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1.
Groups of male Alderly Park mice of proven fertility were dosed by gavage for 5 consecutive days per week for 8 weeks or 5 consecutive days only with 100 or 150 mg/kg bodyweight ethyl methanesulphonate (EMS) or by intraperitoneal injection once a week for 8 weeks or once only with 500 mg/kg shikimic acid. Animals dosed in this manner were compared in the dominant lethal and heritable translocation assays. Animals were mated for 2 consecutive weeks following the 8-weak treatment and for 8 consecutive weeks after the 1-week treatment: regimes which were thus non-specific and specific respectively for the stages of spermatogenesis. An additional method of measuring dominant lethality involving counting uterine scars after weaning (Soares (1972) Mutation Res., 16, 425–427) was used and also compared with the conventional method.EMS was clearly confirmed as a mutagen but this was not the case for shikimic acid. For screening purposes the dominant lethal 8-week mating assay was much more efficient in return for the same effort for detecting mutagenic responses than an 8-week mating heritable translocation assay, since the induction of dominant lethal effects paralleled the induction of heritable translocations. 8-week treatment with EMS showed increased dominant lethality but severely reduced fertility and the small numbers of male offspring born made potential heritable effects difficult to assess. The 1-week treatment with EMS produced both dominant lethal and heritable effects. Soares' method can be useful for determining determinant lethal effects in a heritable translocation assay. The “sieving” method of mating to determine partial and total sterility questions the necessity for a negative control in a heritable translocation study. 相似文献
2.
For studying, in vivo, chromosomal damage in bone-marrow cells of CD mice the following compounds were used: Trenimon®; Endoxanm® (cyclophosphamide); triethylenemelamine (TEM); methyl methanesulfonate (MMS); ethyl methanesulfonate (EMS); mitomycin C; colchicine; N-methyl- N′-nitro- N-nitrosoguanidine (MNNG) and caffeine. In a first set of experiments the compounds were given twice intraperitoneally with an interval of 24 h. In a second set, effects on bone marrow were studied after 2 i.v. or p.o. administrations of TEM or EMS. All compounds except MNNG and caffeine produced bone-marrow depression and micronuclei, depending on the dose. For the active compounds an interesting difference was revealed by a comparison of the lowest effective dose (as measured by micronuclei formation) with the lethal dose. Trenimon, TEM, cyclophosphamide and MMS (some of which are used in human chemotherapy in similar mg/kg doses) were active on mouse bone-marrow at very low doses compared with their lethal doses. On the other hand, colchicine, mitomycin C and EMS exhibited an effect only at doses very close to, or within, the toxic range. Different routes of administration of either TEM or EMS produced similar effects.The results indicate that the test is especially suitable for initial large-scale screening of suspected chromosomal mutagens and spindle poisons. In addition, the use of the relationship between doses required to induce micronuclei and lethal doses in mice provides a practical measure of the relative potencies of such compounds. 相似文献
3.
Three different routes of administration of ethyl methanesulphonate (EMS) (i.p., oral, i.t.) were compared for their relative efficiencies in the induction of dominant lethal effects. Included in the comparisons between oral and i.p. injections, was a preliminary study into the existence of strain differences in sensitivity to EMS between C3D2 F1 hybrid mice and strain DBA/2J mice. No route of administration dependent effects were found between oral and i.p. injections regardless of the test animal used. I.t. injections of EMS did not induce dominant lethal effects. One treatment related strain difference was observed. 相似文献
4.
Pre-ovulatory oocytes are especially sensitive to mutagenic influences. Since post-dictyotene oocytes are not subject to selection and elimination before fertilization, they may reveal mutagenic effects directly and unrestrictedly. Presuming that a chemical is administered at pro-estrus to female mice one can conclude that the substance or its active metabolite has the chance to reach the gamete during the sensitive pre-fertilization stages. We proved the usefulness of the test system by investigating the effects of alkylating agents. A second step was to investigate other substances. The following treatments induced dominant lethal effects: methyl methanesulfonate 100 mg/kg i.m., cyclophosphamide 200 mg/kg per os, triaziquone 0.25 mg/kg i.p. In contrast, the following agents were ineffective and can be classified as not mutagenic in this method: sodium cyclamate 10 000 mg/kg per os, saccharine sodium, 10 000 mg/kg per os, cyclohexamine sulfate 150 mg/kg per os, ethanol 5 ml/kg per os. 相似文献
5.
