The induction by 224Ra of myeloid leukaemia and osteosarcoma in male CBA mice

Radium-224 was injected into 12-week-old male CBA mice in the range 2-64 kBq per mouse either as a single injection or as eight injections spaced at 3.5 day intervals over 4 weeks. Small but significant yields of myeloid leukaemia or osteosarcoma were obtained in all but the control groups. An effect of mode of administration (single or multiple injections) could not be demonstrated but the combined results showed: a maximum yield of myeloid leukaemia in the region 8-16 kBq 224Ra; a greater yield of osteosarcoma than myeloid leukaemia at 64 kBq 224 Ra injected.     

Toxicity of 241Am in male C57BL mice: relative risk versus 226Ra

A life-span study on male C57BL mice after injection of various doses of 241Am was conducted. The effects on life span were evaluated and the incidence of tumors was determined by procedures that take competing risks into account. Bone tumors were induced in the mice by injections of 22 and 58 Bq 241Am per g. The mice died early from nonneoplastic diseases at the higher dose levels (190, 373, and 1197 Bq 241Am/g). Additionally, spontaneously occurring tumors such as liver carcinomas, lymphosarcomas, and lymphoreticulosarcomas occurred at an enhanced rate with increasing dose level. The data for survival time after 241Am injection and death with bone tumor were compared to data collected previously for 226Ra-injected mice of the same C57BL strain. This enabled direct comparison in the same strain of the effects of the bone-surface seeker 241Am to the effects of the bone-volume seeker 226Ra. The proportional hazards model was applied and the rate of death with bone tumor was 12.9 +/- 5.2 times higher after 241Am injection than after 226Ra injection if the regression covariate was the average dose to the skeleton. The relative risk was 3.5 +/- 1.7 if regressed on the injected radioactivity. The mortality rate after 241Am injection was 20.4 +/- 3.6 times higher than after 226Ra injection if regressed on average dose to the skeleton.     

Long-term effects of negative pions in female mice exposed to whole-body irradiation

Summary Long-term effects, especially the incidence of tumors, of whole-body exposure of female NMRI mice with either negative pions (peak or plateau region) or X rays have been studied in comparison to controls. Animals were irradiated at the age of 10 days after birth. The mice were then regularly examined for deaths and signs of severe disease, moribund animals being killed. A detailed histopathological work-up has been performed. The data show that the survival as defined by death or the time of autopsy is significantly lower in irradiated mice in comparison to controls, that there is no difference in reduction of survival between groups treated either with X rays or pions at peak region, but that a difference can be seen when comparing X rays with pions at plateau region. The incidence of ovarian tumors at any particular age is higher in mice treated with X rays or pions than in control groups, but significantly lower in animals exposed to plateau pions than in those treated with peak pions or X rays.     

Heterogeneity of cancer risk due to stochastic effects: emphasis on radiation-induced effects

Persons with exactly the same genetic background, behavior and environment may differ in radiation cancer risk, due to the stochastic nature of cancer development. These differences are estimated quantitatively by means of the two stage clonal expansion model, in which the number of intermediate cells on their way to malignancy varies stochastically between individuals. For liver cancer after injection of Thorotrast, the estimated relative risk for persons without intermediate cells at age 40 is a factor of more than 10 larger than that for persons with a large number of intermediate cells. The population-based estimate of the relative risk represents an underestimation for most persons at most ages, because for persons showing a large number of intermediate cells liver cancer is not a rare disease.     

Bone cancer risk of (239)pu in humans derived from animal models

Two-mutation model fits to bone cancer mortality data from mice, rats and beagle dogs injected with (239)Pu or (226)Ra show that (1) it is possible to fit the radiation-related parameters for animals from different strains of the same species together; (2) for every species the same significant parameters are found in the models for (239)Pu and in the models for (226)Ra, and the only difference is in the value of the linear mutation coefficient; and (3) the toxicity ratio, when defined as the ratio of the linear mutation coefficients for (239)Pu over (226)Ra, has a relatively uniform value of approximately 8 for the species considered. This relatively constant ratio enables the development of a (239)Pu model for humans that is based on the radium dial painters and the toxicity ratio for beagles. The model predictions agree well with published risk estimates based on other data and derived using alternative approaches. This has two important implications: (1) The two-mutation model appears to be a useful tool in translating from animal models to humans in a meaningful way; and (2) once a two-mutation model for humans has been derived, radiation risks can be calculated that depend on doses, dose rates and ages at exposure. Such a model therefore supplements published risk estimates that often lack such dependences.     

