Nonlinearity in biology, toxicology, medicine最新文献

The aim of the present study was to compare genotoxicity induced by high- versus very low dose-rate exposure of mice to gamma-radiation within a dose range of 5 to 61 cGy using the single-cell gel electrophoresis (comet) assay and the micronucleus test. CBA/lac male mice were irradiated at a dose rate of 28.2 Gy/h (high dose rate) or 0.07 mGy/h (very low dose rate). The comet assay study on spleen lymphocytes showed that very low dose-rate irradiation resulted in a statistically significant increase in nucleoid relaxation (DNA breaks), starting from a dose of 20 cGy. Further prolongation of exposure time and, hence, increase of a total dose did not, however, lead to further increase in the extent of nucleoid relaxation. Doses of 20 and 61 cGy were equal in inducing DNA breaks in mouse spleen lymphocytes as assayed by the comet assay. Of note, the level of DNA damage by 20-61 cGy doses of chronic irradiation (0.07 mGy/h) was similar to that an induced by an acute (28.2 Gy/h) dose of 14 cGy. The bone marrow micronucleus test revealed that an increase in polychromatic erythrocytes with micronuclei over a background level was induced by very low-level gamma-irradiation with a dose of 61 cGy only, with the extent of the cytogenetic effect being similar to that of 10 cGy high-dose-rate exposure. In summary, presented results support the hypothesis of the nonlinear threshold nature of mutagenic action of chronic low dose-rate irradiation.

Humic substances (HSs) are products of biochemical transformations of plant and animal residues that make up a major fraction of the organic carbon of soil and aquatic systems in the environment. Because radioisotopes occur in the Earth's crust and because the entire biosphere is continuously exposed to cosmic radiation, ionizing radiation continually interacts with HSs. This chronic irradiation could have a significant ecological impact. However, very few publications are available that address possible consequences of chronic exposure of HSs to ionizing radiation from terrestrial and cosmic sources. This study was conducted to investigate possible impacts of exposure of HSs to ionizing radiation.Dried humic acid (HA) or its associated aqueous solution (in 0.1 M Na(2)CO(3)) were exposed to absorbed gamma-radiation in high doses of 1-90 kGy using a (60)Co source. Following the gamma-ray exposures, a secondary, ultraweak radiation emanation with wavelengths in the spectral range lambda= 340-650 nm was recorded as a long-lived chemiluminescence (CL) from the aqueous solutions; however, the CL was not observed after irradiating dry HA.Absorption spectra (for lambda=240-800 nm) of irradiated solutions indicated that polymerization/degradation processes were operating on the HA macromolecules. The effect of specific CL enhancers (luminol and lucigenin) on the intensity and kinetics of the CL implicated the participation of reactive oxygen species and free radicals in the CL and polymerization/degradation processes. For the range of absorbed doses used (1-10 kGy), the intensity of the induced CL was nonlinearly related to dose, suggesting that complex radical formation mechanisms were involved.

The percentage of cells with chromosome aberrations or micronuclei induced by low doses of acute (dose rate of 47 cGy/min) or chronic (dose rate of 0.01 cGy/min) gamma-irradiation was studied in vitro in Chinese hamster fibroblasts, human lymphocytes, and Vicia faba seeds and seedlings. The sensitivity of the indicated biological entities to low doses was greater than expected based on linear extrapolation from higher doses. The dose-response curves for cytogenetic damage that were obtained were nonlinear when evaluated over the full range of the doses used. At very low doses, the dose-response curves appeared linear, followed by a plateau region at intermediate doses. At high doses the dose response curves again appeared linear with a slope different from that for the low-dose region. There was no statistically significant difference between the yields of cells with micronuclei induced by low doses of acute versus chronic irradiation. Similar data were obtained both for human lymphocyte culture and for roots and seeds of Vicia faba. Our experiments revealed that the dose range over which the plateau occurs depends on the type of cells irradiated. We have also shown that the modifying effects of the repair inhibitor caffeine and the radioprotector mercaptoethylenamine (MEA) are absent at low doses of gamma irradiation and that caffeine increased the number of cells with cytogenetic damage when evaluated over the plateau region. In the presence of MEA, the upper end of the plateau region was extended from just above 1 Gy to about 2 Gy. We therefore provide direct evidence that a plateau exists in the dose-response curve for the indicated radiation-induced stochastic effects. Furthermore, our results suggest that, for low linear energy transfer radiation, the induction of DNA repair occurs only after a threshold level of cytogenetic damage and that the higher yield of cytogenetic damage per unit dose at low radiation doses is attributable to an insignificant contribution or the absence of DNA repair processes.