An ethyl methanesulfonate (EMS) induced dominant lethal dose response experiment was conducted in strain DBA/1J male mice. Two methods of scoring for dominant lethals, the classic method (dissecting females at mid-pregnancy) and an alternative method (inspection of uterine scars after litters were weaned) were compared. Results indicate that strain DBA/1J has a similar sensitivity to EMS-induced dominant lethals as has been previously reported for other mouse genotypes. Of the two methods used to score dominant lethals, the classic method is more sensitive. 相似文献
6.
An ethyl methanesulfonate (EMS) induced dominant lethal dose response experiment was conducted in strain DBA/1J male mice. Two methods of scoring for dominant lethals, the classic method (dissecting females at mid-pregnancy) and an alternative method (inspection of uterine scars after litters were weaned) were compared. Results indicate that strain DBA/1J has a similar sensitivity to EMS-induced dominant lethals as has been previously reported for other mouse genotypes. Of the two methods used to score dominant lethals, the classic method is more sensitive. 相似文献
7.
There is a close relationship between the rates at which dominant lethal mutations and heritable translocations are induced by ethyl methanesulfonate (EMS) or triethylenemelamine (TEM) in male postmeiotic germ cells. This relationship does not hold for isopropyl methanesulfonate (IMS), which induced only negligible frequencies of heritable translocations at doses that induced high levels of dominant lethal mutations. Nor does IMS behave like EMS and TEM in the degree to which eggs of different stocks of females repair premutational lesions that are carried in the sperm-large differences between stocks for IMS treatment and small differences for EMS or TEM treatment. These dissimilarities between IMS and the other two alkylating chemicals are postulated to be attributable to differences in the types of lesions present at the time of repair activity and to whether or not chromosomal aberrations are already fixed prior to postfertilization pronuclear DNA synthesis. 相似文献
8.
Using a sequential mating procedure, the induction of specific-locus mutations by ethyl methanesulfonate (EMS) was reinvestigated in male mice. Doses of 175 mg/kg b.w. and 250 mg/kg b.w. of EMS induce gene mutations in the mating intervals 5-8 and 9-12 days post treatment. However, only the frequency of dominant lethal mutations increases with the dose, not the frequency of specific-locus mutations. This observation implies that with a higher dose of EMS a larger fraction of mutagenized spermatozoa and spermatids are selectively eliminated, leading to underestimation of the specific-locus mutation yield at high doses. EMS does not induce specific-locus mutations in spermatogonia. 相似文献
9.
Dominant lethal tests were performed on female mice injected intraperitoneally with cyclophosphamide (200 mg/kg) or with mitomycin C (0.2 or 5 mg/kg) at the preovulatory stage of oogenesis. Complementary experiments were undertaken to clarify the results obtained. Embryo culture showed that sterility found after treatment with cyclophosphamide or with the high dose of mitomycin C was the reflection of true dominant lethal effects. Mortality after cyclophosphamide treatment occurred predominantly at the 2- and 3-cell stages, while it was reported in all preimplantation stages after treatment with the high dose of mitomycin C. Embryos treated with the low dose of mitomycin C developed normally to the blastocyst stage, confirming the absence of preimplantation effects found with this dose in the dominant lethal test. Cytogenetic analysis of female pronuclei at the first cleavage division were performed after mating treated females with males homozygous for one Robertsonian translocation. This method allowed one to distinguish easily the female pronuclei from the male ones, which exhibited one translocated 'marker' chromosome. After treatment with cyclophosphamide, most female pronuclei showed multiple chromatid exchanges or shattering of the entire genome. After treatment with the high dose of mitomycin C, various types of premature chromosome condensation were found, and they were often accompanied by important interchromosome associations. After treatment with the low dose of mitomycin C, no structural chromosome aberrations were found, and the number of numerical anomalies was not significantly different from that found in control embryos. These last results suggest that the increase in rate of postimplantation loss obtained in the dominant lethal test with the low dose of mitomycin C was not due to clastogenic effects of this compound in the female germ cells, but rather to indirect effects on the maternal organism. 相似文献
10.
