Genetic effects of the decay of radionuclide products of nuclear fission in Saccharomyces cerevisiae cells. Lethal effects of the decay of 89Sr incorporated in cells of different ploidies and radiosensitivity

Decay of 89Sr incorporated in yeast cells produces a pronounced inactivating effect. The transmutation mainly contributes (about 80%) to cell inactivation. Haploid cells are more sensitive to 89Sr disintegration than diploid and tetraploid ones. A radiosensitive mutant XRS2, that is particularly sensitive to the transmutation effect of radionuclides, has proved to be sensitive to 89Sr transmutation as well. At the same time, another radiosensitive mutant, rad 54, does not virtually differ from the wild-type strain by its sensitivity to 89Sr decay.     

Biochemical changes of the liver in rats with a combined lesion from 89Sr and 131I

The results of the biochemical changes induced by 89Sr and 131I in a rat liver after their separate and combined administration within a wide range of doses are presented. Administered in a combination the radionuclides produced the additive effect when estimated by some indices, and more than additive, according to other tests.     

Removal of radioactive strontium from the rat by feeding stable strontium

The effect of administering the stable isotope of strontium (as phos-phate) at different dietary levels to adult rats (fed on a cereal and pulse-based diet containing 0.4% Ca) on the retention of radiostrontium (⁸⁹Sr) and radiocalcium (⁴⁵Ca) in the femur and the whole skeleton was studied for a period up to 6 weeks after an intraperitoneal injection of the two radioisotopes. The ability of strontium to remove⁸⁹Sr under the above dietary conditions was examined. Feeding Sr at 0.5% or 1% levels for 6 weeks had no effect on the skeletal content of⁸⁹Sr or⁴⁵Ca while a dietary regimen of 2% Sr (2000 times the normal content), significantly lowered the⁸⁹Sr and⁴⁵Ca content by about 30% in the femur but not in the whole skeleton. At this Sr level, the urinary excretion of the isotopes increased with a concomitant decrease in their excretion in the faeces. This study underscores the limitations of dietary Sr to mobilise⁸⁹Sr from the bones after it is incorporated in the bone mineral.     

Radiostrontium distribution measured in vitro between bound and free forms in the soft tissues of rat.

The distribution of 89Sr (carrier-free) in the bound (non-diffusible) and free (diffusible) forms was studied in vitro in the soft tissues of the albino rat by the ultrafiltration method. The influence of factors such as time and temperature of incubation with 89Sr, concentration and medium of the homogenate, pH and age of the animal on the binding of 89Sr was investigated. The binding increased with rise in pH, being maximum in the pH range 7.0--9.0. The distribution pattern varied with the tissues, the bound form (at pH 7.4) being as high as 84 per cent in the small intestine and as low as 20 per cent in the skin, whereas it was about 40--45 per cent in kidney, liver, lung, skeletal muscle and blood serum. The bound form in most of the tissues of the weanling rats was in general lower than that in 6-month or 1-year-old rats. In the serum, 89Sr was mostly bound to globulins. The bound form of 89Sr was also determined by the method of equilibrium dialysis for comparison.     

Genetic effects of the decay in Saccharomyces cerevisiae yeast cells of the radionuclide products of nuclear fuel fission. II. Lethal mutagenic effects and the nature of mutations induced by an equilibrium mixture of 90Sr-90Y and 89Sr

The lethal and mutagenic effects and the nature of mutations induced by 90Sr-90Y and 89Sr in cells of the yeast Saccharomyces cerevisiae were studied. The lethal efficiency was determined for 89Sr as (7,6 +/- 1,05) X 10(-5) decay-1, for 90Sr-90Y-(3,3 +/- 1,6) X 10(-4) decay-1. The mutagenic efficiency for ade1 and ade2 genes was determined for 89Sr as (8,3 +/- 2,5) X 10(-9) decay-1, for 90Sr-90Y-(2,9 +/- 1,5) X 10(-8) decay-1. For ade2 locus, the spectrum of mutations induced by 89Sr was a follows: one deletion, 17% of frameshifts and 83% of base pair substitutions--51% of transversions, 22% of GC-AT transitions and 10% of AT-GC transitions. The data of the present work suggest that 90Sr-90Y and 89Sr are very efficient physical mutagens. The relative mutagenic efficiency (RME) was estimated for radionuclides studied.     

