Biomedical subjects
Publications and source records attributed to A Basler.
The genotoxicity of 51 epoxides is studied with the SOS-Chromotest using Escherichia coli PQ37 as tester strain. The results obtained with this test system are compared with results of the Ames test. Out of 51 epoxides, 39 are shown to be mutagenic in Salmonella typhimurium whereas only 27 mutagenic epoxides induced the SOS response in Escherichia coli PQ37.
The genotoxicity of 10 epoxides was investigated in the UDS test with primary rat hepatocytes. The sensitivity of the assay was demonstrated using 2-acetylaminofluorence. The epoxides 1,2-epoxyoctane, 1,2-epoxydecane, epoxycyclooctane, epoxycyclododecane, (+)-limoneoxide, alpha-pinaneoxide, transstilbeneoxide, and cis-2,3-epoxysuccinic acid, which are known to be non-mutagenic in the Ames test, as well as the bacterial mutagen, 1,2-epoxyphenoxypropane did not induce UDS in primary hepatocytes of the rat. However, a positive UDS response obtained with glycidyltrimethylammonium chloride showed that metabolic inactivation of the oxirane ring in hepatocytes is influenced by further structural substituents.
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In the present investigation, the SOS chromotest with E. coli PQ37 was evaluated. The potential to identify different kinds of bacterial mutagens was examined. 124 chemicals of different chemical classes were tested. Their responses in the SOS chromotests were compared to reported test results obtained with the Ames test.
8 antioxidants were tested in the SOS chromotest for induction of SOS function and for modulation of benzo[a]pyrene-induced SOS function. None of the antioxidants leads to increased beta-galactosidase activity by itself. Butylated hydroxytoluene at concentrations between 10(-5) M and 3 X 10(-4) M enhances benzo[a]pyrene-induced SOS function at benzo[a]pyrene concentrations between 10(-6) M and 3 X 10(-5) M. Butylated hydroxyanisole, ethoxyquin, propyl gallate and octyl gallate also slightly enhance benzo[a]pyrene-induced SOS function at concentrations up to 3 X 10(-4) M though to a lesser degree than butylated hydroxytoluene. Dodecyl gallate, vitamin C and alpha-tocopherol do not increase benzo[a]pyrene action. In concentrations exceeding 3 X 10(-4) M all synthetic antioxidants tested but not vitamin C and alpha-tocopherol decrease beta-galactosidase activity both in the absence and, more extensively, in the presence of benzo[a]pyrene. Preliminary data suggest that the apparent suppression of benzo[a]pyrene-induced SOS function is not due to an effect on the formation of benzo[a]pyrene metabolites by the metabolizing system used.
Three-carbon chemicals (chlorinated and nonchlorinated, saturated and unsaturated, hydroxy- and oxo-hydrocarbons) were assayed for genotoxicity. The sister chromatid exchange test in vitro served as the test system. Without S9 mix, the nonchlorinated solvents 1-propanol, 2-propanol, and 2-propanone (acetone) did not increase the SCE frequencies. All chlorinated 3-C hydrocarbons, except 1,2,3-trichloropropane, proved to be potent SCE inducers in V79 cells without S9 mix. In the presence of S9 mix, the results obtained with the nonchlorinated solvents were also negative, whereas 1,2,3-trichloropropane was transformed to SCE-inducing metabolites. The addition of S9 mix resulted in an increased SCE rate for 2,3-dichloropropanol, whereas genotoxicity of 2,3-dichloropropene, 1,2-dichloropropane, 1,3-dichloropropene, and 1,3-dichloropropanone was reduced. 1,3-dichloropropanol, 1,3-dichloropropene, and epichlorohydrin were substantially inactivated by S9 mix in the V79/SCE test. It can be concluded that the reactivity of the saturated dichloro compounds in the SCE test depends on the degree of oxidation. There is no general difference between the reactivity of alpha, beta-dichloro and alpha, omega-dichloro compounds.
Genotoxic properties of the food additive propionic acid were analysed using the Escherichia coli DNA repair assay, the SOS chromotest, the Salmonella/microsome mutagenicity test, the sister chromatid exchange test in vitro and the micronucleus test in vivo. All tests except the DNA repair assay with E. coli yielded negative results. These data support other evidence that propionic acid is not mutagenic and that genotoxic events are unlikely to be the cause of forestomach lesions in rats fed propionic acid in the diet (Griem, Bundesgesundheitsblatt 1985, 28, 322).
The androgen trenbolone, and the mycoestrogen zeranol, both anabolic drugs, were tested for their genotoxic potential. Test systems were the SOS-chromotest, the rec-assay and the V79 sister chromatid exchange test without and with metabolic activation using rat liver homogenates and primary rat hepatocytes. It is still a matter of debate if trenbolone has carcinogenic properties, because of its cell transforming activity in vitro. Trenbolone, however, did not demonstrate any genotoxic effect in the assays performed. The results obtained for zeranol were also negative in the SOS-chromotest and V79 sister chromatid exchange test but positive in the rec-assay.
Chinese hamsters were exposed to acetone, methyl ethyl ketone, ethyl acetate and 2-methoxy ethyl acetate, known to be strong inducers of aneuploidy in the yeast Saccharomyces cerevisiae. All solvents yielded negative results in the micronucleus test, whereas the vinca alkaloid vindesine--used as a positive control substance--proved to act as a spindle poison in mammals in vivo.
