Dominant Lethal Mutations In Mice Research Articles

Male-mediated dominant lethal mutations in mice following prooxidant treatment

This study's primary aim is to examine if prooxidant treatment has the propensity to induce dominant lethal (DL) type mutations in a randomly bred closed colony of CFT-Swiss mice. Initially, graded doses of both organic hydroperoxides viz., t-butyl hydroperoxide (tbHP), and cumene hydroperoxide (cHP) were administered (i.p.) to adult males and the mortality data was analysed to determine the LD 50 values. cHP was relatively more toxic compared to tbHP. The computed LD 50 values were 1500 and 3000 μmol (kg body weight) −1 for cHP and tbHP, respectively. Subsequently, adult males were administered (i.p.) with 1/10 LD 50 doses of hydroperoxide (HP) (tbHP — 30 μmol (100 g body weight) −1 and cHP — 15 μmol (100 g body weight) −1) on 5 consecutive days and were mated with virgin females for a period of 5 weeks to characterise the male-mediated DL mutations. Male-based analysis of the three major variables viz., implantations, live embryos and dead implants (DI) were carried out to assess the DL-type response induction. While tbHP induced significant increases (2- to 5-fold) in the incidence of DI during the first 4 weeks, cHP induced a marginal increase only during the first week. These results suggest that prooxidants induce DL-type effect only in specific post-meiotic stages of spermatogenesis and stress the need to further investigate the implications of chronic oxidative stress on the male reproductive system.

Genetic effects of 1,3-butadiene and associated risk for heritable damage

A summary of the results of the studies conducted in the EU Project `Multi-endpoint analysis of genetic damage induced by 1,3-butadiene and its major metabolites in somatic and germ cells of mice, rats and man' is presented. Results of the project are summarized on the detection of DNA and hemoglobin adducts, on the cytotoxic and clastogenic effects in somatic and germinal cells of mice and rats, on the induction of somatic mutations at the hprt locus of experimental rodents and occupationally exposed workers, on the induction of dominant lethal mutations in mice and rats, and on heritable translocations induced in mice, after exposure to butadiene (BD) or its major metabolites, butadiene monoepoxide (BMO), diepoxybutane (DEB) and butadiene diolepoxide (BDE). The primary goal of this project was to collect experimental data on the genetic effects of BD in order to estimate the germ cell genetic risk to humans of exposure to BD. To achieve this, the parallelogram approach of Sobels was employed. The presented estimates of heritable damage in man as a consequence of butadiene exposure are based on data for heritable translocations and bone marrow micronuclei induced in mice and chromosome aberrations observed in lymphocytes of exposed workers. A doubling dose for heritable translocations in human germ cells of 4900 ppm/h is estimated, which, assuming cumulative BD exposure over the sensitive period of spermatogenesis, corresponds to 5–6 weeks of continuous exposure at the workplace to 20–25 ppm. Alternatively, the rate of heritable translocation induction per ppm/h of BD exposure is estimated to be approximately 0.8 per million live born, compared to a spontaneous incidence of balanced translocations in humans of approximately 800 per million live born. These estimates have large confidence intervals and are only intended to indicate orders of magnitude of human genetic risk. These risk estimates are based on data from germ cells of BD-exposed male mice. The demonstration that clastogenic damage was induced by DEB in preovulatory oocytes at doses which were not ovotoxic implies that additional studies on the response of mammalian female germ cells to BD and its metabolites are needed. The basic assumption of the above genetic risk estimates is that experimental mouse data obtained after BD exposure can be extrapolated to humans. Several points exist in the present report and in the literature which contradict this assumption: (1) the level of BMO–hemoglobin adducts was significantly elevated in BD-exposed workers; however, it was considerably lower than would have been predicted from comparable rat and mouse exposures; (2) the concentrations of the metabolites DEB and BMO were significantly higher in mouse than in rat blood after BD exposure. Thus, while metabolism of BD is qualitatively similar in the two species, it is quantitatively different; (3) no increase of HPRT mutations was shown in 19 workers exposed on average to 1.8 ppm of BD, while in a different population of workers from a US plant exposed on average to 3.5 ppm of BD, a significant increase of HPRT variants was detected; and (4) data from cancer bioassays and cancer epidemiology suggest that rat is a more appropriate model than mouse for human cancer risk from BD exposure. However, the dominant lethal study in rats gave a negative result. At present, we do not know which BD metabolite(s) may be responsible for the genetic effects even though the bifunctional alkylating agent DEB is the most likely candidate for the induction of clastogenic events. Unfortunately, methods to measure DEB adducts in hemoglobin or DNA are only presently being developed. Despite these several uncertainties, the use of the mouse genetic data is regarded as a justifiable and conservative approach to human genetic risk estimation given the considerable heterogeneity observed in the biotransformation of BD in humans.

