Influence of ionizing radiation on the attractiveness of male mice to chemosignals of intact individuals

Within short-terms after exposure to ionizing radiation, CBA and C57Bl/6 male mice were found not only to retain but also to enhance their attractiveness to chemosignals of intact males of the same genotype (syngenic). It was shown that the time period of higher attractiveness increased with the absorbed dose (from 1 to 6 Gy). Within several days after exposure to 6-Gy irradiation, male mice were temporarily unable to discriminate between chemosignals of syngenic and allogenic (alien genotype) individuals. Unlike male mice of the CBA strain, male mice of the C57Bl/6 strain displayed no changes after exposure to 1-Gy irradiation, but the effect of 2-6 Gy was more persistent. These phenomena can be explained by the lower olfactory reactivity combined with higher radiosensitivity of C57Bl/6 mice. Irradiated male mice temporarily lost their olfactory ability to discriminate the genotype of females' volatile secretions and to distinguish between females' and males' volatile secretions.     

Pregnancy in female house mice exposed to urinary chemosignals from other females.

Seven experiments were performed to investigate pregnancy termination, urinary chemosignals, and litter sex ratio variation in female house mice. Experiments tested the effects of urine from adult and prepubertal females, housed individually or in groups, on successful insemination and litter production by females treated at different times and for different periods during the 3 weeks before mating and during gestation. Treatment of females with urine from adult females housed eight per cage or with urine pooled from eight adult females housed individually for 2 or 3 weeks before mating resulted in fewer successful pregnancies and significantly more female-biased litters. Treatment with urine from adult or prepubertal females housed eight per cage or with urine pooled from eight mice housed individually for the first 6 days of gestation or throughout pregnancy resulted in a significant increase in the rate of pregnancy termination. These treatments resulted in lower body weights at birth and slower growth rates in all males and in some females. Puberty was delayed in female progeny from urine-treated dams in five of seven experiments, and these young females attained first oestrus at greater mean body weights than mice in other treatments. These findings indicate that, in mice, at high population density, communication via a urinary chemosignal can alter reproduction in recipient females. Availability of, and competition for, resources such as food would be greater at higher densities, possibly lowering the probability of reproductive success. Pregnancy termination and delays in reproduction and attainment of sexual maturity might lead to greater successful reproduction at a later time.     

The effect of He-Ne laser radiation on the survival of HeLa cells subjected to ionizing radiation]

A monolayer of HeLa cells, at the stationary phase of growth, exposed to He-Ne laser radiation (632.8 nm; 100 J/m2) either 5 min or 60 min prior to gamma irradiation (0.1-10 Gy; 6.75 Gy/min), or 5 min after irradiation has been investigated. With a 5-min interval between irradiation sessions (both sequences) the survival curves are virtually the same as those for gamma-irradiated cells only. With He-Ne laser radiation delivered 60 min before gamma irradiation with doses exceeding 5 Gy, a fraction of radioresistant cells is identified whose D0 is almost twice as high as D0 of basic cell mass (3.6 and 1.7 Gy respectively. The survival curve becomes a two-component one. A hypothesis is proposed that He-Ne laser radiation activates, in some cells, the processes that promote the repair of radiation damages.     

Quantitative analysis of biological responses to ionizing radiation, including dose, irradiation time, and dose rate

Because biological responses to radiation are complex processes that depend on both irradiation time and total dose, consideration of both dose and dose rate is necessary to predict the risk from long-term irradiations at low dose rates. Here we mathematically and statistically analyzed the quantitative relationships between dose, dose rate and irradiation time using micronucleus formation and inhibition of proliferation of human osteosarcoma cells as indicators of biological response. While the dose-response curves did not change with exposure times of less than 20 h, at a given dose, both biological responses clearly were reduced as exposure time increased to more than 8 days. These responses became dependent on dose rate rather than on total dose when cells were irradiated for 20 to 27 days. Mathematical analysis demonstrates that the relationship between effective dose and dose rate is well described by an exponential function when the logarithm of effective dose is plotted as a function of the logarithm of dose rate. These results suggest that our model, the modified exponential (ME) model, can be applied to predict the risk from exposure to low-dose/low-dose-rate radiation.     