前列腺癌患者^89Sr核素治疗后免疫功能的变化

目的：探讨分析前列腺癌患者^89Sr治疗后机体免疫功能的变化及其临床意义。方法：87例前列腺癌患者经^89Srcl2治疗1月,采用流式细胞术检测治疗前后其外周血淋巴细胞亚群,速率散射免疫比浊分析法检测其免疫球蛋白的含量。结果：经^89Sr治疗后,患者CD3、CD19、CD4比例均明显升高,CD8比例明显降低,差异均有统计学意义畔0．05）,而CD16^＋CD56^＋无明显变化;IgG和IgA明显升高,差异均有统计学意义（P〈0．05）,而IgM无明显变化。结论：用^89Srcl2治疗前列腺癌可以有效提高患者的免疫水平,可通过监测机体免疫功能指标的变化^89Sr核素的疗效。     

In vitro activation of suppressor cells from spleens of mice treated with radioactive strontium

Mice were treated with two 100-muCi injections of 89Sr to deplete marrow-dependent (M) cells. Mice so treated responded normally to immunization with sheep red blood cells (SRBC) in vivo; moreover, spleen cells from 89Sr-treated mice were able to respond to SRBC after infusion into irradiated recipient mice. However, spleen cells from mice treated with 89Sr did not respond to SRBC in vitro and mixtures of normal spleen cells with the latter were also not able to respond in vitro. The discrepancy between in vivo and in vitro responses was abolished by culturing spleen cells for 24 hr before testing their ability to respond to SRBC in the adoptive transfer in vivo. Pretreatment of spleen cells from 89Sr-treated mice with 1000 R of gamma-radiation lessened their suppressive activity. The suppressor cells were detected in spleens of athymic nude mice treated with 89Sr. The suppressive activity, after the 24-hr culture period, was not abolished by irradiation and was active in vivo as well as in vitro. Thus, depletion of M cells by 89Sr results in the appearance within the spleen of thymus-independent suppressor cells, which require a short period of in vitro cultivation before becoming functionally active.     

B lymphocyte differentiation in lethally irradiated and reconstituted mice. I. The effect of Strontium-89 induced bone marrow aplasia on the recovery of the B cell compartment in the spleen.

The influence of ⁸⁹Sr-treatment on the recovery of the B cell compartment in lethally irradiated, fetal liver reconstituted mice was studied by means of membrane fluorescence. ⁸⁹Sr is a bone-seeking radio-isotope which causes in a dose of 3 μCi ⁸⁹Sr/g body weight a depletion of all nucleated cells, including immunoglobulin-bearing (B) cells, of the bone marrow.Treatment of irradiated and fetal liver reconstituted mice with 3 μCi ⁸⁹Sr/g body weight immediately and at 17 days after irradiation and reconstitution prevented recovery of the nucleated cell population, including B cells, in the bone marrow. In the spleen of such mice both nucleated cells and B cells reappeared at day 7 and 14 respectively. The B cell population in the spleen did not recover up to normal values during the experimental period of 45 days. It is concluded that B cell differentiation in lethally irradiated, fetal liver reconstituted mice can take place outside the bone marrow. The efficiency of this extra-medullary differentiation is discussed. The conclusion was drawn that mice with a ⁸⁹Sr-induced bone marrow aplasia are able to generate B lymphocytes. Consequently the bone marrow microenvironment seems not to be obligate to the differentiation of B lymphocytes. The peripheral lymphoid organs of such mice were found to be unable to compensate completely for the absence of B lymphocyte production in the bone marrow.     

Strontium-calcium discriminationin vitro by rat tissues

Uptake of⁸⁹Sr and⁴⁵Ca by 15 soft tissues of adult rat was studiedin vitro to assess the extent of discrimination between Sr and Ca. While brain, kidney, placenta and uterus have lower uptake of⁸⁹Sr and 45 Ca that of diaphragm, lactating mammary gland, skeletal muscle, skin, spleen and testes is higher. Tissues with medium range uptake are heart, small intestine, liver, lung, non-lactating mammary gland and ovary. The 6 tissues displaying discriminating ability, as expressed by⁸⁹Sr/⁴⁵Ca (tissue/medium), in the decreasing order are: small intestine, kidney, lactating mammary gland, placenta, diaphragm and heart. Non-lactating mammary gland and the other tissues did not differentiate between Sr and Ca. The efect of several enzyme inhibitors, compounds influencing Sr-Ca metabolism and other factors was studied in terms of the nature and mechanism of Sr-Ca discrimination.     