Cellular activities are regulated by intracellular signals initiated by stimulation from the external and internal environments. Different signal pathways are involved in the initiation of different cellular functions. In connection with cell proliferation in response to mitogenic stimulation, the dose-effect relationship of the magnitude of (3)H-TdR incorporation into lymphocytes after exposure to different concentrations of concanavalin A (Con A) showed an inverted U-shaped curve in the concentration range 2-30 mug/ml. In previous studies it has been observed that the stimulatory effect of Con A (5 mug/ml) on lymphocyte proliferation was potentiated by whole-body irradiation (WBI) with low dose (0.075 Gy) and suppressed by WBI with high dose (2 Gy). When different concentrations of corticosterone, ranging from 10(-12) to 10(-7) M, were added to the Con A-stimulated lymphocytes, low-concentration stimulation and high-concentration suppression of lymphocyte proliferation were demonstrated. In the presence of 5 x10 (-12) M (subphysiological concentration) of corticosterone the proliferation of thymocytes and splenic T cells in response to Con A was further up-regulated after low-dose radiation. Low-dose radiation (0.075 Gy) caused lowering of serum ACTH and corticosterone concentration as well as down-regulated transcription of the hypothalamic proopiomelanocortin gene. The present paper intends to show that multiple neurohormonal factors, including the pineal gland and neurotransmitters, in addition to the hypothalamic-pituitary-adrenocortical axis, are involved in the stimulation of immune responses induced by low-dose ionizing radiation. The complex nature of the interrelationship between the intracellular signaling of lymphocytes and the neuroendocrine regulation after WBI is discussed.

The bystander effect refers to the biological response of a cell resulting from an event in an adjacent or nearby cell. Such effects depend on intercellular communication and amplify the consequences of the original event. These responses are of particular interest in the assessment of ionizing radiation risk because at public or occupational exposure levels not every cell receives a radiation track. Current radiation protection regulations and practices are based on the assumption of a linear increase in risk with dose, including low doses where not all cells are hit. Mechanisms that amplify biological effects are inconsistent with these assumptions. Evidence suggests that there are two different bystander effects in mammalian cells. In one type, a radiation track in one cell leads to damaging, mutagenic, and sometimes lethal events in adjacent, unhit cells. In the other type, a radiation track in one cell leads to an adaptive response in bystander cells, increasing resistance to spontaneous or radiation-induced events. This paper describes some of the data for radiation-induced bystander effects in vitro and correlates that data with in vitro and in vivo observations of risk at low doses. The data suggest that protective effects, including beneficial bystander effects, outweigh detrimental effects at doses below about 100 mGy, but that the reverse is true above this threshold.

Asbestos is a group of naturally occurring mineral fibers which are associated in occupational settings with increased risks of malignant mesothelioma (MM), lung cancers, and pulmonary fibrosis (asbestosis). The six recognized types of asbestos fibers (chrysotile, crocidolite, amosite, tremolite, anthophyllite, and actinolite) are different chemically and physically and may have different dose-response relationships in the development of various asbestos-associated diseases. For example, epidemiologic and lung fiber content studies suggest that the pathogenic potential and durability of crocidolite is much greater than chrysotile asbestos in the causation of human MM. We have used isolated mesothelial cells, the target cells of MM, as well as epithelial cells of the lung, the target cells of lung cancers, in vitro to elucidate the dose-response relationships in expression of early response protooncogenes and other genes critical to cell proliferation and malignant transformation in cells exposed to crocidolite and chrysotile asbestos, as well as a number of nonpathogenic fibers and particles. These studies reveal distinct dose-response patterns with different types of asbestos, suggesting a threshold for effects of chrysotile both in in vitro studies and inhalation experiments. The different patterns of gene expression have been confirmed in lungs of rats exposed by inhalation to these types of asbestos. Experiments also suggest no observed adverse effect levels after evaluation of lung injury, inflammation, and fibrosis at lower concentrations of both types of asbestos.