Study of the mutagenicity of phenazepam and sidnocarb

The authors investigate the influence of the drugs phenazepam and sidnocarb on the levels of gene mutations in Drosophila, dominant lethal mutations in mice, chromosome aberrations, and sister chromatid exchanges in human lymphocytes in vitro. Mice were used in the experiments in a human peripheral blood lymphocyte culture where phenazepam and sidnocarb were injected and the collected blood was monitored radiochromatographically on a separate group of animals using (/sup 14/C)phenazepam and (/sup 14/C)sidnocarb. The authors conclude that phenazepam and sidnocarb in doses corresponding to the therapeutic dose when used separately or together, do not induce genetic damages.

Non-induction of dominant lethal mutations in mice fed gamma-irradiated glucose.

Non-induction of dominant lethal mutations in mice fed gamma-irradiated glucose.

Mutagenic potential of cis-dichlorodiammine platinum II in rodents

The ability of cis-dichlorodiammine platinum II to cause chromosomal aberrations in rats and dominant lethaloty in mice was studied. Five daily intraperitoneal doses raging from 0.25 to 2.00 mg/kg/day failed to result in the observance of dominant lethal mutations in mice. Intraperitoneal doses of 0.13 and 0.52 mg/kg/day for 5 days in rats did, however, cause chromosomal aberrations in bone marrow cells collected and harvested 24 h after the last dose. The incidence of total aberrations obeserved at the 0.52 mg/kg/day dose level was 5.5-fold greater than that seen for the vehicle control group. Thus, cis-dichlorodiammine platinum II appears to be clastogenic in rats.

The cytogenetic basis of dominant-lethal mutations in mice: studies with TEM, EMS, and 6-mercaptopurine

The cytogenetic basis of dominant-lethal mutations in mice: studies with TEM, EMS, and 6-mercaptopurine

Detection of X-ray induced dominant lethal mutations in mice: An in vitro approach

The expression of dominant lethal mutations induced by 450 rad of X-radiation in the germ cells of male mice was detected by an in vitro analysis. Embryos sired by irradiated males had a higher incidence of developmental failures in early cleavage, at the late morula stage, and at the late blastocyst stage due to dominant lethal mutations than did control embryos. Dominant lethal mutations were induced most frequently in germ cells exposed as early spermatids and spermatocytes and next most frequently in germ cells exposed as sperm. A decrease in fertilizations, presumably reflecting cell killing, was found in irradiated spermatocytes. These observations indicate that in vitro analysis permits a more detailed description of mutations that are expressed as preimplantation failures than does in vivo analysis.

Dominant Lethal Mutations in Mice Resulting from Chronic Tritiated Water (HTO) Ingestion

CARSTEN, A. L., AND COMMERFORD, S. L. Dominant Lethal Mutations in Mice Resulting from Chronic Tritiated Water (HTO) Ingestion. Radiat. Res. 66, 609-614 (1976). The possible genetic consequences of continued ingestion of tritiated water (HTO) have been investigated in Hale-Stoner-Brookhaven strain mice maintained on HTO (3 yCi/ml). Second-generation females on HTO were sacrificed in late pregnancy and the corpora lutea, viable, nonviable embryos (early death and late death) and preimplantation loss determined to calculate the mutation rate. The breeding efficiency (pregnancy rate and litter size), was also measured. Analysis of results by both parametric and nonparametric tests has indicated a significant reduction in the number of viable embryos resulting from matings between animals maintained on the tritium regimen, with no effect on breeding efficiency. The integrated radiation dose to the testes and ovary, based on average tissue tritium content from fetal origin through breeding of the 8-week-old animals, was calculated.

Differential spermatogenic response of mice to the induction of mutations by antineoplastic drugs

Summary 2,2′-Dichloro- N -methyldiethylamine- N -oxide (DMO) induced dominant lethal mutations in mice exclusively in spermatozoa. Spermatozoa were not affected by N -isopropyl-α-(2-methylhydrazino)- p -toluamide (IMT). IMT induced dominant lethal mutations in mice in spermatids and spermatocytes. IMT also affected the development of spermatocytes and spermatogonia. Mitomycin C (MC) significantly increased the frequency of specific locus mutations in spermatogonia of mice but not in postspermatogonial germ-cell stages. The differential spermatogonic response of mice to the induction of mutations is very likely due to the different mode of action of the chemical mutagens and their distinct effects on the structural and macromolecular changes during the development of the germ cells. The germ-cell stage-specific induction of mutations is an important clue for the evaluation of genetic risks of antineoplastic drugs.

Estimating the frequency of induced dominant lethal mutations in mice. II. The evaluation of a new method.

Estimating the frequency of induced dominant lethal mutations in mice. II. The evaluation of a new method.

Comparative investigations on the chemical induction of point mutations and dominant lethal mutations in mice.

