P.G.N. Kramers

Mutagenicity of hycanthone in Drosophila melanogaster.

Abstract The schistosomicidal agent hycanthone was tested for mutagenicity in Drosophila melanogaster . The compound was administered either by injection into adult males or by larval feeding. The following types of genetic damage were measured: (1) complete and mosaic sex-linked recessive lethal mutations; (2) II–III translocations; and (3) dominant lethals. In postmeiotic germ cells, especially in late spermatids, a pronounced increase was found in the frequency of sex-linked recessive lethals, both completes and mosaics. By contrast, translocations and dominant lethals were not induced.

Mutagenecity tests with captan and folpet in Drosophila melanogaster

Abstract Captan (N-(trichloromethylthio)-3a,4,7,7a-tetrahydrophthalimide) and folpet (N-(trichloromethylthio)-phthalimide), two closely related fungicides, were tester for mutagenicity in Drosophila melanogaster. The compounds were administered either by injection into adult males or by feeding to larvae. The following types of genetic damage were measured: (1) complete and mosaic sex-linked recessive lethal mutations, (2) II–III translocations, and (3) dominant lethals. In some of the sex-linked lethal tests a slight increase in mutation rate was obtained, but this could not be confirmed in replicate experiments. It is concluded that in the system used the mutagenicity of captan and folpet could not be demonstrated, although a very weak effect cannot be excluded.

Studies on the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by nitroheterocyclic compounds

24 nitroheterocyclic compounds were investigated for their capacity to induce sex-linked recessive lethals in Drosophila, by the adult feeding technique, and in some cases injection or larval-feeding methods. Out of 9 5-nitroimidazoles, ZK 26.173 and ZK 25.095 (moxnidazole) were clearly active whereas nimorazole and ronidazole were marginally mutagenic. Out of 10 5-nitrofurans, nitrovin, furazolidone and furaltadone were unambiguously mutagenic, whereas nitrofurantoin was a borderline case. Nitrofurans were active at lower molar concentrations than nitroimidazoles. Out of a group of 5 related nitro compounds (2 nitrothiophenes, picrolonic acid, niridazole and 4-NQO), only 4-NQO was clearly mutagenic, when fed to larvae. Experiments with germ-free flies showed that, for ZK 26.173 and furazolidone, the gut flora of Drosophila do not play a role in the activation of the compounds to mutagenic metabolites. Furazolidone, 4-NAO, ZK 26.173, ZK 25.095 and furaltadone were tested in mal and cin strains, both of which lack xanthine dehydrogenase and aldehyde oxidase. The latter enzyme and xanthine oxidase are known to carry out nitro reduction in mammalian tissues. For ZK 26.173, the mutation frequencies were drastically reduced in the enzyme-deficient strains, indicating the involvement of one of these enzymes in the activation of this substance.

Mutagenicity of saccharin in drosophila: The possible role of contaminants

Abstract Drosophila tests for sex-linked recessive lethal mutations were carried out with two samples of saccharin, and two commonly occurring impurities of saccharin: ortho-toluene-sulfonamide and para-toluene-sulfonamide. A weak but rather consistent effect was detected with one of the saccharin samples, whereas the other substances were negative. The results suggest that the mutagenicity of saccharin as detected in Drosophila may be due to a contaminant other than ortho-toluene-sulfonamide or para-toluene-sulfonamide.

High proportion of multi-locus deletions among hycanthone-induced X-linked recessive lethals in Drosophila melanogaster.

328 X-linked recessive lethal mutations induced in late spermatids by hycanthone methanesulfonate were tested for coverage by duplications that comprised, in total, about 24% of the euchromatic X chromosome; 78 lethals appeared to be covered. Crossover localization tests of a random sample of 38 non-covered lethals revealed 4 chromosomes carrying a lethal within a duplicated segment. Lethals localized to a particular region were crossed to reference deficiencies and single-locus mutations, and inter se, to ascertain their genetic extent. The proportion of multi-locus deletions among these 78 covered and 4 non-covered lethals was 3/48, 1/10 and 13/24 for the distal, medial and proximal regions, respectively. A storage period of 9 days did not noticeably influence these proportions. In the sample of 38 non-covered lethals, and among 17 of the covered single-site lethals, 4 cases of strong crossover suppression were detected. Comparison of these results with data obtained with other mutagens suggests that induction of multi-locus deletions, and possibly of other types of chromosome rearrangement, could in part depend on other mechanisms than those acting in the formation of translocations and chromosome loss. For the purpose of mutagen testing, these findings imply that, in Drosophila, results in the regular genetic tests for chromosome breakage events do not always accurately predict the capacity of a mutagen to induce multi-locus deletions. This is of importance since transmissible multi-locus deletions have been considered a significant source of genetic damage in man.

Comparison of the mutagenic potency of 2-chloroethanol, 2-bromoethanol, 1,2-epoxybutane, epichlorohydrin and glycidaldehyde in Klebsiella pneumoniae, Drosophila melanogaster and L5178Y mouse lymphoma cells

A series of 2 haloethanols and 3 epoxides was investigated in 3 mutagenicity test systems, namely (1) the fluctuation test in Klebsiella pneumoniae, (2) the sex-linked recessive lethal test in Drosophila melanogaster, and (3) the HGPRT test with L5178Y mouse lymphoma cells. The order of mutagenic potency was, in Klebsiella: glycidaldehyde greater than 2-bromoethanol = epichlorohydrin greater than 1,2-epoxybutane greater than 2-chloroethanol; in Drosophila: glycidaldehyde = epichlorohydrin greater than 1,2-epoxybutane; in mouse lymphoma cells: epichlorohydrin greater than 1,2-epoxybutane. The haloethanols were non-mutagenic in Drosophila. 2-Chloroethanol and glycidaldehyde were negative in mouse lymphoma cells. The high mutagenic potency of epichlorohydrin as compared with 1,2-epoxybutane was consistent in all systems, and with published data.

Mechanism of hycanthone mutagenesis: The induction of temperature-sensitive mutations in Drosophila melanogaster

A total of 358 sex-linked recessive lethals induced by hycanthone methane sulphonate (HMS) were checked for temperature sensitivity, along with 239 EMS-induced lethals as a positive control. Only about 1-2% of the HMS-induced lethals were temperature-sensitive, in contrast to about 7-8% for EMS-induced lethals. This can be reasonably explained by assuming that in Drosophila, HMS mainly acts by inducing frame-shift mutations or deletions.

Low mutagenic activity of four hycanthone analogues in Drosophila melanogaster

Four structural analogues of the antischistosomal drug hycanthone, indicated as IA-3, IA-4, IA-5, and IA-6, were tested for their ability to induce sex-linked recessive lethal mutations in Drosophila melanogaster. The compounds were administered to adult male flies, by abdominal injection or by feeding. Although in some cases a slight enhancement of the mutation frequency was observed, the analogues tested are considerably less mutagenic in this system than hycanthone itself, the concentrations applied being approximately of equal molarity.

Absence of mutagenic effects of morphine in drosophila

Morphine hydrochloride was tested for its ability to induce sex-linked recessive lethal mutations, II--III translocations or dominant lethal mutations, in Drosophila melanogaster. The results provide no evidence for the induction of any of these types of genetic damage in this system