The effect of thyroparathyroidectomy, parathyroid hormone and calcitonin on plasma strontium in rats

The effect of thyroparathyroidectomy (TPTX) on the plasmatic Sr concentrations in rats previously supplemented with this element, has been studied, as well as its effect on the treatment of TPTX rats with hormonal combinations and, finally, the one presenting hormonal excess or defect of the phosphocalcium metabolism regulating hormones: parathormone (PTH) and calcitonin (CT). Twenty four hours after TPTX, the plasmatic Sr concentrations show a pattern similar to those of Ca and Mg and contrary to Pi. The subsequent evolution is different, as the plasmatic concentrations increase, probably due to the maintenance of Sr supplementation. The administration of this element to TPTX rats and the treatment with a hormonal combination with two of the following hormones: PTH, CT and T4 antagonize the hormonal effect on the restoration of the plasmatic concentrations of the elements analyzed. The PTH excess and defect (TPTX treated with CT + T4) show plasmatic increases in Sr; the CT excess provokes decreases while the defect (administration of PTH + T4) causes increases. The T4 administration reproduces the CT effects, but inconsistently. These results suggest that CT may be the hormone that plays a regulating role in the plasmatic Sr concentrations.     

A comparison between Ca and Sr cycling in forest ecosystems

In favourable conditions, the ⁸⁷Sr/⁸⁶Sr isotope ratios of the Sr delivered by rain and soil mineral weathering differ. Assuming that Ca and Sr behave similarly in forest ecosystems, several authors have used the ⁸⁷Sr/⁸⁶Sr variation in forest compartments to calculate the contribution of rain and mineral weathering to Ca fluxes and pools. However, there are a number of experimental reports showing that Ca and Sr may behave differently in the soil and in the plant. We have tested this Ca–Sr analogy in the field by measuring the variation of Sr and Ca concentrations, fluxes and pools in spruce, beech and maple stands on granite, sandstone and limestone. Results show that (1) variations of Ca and Sr concentrations are generally correlated at each level of the ecosystems. (2) In spruce on acid soils, a preferential uptake of Ca over Sr occurs (Aubure spruce Sr/Ca = 0.8×10⁻³; soil exchangeable Sr/Ca between 2 and 6×10⁻³). On calcareous soils, a preferential uptake of Sr over Ca by spruce may occur. (3) In spruce and beech on acid and calcareous soils, a preferential translocation of Ca over Sr from roots to leaves occurs ((Sr/Ca) in leaves was between 10 and 90% of that in roots). (4) The biological cycling of Ca and Sr leads to an enrichment of the upper soil layers in Ca and Sr. Compared to Sr, Ca accumulates in the upper layer of acid soils because Ca cycling through litterfall is favoured over Sr cycling, and possibly because of the selectivity of acid organic exchangers for Ca. This revised version was published online in June 2006 with corrections to the Cover Date.     

Bone marrow depletion by 89Sr complements a preleukemic defect in a long terminal repeat variant of Moloney murine leukemia virus.

We previously described a preleukemic state induced by Moloney murine leukemia virus (Mo-MuLV) characterized by hematopoietic hyperplasia in the spleen. Further experiments suggested that splenic hyperplasia results from inhibitory effects in the bone marrow, leading to compensatory extramedullary hematopoiesis. An enhancer variant of Mo-MuLV, Mo + PyF101 Mo-MuLV, fails to induce preleukemic hyperplasia and has greatly reduced leukemogenicity, indicating the importance of this state to efficient leukemogenesis. An alternative method for induction of preleukemic hyperplasia was sought. Treatment of mice with 89Sr causes specific ablation of bone marrow hematopoiesis and compensatory extramedullary hematopoiesis in spleen and nodes. NIH Swiss mice were inoculated neonatally with Mo + PyF101 Mo-MuLV and treated with 89Sr at 6 weeks of age. Approximately 85% developed lymphoid leukemia with a time course resembling that caused by wild-type Mo-MuLV. In contrast, very few animals treated with Mo + PyF101 Mo-MuLV or 89Sr alone developed disease. In approximately one-third of cases, the Mo + PyF101 Mo-MuLV proviruses were found at common sites for wild-type Mo-MuLV-induced tumors (c-myc, pvt-1, and pim-1), indicating that this virus is capable of performing insertional activation in T-lymphoid cells. These results support the proposal that splenic hyperplasia results from inhibitory effects in the bone marrow. They also indicate that Mo + PyF101 Mo-MuLV is blocked in early and not late events in leukemogenesis.     

