Lethals In Mice Research Articles

Base Excision Repair in Early Zebrafish Development: Evidence for DNA Polymerase Switching and Standby AP Endonuclease Activity

The base excision repair (BER) pathway recognizes and repairs most nonbulky lesions, uracil and abasic (AP) sites in DNA. Several participants are embryonic lethals in knockout mice. Since the pathway has never been investigated during embryogenesis, we characterized the first three steps of BER in zebrafish extracts from unfertilized eggs, embryos at different developmental stages, and adults. Using a 45-mer double-stranded substrate with a U/G mispair at position 21, we showed that extracts from all stages are capable of performing BER. Before 3 days postfertilization (dpf), aphidicolin-sensitive polymerases perform most nucleotide insertion. In fact, eggs and early stage embryos lack DNA polymerase-beta protein. After the eggs have hatched at 3 dpf, an aphidicolin-resistant polymerase, probably DNA polymerase-beta, becomes the primary polymerase. Previously, we showed that when the zebrafish AP endonuclease protein (ZAP1) level is knocked down, embryos cease dividing after the initial phase of rapid proliferation and die without apoptosis shortly thereafter. Nevertheless, extracts from embryos in which ZAP1 has been largely depleted process substrate as well as extracts from control embryos. Since apex1 and apex2 are both strongly expressed in early embryos relative to adults, these data indicate that both may play important roles in DNA repair in early development. In brief, the major differences in BER performed by early stage embryos and adults are the absence of DNA polymerase-beta, leading to predominance of replicative polymerases, and the presence of backup Mg(2+)-dependent endonuclease activity in early stage embryos. The switch to normal, adult BER occurs fully when the embryos hatch from the chorionic membrane and encounter normal oxidative stress.

The reproductive effects assessment group's review of the mutagenicity of vinylidene chloride.

A large number of studies indicate that vinylidene chloride is mutagenic to bacteria and that this activity is largely dependent on microsomal activation. Vinylidene chloride gave positive results for gene reversion and conversion in yeast that was also dependent on metabolic activation, and was positive in tradescantia. In mammalian systems, vinylidene chloride failed to induce gene mutations in V79 cells at two separate loci, failed to induce chromosomal aberrations in mouse bone marrow in vivo, and failed to induce dominant lethals in either mice or rats. Vinylidene chloride was found to alkylate DNA of mice exposed through inhalation and may have caused unscheduled DNA synthesis in kidneys of similarly exposed mice. The studies on the mutagenicity of vinylidene chloride are evaluated in this review.

The influence of mating status and age on the induction of chromosome aberrations and dominant lethals in irradiated female mice

Young and old hybrid female mice were given 0.5 Gy or 2 Gy acute x-irradiation, followed by (i) in utero examination for dominant lethal mutations, or (ii) examination of metaphase I oocytes for chromosome aberrations 2–3 weeks after the irradiation. Some of the old females had been mated when young to males of a specific locus stock. Others were left unmated until after the irradiation when they, and the young females, were mated to the same specific locus stock and allowed to have 1 (if given 2 Gy) or 2 (if given 0.5 Gy) litters before the dominant lethal test. In both the 0.5 -Gy and 2-Gy series, mean sizes of first litters in the old late-mated group were markedly lower than in the old early-mated or young groups, the differences being significant at the 2-Gy level. The intrauterine examinations showed that this difference was largely the result of a reduced ovulation rate in the old late-mated females. Preimplantation loss tended to be higher in all the old females than in the young ones, but differences between the groups in postimplantation lethality were less pronounced. In the chromosome studies, only about half as many oocytes were recovered from the ovaries of old females than from young ones. At both the 0.5-Gy and 2-Gy dose levels interchange frequencies were non-significantly higher in old than in young females (with no clear-cut effect of mating status), while the overall frequency of aberrations (interchanges + fragments) was significantly higher in oocytes of old than young females after 2 Gy X-rays (35.5% against 12.5%). No specific locus mutations were found in 5616 offspring of unirradiated females.

