Cellular signal adaptation with damage control at low doses versus the predominance of DNA damage at high doses.

Ionizing radiation is known to potentially interfere with cellular functions at all levels of cell organization and induces DNA lesions apparently with an incidence linearly related to D, also at low doses. On the other hand, low doses have also been observed to initiate a slowly appearing temporary protection against causation and accumulation of DNA lesions, involving the radical detoxification system, DNA repair and removal of DNA damage. This protection apparently does not operate at high doses; it has been described to be nonlinear, increasing initially with D, beginning to decrease when D exceeds approximately 0.1-0.2 Gy, and eventually disappearing at higher D. The various adaptive responses have been shown to last individually from hours to weeks in different cell types and resemble responses to oxidative stress. Damage to DNA is continuously and endogenously produced mainly by reactive oxygen species (ROS) generated in a normal oxidative metabolism. This endogenous DNA damage quantitatively exceeds DNA damage from low-dose irradiation, by several orders of magnitude. Thus, the protective responses following acute low-dose irradiation may be presumed to mainly counteract the endogenous DNA damage. Accordingly, the model described here uses two dose-effect functions, a linear one for causing and a nonlinear one for protecting against DNA damage from whatever cause in the irradiated cells and tissues. The resulting net dose-risk function strongly suggests that the incidence of cancer versus dose in the irradiated tissues is much less likely to be linear than to exhibit a threshold. The observed cancer incidence may even fall below the spontaneous incidence, when D to cells is below approximately 0.2 Gy. However incomplete, these data support a reexamination of the LNT hypothesis.

Lipid peroxidation in microsomes of murine bone marrow after low-dose gamma-irradiation.

The principal aim of the study was to investigate the effect of low-dose gamma-irradiation on lipid peroxidation (LPO) in murine bone marrow. To this end, the degree of LPO in suspensions of microsomes of murine bone marrow cells (BMC) was determined in terms of malondialdehyde (MDA) formation after whole-body or in vitro exposure to various doses of gamma-radiation. These effects were compared to some extent with similar effects in liver and spleen preparations. As to the effect of gamma-irradiation on LPO in BMC, the response depends on the dose level and on whether whole-body or in vitro exposures are involved. Whole-body irradiation did not result in an increase in LPO in BMC microsomes, even at such high doses as 15 Gy, although hepatic microsomes showed a marked increase. In contrast, in vitro irradiation of BMC microsomes with 0.1, 10 and 50 Gy brought about an increase in LPO. This increase was already significant (P < 0.05) at 0.1 Gy following a post-irradiation incubation and substantial at 50 Gy, even without subsequent incubation. The results show that low doses of gamma-irradiation are able to induce an elevation of LPO in murine BMC microsomes, but only after in vitro irradiation. In the case of whole-body irradiation cellular radical scavengers and other metabolic reactions may prevent a measurable increase in LPO. This is partly illustrated by the case of vitamin-E deficiency, where a substantial increase in LPO in BMC microsomes is observed even without gamma-irradiation in comparison with euvitaminotic mice because normally occurring radicals are not scavenged sufficiently.

Rubidium transport in irradiated vitamin-E-deficient bone marrow cells.

We showed previously that the Rb+ transport rate in bone marrow cells (BMC) of vitamin-E-deficient mice is significantly lower than that in BMC of euvitaminotic mice. It is now evident that 4 h after whole-body, low-dose (0.01-1.0 Gy) gamma-irradiation of avitaminotic mice, there is an increase in the rate of Rb+ transport. This increase is quite pronounced, exceeding at all dose levels the rate of Rb+ transport in euvitaminotic mice exposed to the same radiation dose.

Influence of a stationary magnetic field on acetylcholinesterase in murine bone marrow cells.