Therapeutic efficiency of spleen or bone marrow CFU in X-irradiated 89Sr marrow-ablated mice.

Experiments were carried out to compare the therapeutic efficiency (TE: number of CFU required to reduce the mortality from 100 to 50 per cent) of spleen or marrow (BM) stem cells (CFU) grafted into lethally irradiated mice (807 rad) which had been previously treated with 89Sr or splenectomized. It was found that during the reconstitution of the haemopoietic organs, the spleen does not provide more than 10 per cent of the functional cells necessary for survival. Besides, the BM-derived CFU growing in 89Sr marrow-ablated mice remain twice as efficient as the spleen-derived ones. Similarly, spleen-derived CFU transplanted into splenectomized mice are half as efficient as BM-derived ones. It may therefore be assumed that haemopoietic stem cells grafted into a foreign microenvironment retain their original kinetics of growth and differentiation during 7 to 10 days after their transplantation.     

Aminotransferase and lactate dehydrogenase activity in the blood of dogs exposed to the joint action of external gamma- and internal alpha-radiation

After the effect of external gamma-radiation (6.5 to 51.6 mC/kg) and inhaled 239Pu submicron oxide, containing 25% of 241Am, (approximately 7 to 10 kBq/kg) delivered separately and in a combination, activities of alanine-aspartate aminotransferase and lactate dehydrogenase changed in an undulatory manner tending to increase at later times; the change rating was a function of type and level of radiation as well as the time lapsed from the onset of exposure. The combined effect of gamma- and alpha-radiation did not exceed the additive effect of the two factors delivered separately.     

Biosynthetic exchange of bromide for chloride and strontium for calcium in the photosystem II oxygen-evolving enzymes

The active site for water oxidation in photosystem II goes through five sequential oxidation states (S(0) to S(4)) before O(2) is evolved. It consists of a Mn(4)Ca cluster close to a redox-active tyrosine residue (Tyr(Z)). Cl(-) is also required for enzyme activity. To study the role of Ca(2+) and Cl(-) in PSII, these ions were biosynthetically substituted by Sr(2+) and Br(-), respectively, in the thermophilic cyanobacterium Thermosynechococcus elongatus. Irrespective of the combination of the non-native ions used (Ca/Br, Sr/Cl, Sr/Br), the enzyme could be isolated in a state that was fully intact but kinetically limited. The electron transfer steps affected by the exchanges were identified and then investigated by using time-resolved UV-visible absorption spectroscopy, time-resolved O(2) polarography, and thermoluminescence spectroscopy. The effect of the Ca(2+)/Sr(2+) and Cl(-)/Br(-) exchanges was additive, and the magnitude of the effect varied in the following order: Ca/Cl < Ca/Br < Sr/Cl < Sr/Br. In all cases, the rate of O(2) release was similar to that of the S(3)Tyr(Z)(.) to S(0)Tyr(Z) transition, with the slowest kinetics (i.e. the Sr/Br enzyme) being approximately 6-7 slower than in the native Ca/Cl enzyme. This slowdown in the kinetics was reflected in a decrease in the free energy level of the S(3) state as manifest by thermoluminescence. These observations indicate that Cl(-) is involved in the water oxidation mechanism. The possibility that Cl(-) is close to the active site is discussed in terms of recent structural models.     

Effect of iodine-131 on the induction of osteosarcoma by strontium-90

The paper submits the results of estimation of the osteosarcomogenic effectiveness of 90Sr in a combination with 131I incorporated prior to or after the administration of 90Sr. It was demonstrated that the incidence of osteosarcomas increased in rats received 131I a weak after the administration of 90Sr.     