Fetal development in mice exposed to isoflurane

The developmental toxicity of trace (0.006%), subanesthetic (0.06%), and light anesthetic (0.6%) exposure to isoflurane was examined in Swiss/Webster mice. No adverse effects were demonstrated following exposure of dams to 0.006% (n = 26) and 0.06% (n = 27) isoflurane for 4 hr daily on days 6-15 of pregnancy. Exposure to 0.6% isoflurane (n = 23) for the same period resulted in significantly decreased fetal weight, decreased skeletal ossification, minor hydronephrosis, and increased renal pelvic cavitation. The incidence of cleft palate also was significantly increased, abnormalities occurring in 12.1% of fetuses and affecting 11 of 23 litters. This incidence was considerably higher than that of the combined treatment and colony control groups (0.75%) and those that we have found in previous experiments with this mouse strain following exposure to halothane (1.2%) or enflurane (1.9%).     

Reinterpreting polarity and cancer: The changing landscape from tumor suppression to tumor promotion

Cell polarity is a fundamental property used to generate asymmetry and structure in all cells. Cancer is associated with loss of cell and tissue structure. While observations made in model system such as Drosophila, identify polarity regulators as tumor suppressors that cause inappropriate cell division, studies in mammalian epithelia do not always support such a causative contribution. Our analysis of published cancer dataset shows that many polarity genes, including PARD6B, SCRIB, PRKCI, DLG1, DLG2, DLG5 and LLGL2, are frequently amplified in multiple cancers raising the possibility that mammalian epithelia may have evolved to use polarity proteins in multiple ways where they may have tumor promoting functions. In this review, we reinterpret the published results and propose a modified perspective for the role of polarity regulators in cancer biology. In addition to the traditional form of cell polarity, which is involved establishment of maintenance of normal cell structure and asymmetry, we propose that some mammalian polarity proteins also regulate subcellular polarity (intracellular asymmetry), which can improve cellular fitness to carry out functions such as proliferation, apoptosis, stress adaptation, stemness and organelle biology. Here, we define subcellular polarity and discuss evidence that supports a role for subcellular polarity in biology.     

Regional heterogeneity in murine lung fibroblasts from normal mice or mice exposed once to cigarette smoke

Chronic obstructive lung disease (COPD) is characterized by matrix deposition in the small airways but matrix loss from the parenchyma, phenomena which must depend on the ability of local fibroblasts to produce matrix after smoke exposure. To investigate this idea, we exposed C57Bl/6 mice once to cigarette smoke or to air (control) and prepared primary cultures of lung fibroblasts by microdissecting large airways (trachea, LAF), medium size airways (major bronchi, MAF) and parenchyma (PF). Control PF showed the lowest rate of wound closure and wound closure was depressed in all lines by a single in vivo smoke exposure. Gene expression of matrix proteins differed considerably among the sites; decorin, which may sequester TGFβ, was markedly higher in PF. PF showed higher intrinsic ratios of pSmad2/Smad2. Smoke caused much greater increases in secreted and matrix deposited collagens 1 and 3 in PF than in LAF or MAF. Expression of Thy-1, a gene that suppresses myofibroblast differentiation, was increased by smoke in PF. We conclude that there is considerable regional heterogeneity in murine lung fibroblasts in terms of matrix production, either basally or after in vivo smoke exposure; that PF have lower ability to repair wounds and higher intrinsic TGFβ signaling; and that a single exposure to smoke produces lasting changes in the pattern of matrix production and wound repair, changes that may be mediated in part by smoke-induced release of TGFβ. However, PF still retain the ability to repair by producing new matrix after a single in vivo smoke exposure.     

Lung cancer risk in mice: analysis of fractionation effects and neutron RBE with a biologically motivated model

Data from Argonne National Laboratory on lung cancer in 15,975 mice with acute and fractionated exposures to gamma rays and neutrons are analyzed with a biologically motivated model with two rate-limiting steps and clonal expansion. Fractionation effects and effects of radiation quality can be explained well by the estimated kinetic parameters. Both an initiating and a promoting action of neutrons and gamma rays are suggested. While for gamma rays the initiating event is described well with a linear dose-rate dependence, for neutrons a nonlinear term is needed, with less effectiveness at higher dose rates. For the initiating event, the neutron RBE compared to gamma rays is about 10 when the dose rate during each fraction is low. For higher dose rates this RBE decreases strongly. The estimated lifetime relative risk for radiation-induced lung cancers from 1 Gy of acute gamma-ray exposure at an age of 110 days is 1.27 for male mice and 1.53 for female mice. For doses less than 1 Gy, the effectiveness of fractionated exposure to gamma rays compared to acute exposure is between 0.4 and 0.7 in both sexes. For lifetime relative risk, the RBE from acute neutrons at low doses is estimated at about 10 relative to acute gamma-ray exposure. It decreases strongly with dose. For fractionated neutrons, it is lower, down to about 4 for male mice.     