Summary The effectiveness of ethyl methanesulfonate (EMS) as a mutagen in Chlamydomonas reinhardi has been demonstrated in two different systems: reversion to prototrophy of an argine-requiring strain and forward mutation to auxotrophy of the wild-type strain. In these experiments, the toxic effect of EMS was very low. With certain batches of EMS, an unusually high toxicity was observed. In this case, the lethal effects seem to be attributable to the presence of minor impurities in EMS.Chargé de Recherches au Fonds National de la Recherche Scientifique. 相似文献
11.
The molecular dosimetry of methyl methanesulfonate (MMS) in the germ cells of male mice has been investigated. The mice were injected i.p. with 100 mg/kg of [3H]MMS and methylations per sperm head, per deoxynucleotide, and per unit of protamine were then determined over a 3-week period. The methylations per sperm head paralleled the dominant lethal frequency curve for MMS, reaching a maximum of between 22 and 26 million methylations per vas sperm head 8-11 days after treatment. Methylation of sperm DNA was greatest at 4 h (the earliest time point studied) after treatment, with 16.6 methylations/10(5) deoxynucleotides. DNA methylation gradually decreased during the subsequent 3-week period. The methylation of germ-cell DNA did not increase in the stages most sensitive to MMS (late spermatids leads to early spermatozoa) and was not correlated with the dominant lethal frequency curve for MMS. However, methylation of protamine did increase in the germ-cell stages most sensitive to MMS, and showed an excellent correlation with the incidence of dominant lethals produced by MMS in the different germ-cell stages. The pattern of alkylation produced by MMS in the developing germ-cell stages of the mouse is similar to that found for EMS. However, for equimolar exposures, MMS alkylates the germ cells 5-7 times more than does EMS. Hydrolyzed samples of protamine from [3H]MMS-exposed animals were subjected to thin-layer chromatography and amino acid analysis. Both procedures showed that most of the labeled material recovered from the hydrolysates co-chromatographed with authentic standards of S-methyl-L-cysteine. The amino acid analyses showed an average of approximately 80% of the labeled material eluting with S-methyl-L-cysteine. The mechanism of action of both MMS and EMS on the developing germ cells appears to be similar. The occurrence of S-methyl-L-cysteine as the major reaction product in sperm protamine after MMS exposure supports our initial model of how dominant lethals are induced in mouse germ cells by these chemicals: Alkylation of cysteine sulfhydryl groups contained in mouse-sperm protamine blocks normal disulfide-bond formation, preventing proper chromatin condensation in the sperm nucleus. Subsequent stresses produced in the chromatin structure eventually lead to chromosome breakage, with resultant dominant lethality. 相似文献
12.
Male mice were treated with mechlorethamine (2.0 mg/kg), procarbazine (100 mg/kg) and vincristine (0.67 mg/kg) alone, or in 2-drug and 3-drug combinations. 5 weeks later and continuing for 5-8 weeks, embryos fertilized by spermatozoa that were derived from drug-treated spermatogonia were evaluated for drug-induced dominant lethal mutations. Significant mutagenesis was detected for mechlorethamine alone, for 2-drug combinations including mechlorethamine and for 3-drug combinations. Combinations where mechlorethamine was given first were mutagenic whereas combinations where mechlorethamine was not given first were not. Some combinations were more cytotoxic to the germinal epithelium than others. The data suggest that mutagenesis by this combination of drugs which is used extensively in treating Hodgkin's disease is due primarily to the mechlorethamine and that the frequency of mutation-induction may be a function of the order of administration. 相似文献
13.