Use of an inversion to test for induced X-linked lethals in mice

A long X-chromosomal inversion in the mouse was used to suppress crossing-over and thereby to scan 85% of the X-chromosome, or 5% of the genome, for recessive lethal mutations induced by radiation. After a fractionated absorbed dose of 500 + 500 rad X-rays 24 h apart to spermatogonia, 2/536 irradiated and 0/529 control X-chromosomes carried a confirmed lethal. This corresponds to a rate for recessive lethals of 1.9 × 10 −6 / rad/ X-chromosome for single exposures (allowing for the enhancing effect of fractionation). This is believed to be the first demonstration of the induction of transmissible X-linked lethals in mammals. The results are consistent with previous findings by other methods and indicate the relatively low rate of induction of lethals and the value of inversions in detecting them.

Mutagenicity studies on alcohol extracts from gamma-irradiated potatoes--dominant lethal test in mice.

Alcohol extracts freshly prepared from gamma-irradiated and unirradiated potatoes were tested for the ability to induce dominant lethals in BDF1 mice. Male mice were given 0.5 ml of extract twice a day, p.o., for 7 days and then mated with untreated female mice. Female mice were sacrificed on about the 13th day of pregnancy. No significant difference was observed in the number of living implants between the group treated with extract prepared from unirradiated potatoes and that treated with the extract from 150 Gy (15 krad) irradiated potatoes.

Dominant lethal mutation induced in male rats by 1,2-dibromo-3-chloropropane (DBCP)

1,2-Dibromoethane (DBE) and 1,2-dibromo-3-chloropropane (DBCP), soil fumigants, were investigated for their potential mutagenicity by dominant lethal studies in the rat and mouse. Dominant lethal mutation was induced by DBE in neither of the species. DBCP, on the other hand, induced dominant lethals in rats in the post-meiotic stage of spermatogenesis, especially in the early spermatid stage. However, DBCP did not cause dominant lethals in mice.

Dominant and recessive effects of induced lethals in female mice by exposure to gamma-irradiation during the 10th to 14th day of intrauterine life

The frequency of (dominant and) recessive lethal mutations induced by 160-rad chronic gamma-irradiation given with a dose rate of 0.03 rad/min during the 10th to 14th day of gestation has been studied in female CBA-mice. An increased rate of recessive lethal equivalents by about 10% has been noted. This increase corresponds to a mutation rate of 6.3 × 10 −4 mutation/rad/ genome. There were not found any dominant mutations, nor any dominance effects from the induced recessive lethal equivalents. The hazards after irradiation during foetal development are discussed.

3082. More doubts about furylfuramide: Soares, E. R. & Sheridan, W. (1975). Lack of induction of dominant lethals in mice by orally administered AF-2. Mutation Res.31, 235. Nomura, T. (1975). Carcinogenicity of the food additive furylfuramide in foetal and young mice. Nature, Lond.258, 610

3082. More doubts about furylfuramide: Soares, E. R. & Sheridan, W. (1975). Lack of induction of dominant lethals in mice by orally administered AF-2. Mutation Res.31, 235. Nomura, T. (1975). Carcinogenicity of the food additive furylfuramide in foetal and young mice. Nature, Lond.258, 610

Lack of induction of dominant lethals in mice by orally administered AF-2

Lack of induction of dominant lethals in mice by orally administered AF-2

Lack of induction of dominant lethals in mice by orally administered AF-2

In a series of toxicity tests, male mice of three inbred strains were exposed to several doses of orally administered furylfuramide (AF-2). Subsequent to these tests the effects of AF-2, as measured by induced dominant lethals, were tested in strain DBA/2J mice. AF-2 at the doses used in this study was relatively non-toxic to the strains of mice tested. No indication of AF-2 induced dominant lethality was observed.

Comments on tests of dominant lethals in mice

Comments on tests of dominant lethals in mice

The mutagenic effect or lysergic acid diethylamide II. Dominant lethal test in mice

Summary The mutagenic effect of lysergic acid diethylamide (LSD) was studied by using the dominant lethal test. ICR male mice were treated intraperitoneally with a single dose of 10, 100 or 1000 μg LSD/kg b.w. and with repeated doses Of 5 x 500 and5 x 1000 μg LSD/kg b.w. ICR female mice were given i.p. a single dose of 1000 μg LSD/kg b.w. LSD induced dominant lethals in both male and female mice. The frequency of dominant lethals was dependent on the dose applied as well as on the stage of spermatogenesis.