Metabolomic response of human skin tissue to low dose ionizing radiation

Understanding how human organs respond to ionizing radiation (IR) at a systems biology level and identifying biomarkers for IR exposure at low doses can help provide a scientific basis for establishing radiation protection standards. Little is known regarding the physiological responses to low dose IR at the metabolite level, which represents the end-point of biochemical processes inside cells. Using a full thickness human skin tissue model and GC-MS-based metabolomic analysis, we examined the metabolic perturbations at three time points (3, 24 and 48 h) after exposure to 3, 10 and 200 cGy of X-rays. PLS-DA score plots revealed dose- and time-dependent clustering between sham and irradiated groups. Importantly, delayed metabolic responses were observed at low dose IR. When compared with the high dose at 200 cGy, a comparable number of significantly changed metabolites were detected 48 h after exposure to low doses (3 and 10 cGy) of irradiation. Biochemical pathway analysis showed perturbations to DNA/RNA damage and repair, lipid and energy metabolisms, even at low doses of IR.     

Individual differences in aggressiveness of female hamsters: response to intact and castrated males and to females

The aggressive behaviour of female hamsters was studied while they were housed in large enclosures with males and in brief tests with males or females. Some females are not aggressive with any male, whereas others are very aggressive toward all males in both testing conditions. Females that are not aggressive toward intact males may be very aggressive toward castrated males or females. When the animals are housed together for long periods of time, males dominate only if they are much heavier. Male dominance takes a relatively long time to establish and often there is an equivocal period characterized by reversals of dominance. Female dominance is rapidly established. Unless the male is much heavier, the female determines the presence or absence of agonistic behaviour.     

The growth and development of Schistosoma mansoni in mice exposed to sublethal doses of radiation

The maturation of Schistosoma mansoni was studied in mice exposed to various sublethal doses of radiation. Although the treatment of mice with 500 rads of radiation prior to infection did not alter parasite maturation, doses in excess of 500 rads led to a reduction in worm burden. This could not be attributed to a delay in the arrival of parasites in the hepatic portal system. Worms developing in mice treated with 800 rads commenced egg-laying about 1 wk later than worms in intact mice, and the rate of egg deposition appeared to be lower in irradiated hosts. The data demonstrate that exposure of C57BL/6 mice to doses of radiation in excess of 500 rads impairs their ability to carry infections of S. mansoni. The findings do not support the hypothesis that primary worm burdens in the mouse are controlled by a host immune response.     

DNA damage in non-proliferating cells subjected to ionizing irradiation at high or low dose rates

Ionizing radiation damage to the genome of a non-cycling mammalian cell is analyzed using continuous time Markov chains. Immediate damage induced by the radiation is modeled as a batch Poisson arrival process of DNA double strand breaks (DSBs). Different kinds of radiation, for example gamma rays or alpha particles, have different batch probabilities. Enzymatic modulation of the immediate damage is modeled as a Markov process similar to the processes described by the master equation of stochastic chemical kinetics. An illustrative example is the restitution/complete exchange model, which postulates that radiation induced DSBs can subsequently either undergo enzymatically mediated repair (restitution) or can participate pairwise in chromosome exchanges, some of which make irremediable lesions such as dicentric chromosome aberrations. One may have rapid irradiation followed by enzymatic DSB processing or have prolonged irradiation with both DSB arrival and enzymatic DSB processing continuing throughout the irradiation period. A complete solution of the Markov chain is known for the case that the exchange rate constant is negligible so that no irremediable chromosome lesions are produced and DSBs are the only damage to the genome. Using PDEs for generating functions, a perturbation calculation is made assuming the exchange rate constant is small compared to the repair rate constant. Some non-perturbative results applicable to very prolonged irradiation are also obtained using matrix methods: Perron-Frobenius theory, variational methods and numerical approximations of eigenvalues. Applications to experimental results on expected values, variances and statistical distributions of DNA lesions are briefly outlined.Continuous time Markov chain models are the most systematic of those current radiation damage models which treat DSB-DSB interactions within the cell nucleus as homogeneous (e.g. ignore diffusion limitations). They contain most other homogeneous models as special cases, limiting cases or approximations. However, applying the continuous time Markov chain models to studying spatial dependence of DSB interactions, which is generally believed to be very important in some situations, presents difficulties.     