A selection of mono- and polyfunctional alkylating agents as well as a folic acid antagonist and an acridine derivate were tested with the host-mediated assay, and as far as not known from the literature, with the dominant lethal test for mutagenic activity in mice. In the host-mediated assay system the indicator organisms Salmonella typhimurium G46 His−, Serratia marcescens a 13 His−and a 21 Leu− were used as back mutation systems and E. coli 343 as a forward mutation system. We found indications that polyfunctional alkylating agents induce dominant lethal mutations to a larger extent, whereas monofunctional alkylating agents revealed more mutagenic activity on the molecular level. No definite mutagenicity could be observed for amethopterine, which is mutagenic in cytogenetic investigations. Trypaflavin which is known to be mutagenic in the dominant lethal test, did not induce point mutations in our indicator strains. We conclude that the spectra of mutations, which can be recognized by these two methods, overlap only partially.

Differential spermatogenic response of mice to the induction of dominant-lethal mutations by n-propyl methane-sulfonate and isopropyl methanesulfonate

n-Propyl methanesulfonate (PMS) and isopropyl methanesulfonate (iPMS) induce dominant-lethal mutations in mice. The responses of the various spermatogenic stages to the induction of dominant-lethal mutations differ markedly for PMS and iPMS. PMS induces a high frequency of dominant-lethal mutations in mouse spermatozoa and late spermatids and a low frequency in early spermatids. No dominant-lethal mutations are induced in spermatocytes. The gametogenic response to PMS is similar to that seen after treatment with ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS). In equimolar doses in mice the relative efficiencies of alkyl methanesulfonates in inducing dominant-lethal mutations in spermatozoa and spermatids are as follows: MMS > EMS > PMS. iPMS induces dominant-lethal mutations in all postspermatogonial stages. After injection of 200 mg/kg of iPMS the percentage of dominant-lethal mutations induced in spermatozoa, spermatids, and spermatocytes is above 75. The yield of induced dominant-lethal mutations after injection of 50 mg/kg of iPMS is low in spermatozoa, falls to the control level in early spermatids, but increases drastically in spermatocytes.

Does caffeine induce dominant lethal mutations in mice?

The problem of mutagenic activity of caffeine (1-3-7-trimethylxanthine) in man became more and more urgent because it is; first, one of the most frequently used stimulants in beverages and drugs and; second, recently several contradictory reports have been published [37, 29, 1, 43] which were followed up in public with great interest. We, therefore, tested the spermatogenesis of mice with the method of induction of dominant lethal mutations [42] in order to find a mutagenic effect, and by fractionating the spermatogenesis in eight breeding groups to detect some sensitive stages after a single treatment with a high caffeine dose. The animals used were of the C3H inbred strain of mice, the dose just tolerated by these animals was 0.25 g caffeine/kg body weight. Two experiments were carried out under same conditions with 29 males treated and 10 males in the control group. 373 pregnant females fertilized by the treated males showed among their 3495 implants 15% dead implantations while 201 females fertilized by the control males had 2139 implants, 13.6% of which died during pregnancy. This slight difference does not indicate any mutagenic function of caffeine on the spermatogenesis of mice as a whole. The tested stages of spermatogenesis revealed no sensitivity. A slight increase in pseudopregnancy (P≈0.007) could be observed, which might be physiologically caused. Copulation frequency was considerably decreased, especially in the first week after treatment.

Effect of 2-β-Aminoethylisothiourea (AET) against Genetic Damages Induced by X-Irradiation of Male Mice

Since the radioprotective properties of 2-mercaptoethylamine (MEA) (1) and 2,B-aminoethylisothiourea (AET) (2) became known, many studies have been carried out on the effects of sulfhydryl and related compounds on irradiated germ cells. Thus, Rugh and Wolff (3) found in 1957 that cysteamine decreases the sterilizing effect of X-rays in female mice, and injection of cysteamine before irradiation has a protective effect on the male germ cells of mice (4) and rats (5). In contrast to the studies of Kaplan and Lyon (6), recent results of Liuning et al. (7) indicate that injection of cysteamine reduces the postimplantation death induced by irradiation of spermatozoa by about 25 %. Disappearance of male germ cells after irradiation is slower and their regeneration is faster in animals receiving 2-,3-aminoethylisothiourea (AET) before X-irradiation than in those without treatment (8), and protection of the reproductive capacity after injection of AET has also been observed in X-irradiated female rats (9). On the other hand, the yield of recessive and dominant lethal mutations in Drosophila increases about 10 to 15 % if AET is administered prior to irradiation, whereas it remains unchanged if it is given after the exposure (10). Similar results were found in Neurospora (11). Since no data on the radioprotective action of AET on dominant lethal mutations in mice are as yet available, this problem has now been studied in more detail. The male germ cells of mice react in a different manner depending on whether they are in the postmeiotic or premeiotic stage; therefore spermatozoa, spermatids, and spermatogonia were investigated separately by choosing for the mating different time intervals after irradiation.