A thirty-minute exposure of mice to a homogeneous stationary magnetic field (SMF) of 1.4 Tesla at either 27 degrees C or 37 degrees C body temperature causes an inhibition of about 20 per cent of acetylcholinesterase (AChE, E.C. 3.11.7) in murine bone marrow cells (BMC) after 3.5 and 2 h, respectively, at the two aforementioned body temperatures. The extent of enzyme inhibition is independent of ambient temperature, but dependent on the time after exposure. This initial inhibition of AChE activity is followed by a limited recovery which is dependent upon the temperature during exposure to the SMF and remains incomplete even 15 h afterwards. We describe here certain enzymologic properties of AChE in BMC as well as inhibition studies with diisopropylfluorophosphate (DFP) to differentiate between AChE and nonspecific cholinesterases.

Modification of effects of radiation on thymidine kinase.

Thymidine kinase (TdR-K) and the incorporation of iododeoxyuridine (IUdR) into DNA of murine bone marrow cells are acutely and temporarily inhibited by low doses (0.01 Gy) of whole-body gamma-radiation with a maximal effect at 4 h after exposure and full recovery at 10 h. The inhibitory effect was totally abolished by whole-body exposure to a strong static magnetic field of 1.4T. The present investigation was designed to gain insight into the mechanism(s) underlying the inhibition of TdR-K activity and the incorporation of 125I-UdR by challenging the system with various pharmacological and biochemical means. To this end the response of TdR-K and 125I-UdR incorporation into DNA to the administration of actinomycin-D, cycloheximide, cysteamine, misonidazole and procaine hydrochloride as well as to dietary manipulations, i.e. vitamin E deficiency and enrichment of the diet by soya oil, and to changes in the glutathione levels were investigated in bone marrow cells of irradiated and sham-irradiated mice. Furthermore, the effect of various NaHCO3 concentrations on optimizing the radiation-induced inhibition of TdR-K was investigated under conditions of radiation, vitamin E deficiency and enrichment of the diet by soya oil. The data point to the involvement of the cellular radical-detoxification system in changing the activity of TdR-K, especially on the basis of the concurrent increase of glutathione concentration and decrease in TdR-K activity.

Radiation-induced increase in the release of amino acids by isolated, perfused skeletal muscle.

Local exposure of the hindquarter of the rat to 15 Gy of gamma-radiation resulted, 4-6 h after irradiation, in an increased release of amino acids by the isolated, perfused hindquarter preparation, 70 per cent of which is skeletal muscle. This increase in release involves not only alanine and glutamine which are synthesized to a large extent de novo in muscle, but also those amino acids which are not metabolized by muscle and, therefore, released in proportion to their occurrence in muscle proteins. Because metabolic parameters and content of energy-rich phosphate compounds in muscle remain unchanged, it is unlikely that general cellular damage is the underlying cause of the radiation-induced increase in amino acid release. The findings strongly favour the hypothesis that the increased availability of amino acids results from enhanced protein breakdown in skeletal muscle which has its onset shortly after irradiation. This radiation-induced disturbance in protein metabolism might be one of the pathogenetic factors in the aetiology of radiation myopathy.

Effect of insulin on phosphorus metabolism in red blood cells from patients with schizophrenia and psychotic depressions.

In an exploratory study of the metabolism of selected intermediates of glycolysis in rbc of patients with schizophrenia and with major depressive disorders, statistically significant decreases in the RSA of 2,3-DPG were found in the rbc of patients with psychotic disorders compared to normal subjects. No statistically significant differences were observed in the RSA of any of the other glycolytic intermediates studied comparing patients to normal subjects.

Increased catabolism of muscle proteins as a manifestation of radiation myopathy.

Exposure of the hindquarter of the rat to 1000 rad of gamma-radiation caused a significant increase in the release of glutamine and alanine into the perfusion fluid at 4 h post-irradiation. The extent of the release of glutamine exceeded that of alanine. Furthermore, the exposure to gamma-radiation brought about a significant lowering of the intra-/extracellular concentration gradient with respect to glutamine and alanine.