Induced Aneugenic Effects in Mouse Oocytes In Vivo.

Aneugenic effects of the chemicals with antitumor activity were studied in mouse oocytes in vivo by cytogenetic analysis. In control mice, no oocytes with numerical chromosome aberrations were found. Colchicine (0.2-4 mg/kg), paclitaxel (2.5-7.5 mg/kg), and etoposide (10-60 mg/kg) produced a significant dose-dependent aneugenic effects (induction of up to 25% aneuploid oocytes) and increased the yield of oocytes arrested in the meiotic MI stage and with premature separation of sister chromatid. Paclitaxel induced up to 20% polyploid chromosomes. Doxorubicin (2.5 mg/kg), melphalan (10 mg/kg), and cisplatin (5-10 mg/kg) exhibited weak aneugenic activity (induction of up to 5% aneuploid oocytes). Cyclophosphamide (10-80 mg/kg) had minor effect on the studied parameters. Methotrexate (25-200 mg/kg) exhibited no aneugenic activity, but significantly increased the level of polyploid cells. The observed aneugenic effects included hypo- and hyperploidy in various proportions or hypoploidy, but no solely hyperhaploidy.

[Preclinical safety investigation of GB-115 dipeptide].

Preclinical safety investigations of newly synthesized dipeptide compound GB-115 (amide N-phenylhexanoyl-glycyl-L-tryptophan), an antagonist of cholecystokinin receptors, were performed. No animals were lost after GB-115 acute oral administration at a maximum dose of 6000 mg/kg in mice and at 3500 mg/kg in rats. GB-115 administered per os during 6 months in rabbits and rats (both males and females) at the doses of 0.1 and 10 mg/kg induced no irreversible pathological changes in organs and systems studied. The tested dipeptide exhibited no allergenic, immunotoxic and mutagenic activity, and did not affect generative function and the antenatal and postnatal development of progeny. GB-115 at a dose of 10 mg/kg produced suppression of the inflammatory reaction to concanavalin A.

Evaluation of genotoxicity and reproductive toxicity of silicon nanocrystals.

Silicon crystal 2-5 nm nanoparticles in the form of 1-5-µ granules in water suspension were injected intraperitoneally in a single dose to male F(1)(CBA×C57Bl/6) mice or to outbred albino rats on days 1, 7, and 14 of gestation. Silicon crystal nanoparticles in doses of 5, 25, and 50 mg/kg exhibited no cytogenetic activity in mouse bone marrow cells after 24-h exposure and in doses of 5 and 25 mg/kg after 7 and 14-day exposure. A 24-h exposure to silicon nanoparticles in a dose of 5 mg/kg significantly increased DNA damage (detected by DNA comet assay) in bone marrow cells. In a dose of 50 mg/kg they considerably increased DNA damage in bone marrow and brain cells after exposure of the same duration. Silicon nanoparticles in doses of 5 and 50 mg/kg caused no genotoxic effects in the same cells after 3-h and in a dose of 5 mg/kg after 7-day exposure. Silicon crystal nanoparticles in a dose of 50 mg/kg caused death of 60-80% mice after exposure <24 h. Injected in a dose of 50 mg/kg on days 1, 7, and 14 of gestation, silicon crystal nanoparticles reduced body weight gain in pregnant rats and newborn rats at different stages of the experiment, but had no effect on other parameters of physical development of rat progeny and caused no teratogenic effects.

[Comutagen interaction of verapamil and ribavirin].

The chromosome aberration assay in the bone marrow cells of C57BL/6 mice was used to study the cytogenetic activity of ribavirin (10, 50, 100, 200, and 400 mg/kg, p.o.) alone and in combinations with verapamil (0.25, 2.5, 5, and 10 mg/kg, p.o.). It was established that ribavirin was cytogenetically active upon single administration in a dose of 200 and 400 mg/kg, and it was also active in a dose of 50 and 100 mg/kg when administered for 5 days in combination with verapamil in a dose of 5 or 10 mg/kg and 2.5, 5, or 10 mg/kg, respectively. These results indicate that verapamil and ribavirin exhibit comutagen action.

[Preclinical study of noopept toxicity]. / Doklinicheskoe izuchenie toksichnisti noopepta.

Within the framework of a preclinical investigation, the new nootrope drug noopept (N-phenyl-acetyl-L-propyl-glycine ethylate) was tested for chronic toxicity upon peroral administration in a dose of 10 or 100 mg/kg over 6 months in both male and female rabbits. The results of observations showed that noopept administered in this dose range induced no irreversible pathologic changes in the organs and systems studied and exhibited no allergenic, immunotoxic, and mutagen activity. The drug affected neither the generative function nor the antenatal or postnatal progeny development. Noopept produced a dose-dependent suppression of inflammation reaction to concanavalin A and stimulated the cellular and humoral immune response in mice.

