggests an additional DNA instability of non-apoptotic origin. Whether this increase is associated with an increased repair of oxidative damage in DNA arising due to iron deposits in ring sideroblasts remains to be formally proven. Comet assay provides a promising tool for the investigation of difference between RA and RARS pathobiology.