The molecular dosimetry of ethyl methanesulfonate (EMS) in the germ cells of male mice has been investigated. The mice were injected i.p. with 200 mg/kg of [ 3H]EMS and the ethylations per sperm head, per deoxynucleotide, and per unit of protamine were then determined over a 2-week period. The ethylations per sperm head closely paralleled the dominant-lethal frequency curve for EMS, reaching a maximum of 5 to 6.5 million ethylations per vas sperm head at 8 to 10 days after treatment. Ethylation of sperm DNA was greatest at 4 h after treatment, with 5.7 ethylations/10 5 deoxynucleotides, and gradually decreased to 2.2 ethylations/10 5 deoxynucleotides at 15 days after treatment. The ethylation of sperm DNA did not increase in the germ-cell stages most sensitive to EMS, ans was not correlated with the dominant-lethal frequency curve for EMS. However, ethylation of sperm protamine did increase in the germ-cell stages most sensitive to EMS, and showed an excellent correlation with the incidence of dominant lethals produced by EMS in the germ cells.A model is presented to explain, at a molecular level, how dominant lethals may be induced in mouse germ cells by EMS. Ethylation by cysteine sulfhydryl groups contained in mouse-sperm protamine could block normal disulfidebond formation, preventing proper chromatin condensation in the sperm nucleus. Stresses in the chromatin structure could then eventually lead to chromosome breakage, with resultant dominant lethality. 相似文献
14.
Glued mutations in Drosophila comprise an essential complementation group with complex developmental effects. The original Glued mutation (Gl) has dominant nonlethal effects in heterozygous flies, principally on the morphogenesis of the visual system. Gl also has a recessive lethal effect early in development. Mutations that reverse the dominant visual effects of Gl (GlR mutations) were induced by gamma-radiation or by insertions of the transposable P element. The GlR(G) mutations induced by gamma-radiation do not reverse the lethal effect of Gl; these appear to be null mutations, some of which (and possibly all) delete segments of the Glued region. The GlR(P) mutations induced by insertion of the P element also reverse concomitantly a recessive lethal effect of Gl, suggesting that both the recessive and dominant effects are controlled by the same gene. The reversal of a lethal effect of Gl by the P element is remarkable, since it indicates that an essential gene function can be restored by insertion of unrelated DNA. Another class of lethal Glued mutations was induced in the normal Gl+ strain by ethyl methanesulfonate (EMS). The EMS mutations belong to the same essential complementation group as Gl, but do not have the strong dominant effects of Gl on the visual system. The GlR(P) mutations provide a molecular marker for the Glued gene, which was used to map the gene to the 70C2 band of chromosome 3L by in situ hybridization of a P element probe to polytene chromosomes from the GlR(P) strains and also to isolate clones of Glued genomic DNA for molecular studies of the normal gene and the various Glued mutations. 相似文献
15.
1-Methyl-1-nitrosourea (MNU) induced specific-locus mutations in mice in all spermatogenic stages except spermatozoa. After intraperitoneal injection of 70 mg/kg body weight of MNU a high yield of specific-locus mutations was observed in spermatids (21.8 × 10 −5 mutations per locus per gamete). The highest mutational yield was induced in differentiating spermatogonia. In 1954 offspring we observed 5 specific-locus mutants (44.8 × 10 − mutations per locus per gamete). In addition, 2 mosaics were recovered, which gave a combined mutation rate of 62.7 × 10 −5. In A s spermatogonia the mutation rate was 3.9 × 10 −5. The same dose of 70 mg/kg of MNU induced dominant lethal mutations 5–48 days post treatment, mainly due to post-implantation loss in spermatids and spermatocytes. It is interesting to compare the induction pattern of mutations by MNU with methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS) and ethylnitrosourea (ENU). Based on the different spermatogenic response of the induction of specific-locus mutations we can characterize the 4 mutagens in the following way: EMS = MMS ≠ MNU ≠ ENU. 相似文献
16.