[Corpuscular mutagenesis and its prevention]. / Korpuskuliarnyi mutagenez i ego profilaktika.

The carcinogenic and mutagenic activity of dust containing chrysotile-asbestos and zeolites, as well as the role of active oxygen species in their cytotoxic and mutagenic actions are discussed. Superoxide dismutase (50 mg/ml) was demonstrated to prevent the mutagenic effects of chrysotile-asbestos and latex, catalase (20 mg/ml) to prevent the same of zeolites in experiments on cultured human whole blood. The intraperitoneal administration of dusts of chrysotile-asbestos and zeolites in a dose of 50 mg/kg to C57B1/6 mice was found to elevate the count of cells with chromosomal aberrations in the peritoneal liquid and bone marrow cells of mice, which was dependent on dust exposure time. It was revealed that ascorbic acid, rutin, chemically modified flavonoid of Scutellaria Baicalensis Georgy, drugs such as bemitil and thomersol in the broad range of concentrations (10(-7)-10(-3) M) decreased or completely reduced the clustogenic action of zeolites and chrysotile-asbestos on cultured human whole blood. The ability of bemitil (1.8-19 mg/kg) rather than the others to prevent the mutagenic effect of chrysotile-asbestos was confirmed by the method of recording chromosomal aberrations in the cells of peritoneal liquid and bone marrow in mice. The findings suggest that the mutagenic effects of the corpuscular xenobiotics under study are mediated by active oxygen species and that the use of the models in vitro and in vivo is adequate for investigations into corpuscular mutagenesis. Based on their own data and literature data, the authors have defined possible lines of further research of corpuscular mutagenesis.

Peculiarities of the clastogenic properties of chrysotile-asbestos fibers and zeolite particles.

It has been established that chrysotile-asbestos fibers and zeolite particles induce chromosome aberrations in human lymphocytes from whole blood cultures, peritoneal fluid cells and bone marrow cells of mice. It is shown that the level of cytogenetic response from the intraperitoneal administration of chrysotile-asbestos fibers and zeolite particles depends on the time of their exposure. Further, it is shown that SOD eliminates the cytogenetic effect of chrysotile-asbestos fibers, while catalase inhibits that of zeolite particles. Recommendations concerning testing for the mutagenic properties of mineral fibers and particles are given, and possible mechanisms of their damaging effects are discussed.

[Remote effects in the mutagenic action of chrysotile asbestos and zeolite dusts in vivo]. / Distantsionnyi éffekt v mutagennom deistvii pylei khrizotil-asbesta i tseolita in vivo.

It was proposed that there are a generalized mutagenic actions of chrysotile-asbestos fibers and zeolite particles in vivo. Chrysotile-asbestos fibers and different species zeolite particles in doses 50 mg/kg, intraperitoneally, increased the levels of damaged chromosomes not only in peritoneal cells, but also in bone marrow of C57BL/6 mice. Cytogenetic effect of chrysotile-asbestos does not depends on the time exposure of animals with mutagenic factor. In four weeks followed after administration chrysotile-asbestos fibers there were revealed 19-22% peritoneal cells with damaged chromosomes and 3.2-4.4% aberrant cells of bone marrow. Cytogenetic effect of zeolite particles was observed on 14-28 days after the administration, with peaks at 35.6% in peritoneal and 3.6-4.2% in bone marrow cells. Our data indicate the mutagenic action is realised as in cells contacted with dusts as in cells of other tissues. Probably, these effects are mediated by products of lipid peroxidation.

Oxygen radical-mediated mutagenic effect of asbestos on human lymphocytes: suppression by oxygen radical scavengers.

The mutagenic effect of chrysotile asbestos fibers and zeolite and latex particles on human lymphocytes in whole blood has been studied. It was concluded that their mutagenic activities were mediated by oxygen radicals because they were inhibited by antioxidant enzymes (SOD and catalase) and oxygen radical scavengers (rutin, ascorbic acid, and bemitil). It was proposed that oxygen radicals were released by phagocytes activated upon exposure to mineral dusts and fibers. The study of lucigenin- and luminol-amplified chemiluminescence of peritoneal macrophages stimulated by chrysotile fibers and zeolite and latex particles has shown that their mutagenic action is probably mediated by different oxygen species, namely, by the iron-oxygen complexes (perferryl ions) plus hydrogen peroxide, hydrogen peroxide, and superoxide ion, respectively. From the oxygen radical scavengers studied, rutin was the most effective inhibitor of the mutagenic effect of mineral fibers and dusts.