Alteration of cytokine profiles in mice exposed to chronic low-dose ionizing radiation

While a high-dose of ionizing radiation is generally harmful and causes damage to living organisms, a low-dose of radiation has been shown to be beneficial in a variety of animal models. To understand the basis for the effect of low-dose radiation in vivo, we examined the cellular and immunological changes evoked in mice exposed to low-dose radiation at very low (0.7 mGy/h) and low (3.95 mGy/h) dose rate for the total dose of 0.2 and 2 Gy, respectively. Mice exposed to low-dose radiation, either at very low- or low-dose rate, demonstrated normal range of body weight and complete blood counts. Likewise, the number and percentage of peripheral lymphocyte populations, CD4⁺ T, CD8⁺ T, B, or NK cells, stayed unchanged following irradiation. Nonetheless, the sera from these mice exhibited elevated levels of IL-3, IL-4, leptin, MCP-1, MCP-5, MIP-1α, thrombopoietin, and VEGF along with slight reduction of IL-12p70, IL-13, IL-17, and IFN-γ. This pattern of cytokine release suggests the stimulation of innate immunity facilitating myeloid differentiation and activation while suppressing pro-inflammatory responses and promoting differentiation of naïve T cells into T-helper 2, not T-helper 1, types. Collectively, our data highlight the subtle changes of cytokine milieu by chronic low-dose γ-radiation, which may be associated with the functional benefits observed in various experimental models.     

Age associated alteration in DNA damage and repair capacity in Turbatrix aceti exposed to ionizing radiation

Excision repair capacity was measured in young and old Turbatrix aceti (phylum Nematoda) following exposure to ionizing radiation. Both repair synthesis and removal of 5,6-dihydroxydihydrothymine type (glycol) base damage were quantitated. At least two-fold higher glycol levels were produced in the DNA of young than of old nematodes for the same radiation dose. Young worms also excised glycol damage more rapidly and completely than old worms. Both peak repair synthesis activity and completion of repair synthesis occurred at earlier times during post-irradiation incubation in young nematodes. The data indicate there is a significant age-associated difference in both the incidence and removal of ionizing radiation damage in T. aceti which is used as a model of the ageing process.     

Radioprotective properties of eckol against ionizing radiation in mice

We have investigated the radioprotective efficacy of eckol, a component of brown seaweed Ecklonia cava, against the gamma ray-induced damage in vivo. Our results showed that eckol significantly decreased the mortality of lethally irradiated mice. The mechanisms of eckol's protection were found to include: an improvement in hematopoietic recovery, the repair of damaged DNA in immune cells and an enhancement of their proliferation, which had been severely suppressed by ionizing radiation. Thus, we propose eckol as a candidate for adjuvant therapy to alleviate radiation-induced injuries to cancer patients.     

The effect of low dose rate on metabolomic response to radiation in mice

Metabolomics has been shown to have utility in assessing responses to exposure by ionizing radiation (IR) in easily accessible biofluids such as urine. Most studies to date from our laboratory and others have employed γ-irradiation at relatively high dose rates (HDR), but many environmental exposure scenarios will probably be at relatively low dose rates (LDR). There are well-documented differences in the biologic responses to LDR compared to HDR, so an important question is to assess LDR effects at the metabolomics level. Our study took advantage of a modern mass spectrometry approach in exploring the effects of dose rate on the urinary excretion levels of metabolites 2 days after IR in mice. A wide variety of statistical tools were employed to further focus on metabolites, which showed responses to LDR IR exposure (0.00309 Gy/min) distinguishable from those of HDR. From a total of 709 detected spectral features, more than 100 were determined to be statistically significant when comparing urine from mice irradiated with 1.1 or 4.45 Gy to that of sham-irradiated mice 2 days post-exposure. The results of this study show that LDR and HDR exposures perturb many of the same pathways such as TCA cycle and fatty acid metabolism, which also have been implicated in our previous IR studies. However, it is important to note that dose rate did affect the levels of particular metabolites. Differences in urinary excretion levels of such metabolites could potentially be used to assess an individual’s exposure in a radiobiological event and thus would have utility for both triage and injury assessment.     