In a series of experimental studies we have shown that repetitive mild heat stress has anti-aging hormetic effects on growth and various other cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. We have reported the hormetic effects of repeated challenge at the levels of maintenance of stress protein profile; reduction in the accumulation of oxidatively and glycoxidatively damaged proteins; stimulation of the proteasomal activities for the degradation of abnormal proteins; improved cellular resistance to ethanol, hydrogenperoxide, and ultraviolet-B rays; and enhanced levels of various antioxidant enzymes. We are now undertaking a detailed analysis of the signal transduction pathways to determine alterations in the phosphorylation and dephosphorylation states of extracellular signal-related kinase, c-Jun terminal kinase and p38 MAP-kinases as a measure of cellular responsiveness to mild and severe heat stress. Furthermore, we are also undertaking comparative studies using non-aging immortal cell lines, such as SV40-transformed human fibroblasts, spontaneous osteosarcoma cells, and telomerase-immortalized human bone marrow cells for establishing differences in normal and cancerous cells with respect to their responsiveness to mild and severe stresses.

Changes in the activity of horseradish peroxidase resulting from an addition of ethanol water dilutions of 19 phenolic compounds were observed. For each compound, the enzyme activity was plotted against the degree of dilution expressed as n = -log(100) (mol/L) in the range 0 /= 20. All the curves showed sinusoidal activity, more or less regular, with two to four peaks on average. Each analyzed compound had a characteristic sinusoidal shape, which was constant for samples of peroxidase from various commercial firms. This was clearly visible after function fitting to experimental results based on the Marquadt-Levenberg algorithm using the least-squares method. Among the 19 phenolics, the highest amplitudes were observed for phenol and iso- and vanillate acids and aldehydes. The specific character of each of the analyzed curves offers a possibility of choosing proper dilutions of phenolic compound for activating or inhibiting of peroxidase activity.

Diseases and conditions involving the deposition of excessive amounts of collagen include scleroderma, fibrosis, and scar and surgical adhesion formation. Diseases such as scleroderma may result from acute and chronic inflammation, disturbances in the normal parenchymal area, and activation of fibroblasts. ML-05, a modified form of the hemolytic and cytotoxic bacterial toxin, streptolysin O, is being developed for the treatment of such collagen-related disorders. At sublytic concentrations in vitro, ML-05 was shown to activate CD44 expression. This may modulate production of collagen, hyaluronate, and their associated enzymes to allow a restoration of normal extracellular matrices within tissues. More importantly, ML-05 appeared to decrease skin collagen levels in two in vivo models of collagen disorders, the tight skin mouse (Tsk) model of scleroderma, and the bleomycin-induced mouse skin fibrosis model. In the Tsk model, levels of hydroxyproline (a measure of total collagen) decreased by 25% in the Tsk+ML-05 treatment group relative to the Tsk+saline control group over a 3-month period. In the bleomycin-induced skin fibrosis study, hydroxyproline levels decreased from 15-22% over a 6-week period in a bleomycin-induced ML-05 treatment group (relative to levels in a bleomycin-induced, untreated control group). Hydroxyproline levels in samples from this treatment group were only slightly greater than levels in an uninduced control group at 8 weeks. Thus, ML-05 treatment appeared to reduce collagen levels in two separate mouse skin fibrosis models, one genetically based and the other chemically induced.