Chemical protection against the long-term effects in mice exposed to supralethal doses of X rays

Our results demonstrate that mixtures of radioprotectors increase the degree of protection against the short and the long term effects compared with that obtained with each substance given separately. The most potent mixtures of radioprotectors (AET, MEA, Cyst, GSH, 5-HT) yield for the long term survival a dose reduction factor of 2.1. Pulmonary lesions are most often the cause of death in protected mice irradiated with 13.5 Gy or more. At the time of death signs of sclerosis and atrophy in several tissues are associated with these lung lesions in most mice and increase with dose and time after exposure. The tissues most affected are the kidney, the alimentary tract, the liver and the lymphoid tissues.     

The estimation of molecular and cytogenetic effects in mice exposed to chronic low dose gamma-radiation

Molecular and cytogenetic parameters were estimated in male CBA/lac mice exposed to chronic low dose-rate gamma-radiation (62 cGy/year) for 40, 80, 120, 210, and 365 days. After 40 days of exposure (6.7 cGy), spleen lymphocyte susceptibility to hydrogen peroxide was shown to increase. However, beginning from the day 120 of the treatment (20.4 cGy), the opposite effect was observed. An increase in number of the DNA-protein crosslinks was recorded in spleen lymphocytes only on day 40 of the experiment. The number of DNA breaks increased significantly beginning from day 120 of the experiment, as shown by the DNA-comet method. On the day 210 of irradiation, the frequency of abnormal sperm heads in the mice significantly increased. The number of normochromatic micronucleated erythrocytes of the peripheral blood remained unchanged.     

Immune response in mice exposed to low-dose X-rays

The present paper was conducted to evaluate the immunological effect of low dose gamma-irradiation. The splenocytes of mice (C57BL/6N), 24 hours after the irradiation from 0.087 to 0.87 Gy, were incubated with mitogens of T or B lymphocytes, allo-antigen (splenic cells of BALB/c mice) (MLC) or sheep red blood cells (SRBC) 10 days after immunization with the SRBC in vivo, and then their incorporations of 3H-thymidine were measured. On the other hand, this incorporation in the presence of T-cell growth factor (IL-2) in vitro and a drug of AET in vivo was investigated to examine their radioprotective effects. The dose-response relation, i.e. decrease of 3H-thymidine incorporation in function of increase of the irradiation dose, was demonstrated in these immunological examinations except at the dose of 0.087 Gy. More, their incorporation was remarkably promoted by the administration of the T cell growth factor and the drug, therefore, these substances represent the radioprotective effect.     

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.     

Prolactin sensitivity of mammary epithelial cells from mice exposed neonatally to diethylstilbestrol

We examined the responsiveness to prolactin and growth hormone of mammary epithelial cells from mice exposed neonatally to diethylstilbestrol (DES) and from control mice. The mammary epithelial cells were cultured inside collagen gels with serum-free medium containing insulin, epidermal growth factor, and linoleic acid. This produces prolactin-sensitive cells with low levels of casein production, as measured in cellular homogenates with a specific enzyme-linked immunosorbent assay for alpha-casein. The collagen gels containing these cells were then released and the medium supplements changed to insulin, linoleic acid, and prolactin at concentrations from 10 to 1000 ng/ml and growth hormone at 0, 10, or 100 ng/ml. This second phase of the culture, the differentiation phase, allows the cells to accumulate casein if they have this capacity. When cultured with prolactin only (no growth hormone), the cells from DES-exposed mice consistently accumulated 50-100% of the casein content of normal cells, but never more. Growth hormone, when added to prolactin-containing medium, increased casein accumulation above the levels seen with prolactin alone. Combinations of prolactin and growth hormone enhanced the difference between casein accumulation in DES-exposed and control cells, and DES-exposed cells were much less responsive to growth hormone. In our studies, the isolated mammary epithelial cells of estrogen-exposed mice are not more sensitive to prolactin than cells from normal animals as previous reports reports had suggested, but rather are generally less sensitive to hormonal stimulants.