The efficiency of the adult feeding method for EMS treatment in Drosophila melanogaster was studied by measuring the frequency of induced recessive lethals on the second chromosome. The treatment was most effective when mature spermatozoa or spermatids were treated and was much less effective on earlier stages. The number of mutations induced was proportional to the concentration except at the highest doses. The recessive lethal rate was estimated to be about 0.012 per second chromosome per 10(-4) M. In addition, about 0.004-0.005 recessive lethals per 10(-4) M were found in a later generation in chromosomes that had not shown the lethal effect in the previous generation. When the experiments are done in a consistent manner and gametes treated as mature sperm or spermatids are sampled, the results are highly reproducible. However, modifications of the procedure, such as starvation before EMS treatment, can considerably alter the effectiveness of the mutagen. 相似文献
17.
Males of the fish Oryzias latipes were treated with various chemicals and then mated with normal females. The fertility and hatchability of the eggs laid by the parents were examined, and the dominant lethal effects were estimated. Mitomycin C induced dominant lethals in the fish spermatids and spermatocytes after the males had been treated with concentrations of 2.5 and 25 micrograms/ml. Methyl methanesulfonate (MMS) induced dominant lethals in spermatozoa and spermatozoa and spermatids after the injection of 200 and 400 mg/kg. These results are in good agreement with the results obtained with mice. However, the effects of ethyl methanesulfonate (EMS) were not clear on spermatogenic cells at any stage. We could not recognize any significant induction of dominant lethals by urethanes, bleomycin, caffeine, and two kinds of food-color additives, at least under the present experimental conditions. 相似文献
18.
Three new mutants were induced in a laboratory strain of Anopheles quadrimaculatus (Say), species A, by feeding adult males ethyl methanesulfonate (EMS). Rose eye (ro) is a recessive X-linked trait. Short antenna (Sa) and melanotic (Mel) are dominant autosomal traits that are lethal in the homozygous condition. Linkage crosses and X-autosome translocations were used to assign short antenna to the right arm of chromosome 3 about 45 map units proximal to stripe (st+), and melanotic was located on chromosome 2 near the centromere. 相似文献
19.
In 4 separate dominant lethal experiments groups of mice of either Charles River CD1 or Alderley Park strains were fed laboratory diets (Oakes, 41B, PRD, BP nutrition rat and mouse maintenance diet No. 1). The diets were either untreated (negative control diets) or irradiated at 1, 2.5 and 5 megarad and were freshly irradiated, or stored. The animals were fed their test diets for a period of 3 weeks prior to mating. Groups of mice given a single intraperitoneal injection of 200 mg cyclophosphamide per kg body weight served as the positive controls. Freshly irradiated PRD diet fed to male mice of both strains caused an increase in early deaths in females mated to the males in week 7 and to a lesser extent in week 4. The increase due to irradiation was small by comparison with that produced by the positive control compound. The responses for the other irradiated diets showed no significant increases in early deaths although some values for Oakes diet were high. The effect of storage was examined with PRD and BPN diet on one occasion and produced conflicting results. Thus there was some evidence that irradiated PRD diet has weak mutagenic activity in the meiotic and/or pre-meiotic phase of the spermatogenic cycle which appeared to be lessened on storage; the inclusion of such a diet in toxicological studies would therefore need to be carefully considered. 相似文献
20.
Sensitivity of male F-344 rats to the dominant lethal (DL) mutagenic effect of ethyl methanesulfonate (EMS) was studied in conjunction with an evaluation of EMS-induced depression of glutathione (GSH) in testis, epididymis and vas deferens. At the maximal effect, during week 3 (days 15-19 post-EMS), a dosage of 50 mg/kg caused 13.3% fetal death (FD) vs. 3.3% in controls, while 100 mg/kg caused 56.6% FD in the same interval. EMS maximally depressed GSH to 33%, 54% and 77% of control in vas, epididymis and testis respectively. The slope of the DL dose-response curve for EMS in rats shows a 3-4-fold greater sensitivity than that reported for mice. The steepness of this curve suggests that small perturbations in endogenous protective mechanisms, such as GSH depression, may exert a greater proportional effect on germ-cell mutagenesis in rats which should be more readily observable than in mice. EMS and other electrophilic toxicants may thus influence their own primary reproductive toxicity and/or that of other agents by depression of GSH in male reproductive tissue. 相似文献
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