Inactivation of calcium channel current in the calf cardiac Purkinje fiber. Evidence for voltage- and calcium-mediated mechanisms

We have studied the influence of divalent cations on Ca channel current in the calf cardiac Purkinje fiber to determine whether this current inactivates by voltage- or Ca-mediated mechanisms, or by a combination of the two. We measured the reversal (or zero current) potential of the current when Ba, Sr, or Ca were the permeant divalent cations and determined that depletion of charge carrier does not account for time-dependent relaxation of Ca channel current in these preparations. Inactivation of Ca channel current persists when Ba or Sr replaces Ca as the permeant divalent cation, but the voltage dependence of the rate of inactivation is markedly changed. This effect cannot be explained by changes in external surface charge. Instead, we interpret the results as evidence that inactivation is both voltage and Ca dependent. Inactivation of Sr or Ba currents reflects a voltage-dependent process. When Ca is the divalent charge carrier, an additional effect is observed: the rate of inactivation is increased as Ca enters during depolarizing pulses, perhaps because of an additional Ca-dependent mechanism.     

The effect of bone marrow depletion on prostaglandin E-producing suppressor macrophages in mouse spleen

The i.p. injection of Corynebacterium parvum (CP) into CBA/J mice effected increases in macrophage colony-forming cells (M-CFC) when spleen cells were cultured with L cell culture filtrate as a source of colony-stimulating factor. Significant increases in phagocytic macrophages (M phi) with Fc receptors for IgG2a and IgG2b immune complexes were additionally noted among the spleen cells in these mice. These M phi effectively inhibited Con A-induced lymphocyte proliferation, probably reflecting a 10-fold increase above normal controls in prostaglandin E to 47 ng/3 X 10(6) spleen cells/ml. To determine whether the suppressor M phi are immediate derivatives of splenic M-CFC, we tried to induce suppressor M phi by the injection of CP into mice depleted of bone marrow M-CFC by the earlier administration of the bone-seeking isotope, 89Sr. This procedure reduced M-CFC in the bone marrow to less than 1% of normal for more than 30 days. Monocytes in the blood fell to 5% of normal by day 10 and were 30% on day 30. Levels of resident peritoneal M phi showed relatively little change in this period. By contrast, splenic M-CFC increased to 20-fold higher than the "cold" 88Sr controls. CP-induced suppressor M phi activity, however, was sharply reduced in 89Sr marrow-depleted mice on day 10, despite the striking increase in M-CFC. There was a threefold increase in the number of phagocytic M phi binding IgG2a immune complexes, with no significant increase in IgG2b binding M phi. The kinetics of recovery of suppressor M phi activity showed that on days 20, 30, and 50 after 89Sr injection the activities reached 20%, 30%, and 70% of the "cold" control, respectively, and correlated with the recovery of significant levels of M-CFC in the bone marrow. Taken together, these observations suggest that splenic M-CFC are not an immediate source of PGE-suppressor M phi in vivo. It appears more likely that the CP-inducible suppressor M phi, in particular, originate from radiosensitive bone marrow cells or require for differentiation a microenvironment provided by bone marrow cells. The data also suggest that the expression of the Fc gamma 2b receptor and of suppressor activity by CP-induced splenic M phi are related phenomena.     

Cytogenetic research on the blood lymphocytes of rats exposed separately and jointly to 45Ca and 131I

A cytogenetic study was made of rat blood lymphocytes affected by incorporated 45Ca and 131I delivered separately and in a combination. The cytogenetic effect of a combination of the incorporated radionuclides was lower than that produced by 45Ca alone and, all the more so, lower than the additive effect of 45Ca and 131I.     

Structural and metabolic analysis of the reaction of the central nervous system to the combined action of microwave and ionizing radiations

Structural and functional changes in the central nervous system were shown to be the same with both microwave and ionizing radiation having different mechanism of action. When the two types of radiation were delivered in a combination the sequence of delivery was of a significant importance. Antagonism of the effects was noted when microwave radiation was delivered prior to gamma-radiation. The effect was synergistic when the exposure to microwaves followed gamma-irradiation.