Modulation of apoptosis of eckol against ionizing radiation in mice

To investigate the radioprotective potential of eckol, a component of the seaweed Ecklonia cava, against radiation in vivo, we evaluated the effect of eckol on cyto- and histo-protective capability of the lymphocytes and intestine against damage induced by a single whole body irradiation (WBI) in vivo. Here, we ascertained that eckol protected the lymphocytes’ viability and rescued intestinal cells from radiation-induced apoptosis by decreasing the amount of pro-apoptotic p53 and Bax and increasing that of anti-apoptotic Bcl-2. These findings indicate that the overexpression of anti-apoptotic protein, which may lead to resistance to DNA damage, is involved deeply in protection of gastrointestinal cells after irradiation. Thus, eckol that can protect cells and tissues against ionizing radiation may have considerable potential as adjuncts to successful radiotherapy.     

The yield of genetic disorders in mice exposed to the action of fractionated ionizing radiation in embryogenesis

In studying the occurrence of genetic lesions in mice subjected to daily long-term gamma-irradiation at different periods of the antenatal development, increased preimplantation losses were revealed in offspring of females irradiated with a cumulative dose of 1.25-3.5 Gy. In male offspring the death rate did not significantly vary from the control, but the incidence of abnormal spermatozoa heads and reciprocal translocations in spermatocytes was increased.     

An experimental approach to determining the protective properties of drugs against ionizing radiation in low and sublethal doses]

In experiments with mice, the efficiency of radioprotective agents against acute gamma-irradiation with nonlethal and low doses (0.5-4 Gy) was estimated by nine parameters. The treatment with cystamine, cysteamine and riboxine prior to irradiation (< 2 Gy) did not influence the postirradiation values of the parameters under study. With a dose of up to 4 Gy, the effect of riboxine was noted. The determinations of the number of aberrant mitoses, cellularity and mitotic activity of the bone marrow have proved to be most informative. The data obtained are discussed with due regard for the specific effect of low-level radiation and mechanisms of the protective action of the agents under study.     

Carcinogenesis in laboratory mice after low doses of ionizing radiation

Experimental data on the incidence of solid tumors from various long-term mouse studies performed at the Casaccia laboratories over several years were reconsidered, limiting the analysis to the results available for doses equal to or less than 17 cGy of neutrons and 32 cGy of X rays since these dose limits are reasonably close to the generally accepted low-dose levels for high- and low-LET radiation (i.e. D(high-LET) < 5 cGy and D(low-LET) < 20 cGy, respectively). The following long-term experiments with BC3F1 mice were reviewed: (a) females treated with single doses of 1.5 MeV neutrons or 250 kVp X rays, (b) males treated with fractionated doses of fission neutrons, and (c) mice of both sexes irradiated in utero 17.5 days post coitus with single doses of fission neutrons or X rays. An experiment with CBA mice of both sexes treated with single doses of fission neutrons was also included in this study. Analysis was done on animals at risk; thus all incidences of tumor-bearing animals were expressed as the percentage excess incidence with respect to the controls. Ovarian tumors and other solid neoplasms were considered. The percentage frequencies and mean survival times of tumor-free mice were also recalculated. The results indicate the existence of a region at low doses where the final incidence of solid neoplasms is indistinguishable from the background incidence. These data reinforce the idea that at low doses the effectiveness of ionizing radiation in inducing solid neoplasms in laboratory mice is very low.