The restriction endonuclease Alu I induces chromosomal aberrations and mutations in the hypoxanthine phosphoribosyltransferase (HPRT) locus as measured by 6-thioguanine resistance (TGr) in V79 hamster cells. Alu I does not induce mutations in the Na+/K+ ATPase locus as measured by ouabain resistance (OUAr). The data are interpreted to mean that most if not all Alu I-induced TGr mutations represent chromosomal aberrations.
Formaldehyde-induced sister chromatid exchanges (SCE) in vitro and the influence of the exogenous metabolizing systems, S9 mix and primary rat hepatocytes, were studied. The SCE-frequency in V79 cells was dose dependent. A three- to four-fold increase at non-toxic doses was observed. However, in the presence of an exogenous metabolizing system, the number of formaldehyde-induced SCE decreased. S9 mix as well as hepatocytes reduced the SCE frequency to nearly that of the control range. It could be demonstrated that the reduction was not due to an unspecific binding of formaldehyde to macromolecules of the added S9 mix. The decrease in genotoxic effects, due to rapid metabolisation of formaldehyde in vitro and in vivo, explains the differences between results obtained in the in vitro experiments--performed without metabolizing systems--and in vivo results.
Rats were treated intraperitoneally (ip) with 13.3 mg cyclophosphamide (CP)/kg. Blood was obtained by cardiac puncture 6,24,48,72 hr, 5 da and after treatment. The spontaneous sister chromatid exchange (SCE) frequency (9.94 SCEs/cell) was 4-fold increased (40.49 SCE/cell) in lymphocyte cultures set up 24 hr, after the CP treatment. Within the next 24 hr the SCE frequency began to decline and by 2 wk post-treatment the SCE values were within the control range. The results indicate that the elimination of damage to DNA by existing repair mechanisms is responsible for the reduction of SCEs with time, in addition to lymphocyte turnover.
The effect of ethylnitrosourea (ENU) on chromosomes of mouse bone marrow cells and transplacentally exposed embryonic liver cells was investigated. Chromosome aberrations were found to be dose- and time-dependent. The maximum damage was seen 6 h after the exposure. Chromosome aberrations were also induced in bone marrow cells and lymphocytes of marmosets (Callithrix jacchus) directly exposed to ENU. Aberrations did not, however, occur in offspring whose mothers were treated with ENU before conception. Furthermore, chronic transplacentally exposed offspring have been analyzed. The frequency of chromosome aberrations was not increased in their lymphocytes and fibroblasts. The elimination of chromosome aberrations during embryogenesis is discussed.
A lymphocyte culture system was used to study cytogenetic effects in rats after they had been exposed to genotoxic agents in vivo. The sensitivity of the test system was demonstrated by using cyclophosphamide. The SCE frequencies in lymphocytes of cyclophosphamide-treated rats (13.3 mg/kg; i.p.) was increased about 4-fold compared with those in lymphocytes from untreated rats. Female rats of the strain Wistar II were exposed to cigarette smoke from 30 cigarettes per day in an inhalation chamber. Lymphocyte cultures were performed after an acute exposure and after treatment for 4 weeks. After both treatments, the investigations of chromosomes with regard to SCEs did not reveal any effect.
The oral hypoglycaemic drug 1-(p-chloroben-zenesulfonyl)-3-propylurea (chlorpropamide) was examined for clastogenic properties using human lymphocytes with a microsomal (S9 mix) activation system. Lymphocytes, exposed to the S9 mix only as well as to the solvent DMSO, yielded chromosome aberration levels within the background range. The sensitivity of the S9 mix could be demonstrated using 2-[bis(2-chloroethyl)amino]tetrahydro(2H)-1,3,2-oxazaphosphorine 2-oxide (cyclophosphamide) as a positive control, which only displays clastogenic properties after metabolic activation. Chlorpropamide, however, did not induce structural chromosome aberrations under the in vivo conditions tested in this study.
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Rodents were exposed in vivo to various clinical doses of halothane to observe structural chromosome aberrations, micronuclei, sister chromatid exchanges (SCEs), dominant lethal mutations, and interferences with phases of the cell cycle. The frequency of chromosome aberrations in bone marrow cells was not increased after exposing Chinese hamsters to 1 per cent halothane once for 3 h, twice for 3 h (exposures 24 h apart), or to 0.5 per cent for 24 h. The analysis of SCEs in bone marrow cells was also negative after exposing hamsters to 1 per cent halothane for 3 h, or to 0.5 per cent for 12 h. In halothane-exposed female mice (0.75 per cent for 16 h), oocyte maturation (meiotic stages) was delayed. Another group of exposed female mice (1 per cent for 5 h) were mated with untreated males. The number of dead implants was not increased as compared to controls. In liver cells of 16-day-old living embryos, neither monosomic nor trisomic cells were observed. Male mice were exposed to 1 per cent halothane for 1 h per day for 48 days. On the evening of the forty-eighth day, they were mated with untreated females. Dominant lethal mutations were not increased as compared to controls. In erythrocytes of these chronically exposed male mice, the frequency of micronuclei was not significantly enhanced. The authors conclude that halothane does not induce mutations under the in vivo conditions tested in this study.
5 mg cyclophosphamide, injected intraperitoneally to pregnant hamsters, increased the rate of sister chromatid exchanges (SCEs) in embryonic liver cells from 4.1 to 8.8 SCEs per cell. 20 mg methyl metanesulfonate induced 11.8 SCEs per embryonic cell.