Induced dominant lethals in female mice.

Induced dominant lethals in female mice.

Induced dominant lethals in female mice: effects of triaziquone and phenylbutazone.

Bei weiblichen Mausen induzierte Triaziquon unter konventionellen Laboratoriumsbedingungen dominante Letalfaktoren, wenn die Substanz im Pro-Oestrus oder im Oestrus verabreicht wurde. Weniger gut geeignet erwies sich diese Applikation wenige Stunden nach Kopulation, da embryotoxische Wirkungen auftraten. Im Gegensatz zu Triaziquon fuhrte Phenylbutazon — weiblichen Mausen im Oestrus verabreichtnicht zu dominanten Letaleffekten.

Estimating the frequency of induced dominant lethals in mice by uterine dissectio after weaning progeny

Estimating the frequency of induced dominant lethals in mice by uterine dissectio after weaning progeny

Testing for recessive lethals in mice

Methods to study recessive lethals anywhere in the genome of the mouse are discussed. Specially emphasized are possibilities to exclude pre-existing lethals from newly induced ones. An illustrative example is given.

Dominant effects of recessive lethals in mice: II. Viability and mating ability

Fron 17 F 1 males, suspected of being heterozygous for recessive lethals, F 2 males were produced. The F 2 males were tested for possible dominance effects, and later back-crossed to their daughters. By this method lethality was confirmed in 14 families. Comparisons between lethal-free and lethal carriers indicate no overall deterious effect on viability of lethal heterozygosity evyen though one family showed a significantly increasedp rate of intrauterine death. Examination of the proportion of pregnant females in the dominance test revealed an inferiority in mating ability of lethal heterozygous males as compared with lethal-free males. The importance of tests of various fitness components is stressed.

Dominant lethals in young female mice

Dominant lethals in young female mice

Test for sex-linked lethals in irradiated mice

Tabby males were irradiated with 500 r and mated toBn Mobr♀♀. Daughters conceived during the first 3 weeks after irradiation were tested for the presence of sex-linked recessive mutations in their progeny, each daughter representing one irradiated gamete. One visible, but no lethal, was found in theBn–Mobrsegment among 154 tested gametes; one gamete was proved free of lethals or visibles in theBn–Tasegment, and 21 gametes in theTa–Mobrsegment. Among the whole 176 tested gametes there was no indication of a lethal in the adjoining segments.

The Protective Effect of Cysteamine against Genetic Damages by X-Rays in Spermatozoa from Mice

of these agents on sex cells of various stages. Kaplan and Lyon (1) made a small test of the possible protective action of cysteamine but found no positive response on dominant lethals in mice. Rugh and Wolff (2) found, however, that cysteamine decreased the sterilizing effect of Xrays in female mice. Wang et al. (3) concluded that injection of cysteamine decreased the transient sterility in irradiated male mice. Mandl (4), studying the number of spermatogonia and pre-spermatocytes in irradiated rats, showed that the reduction was less marked in animals that, prior to irradiation, were given injections of cysteamine. Studies with the same technique as that used by Kaplan and Lyon (1) have been undertaken in order to reinvestigate the effects of cysteamine on the induction of dominant lethals induced in spermatozoa and appearing as post implantation deaths. There were reasons to suspect that agents protecting against somatic damages ought to be effective with regard to genetic damages. In some recent studies, not yet published, Frolen (personal communication) has shown that there is a difference in the rate of dominant lethal mutations induced in spermatozoa from different strains of mice. Furthermore, these strains had previously been studied with regard to their tolerance to acute irradiation. Frolen et al. (5) showed that one of the two strains was extremely sensitive to irradiation (Albino, LD50(30) = 446 r), whereas the other one was very resistant (CBA, LD5o(30) = 748 r). In studies of induction of dominant lethals it was evident that the rate of mutations was higher in the albino than in the CBA strain. Hence, there is an agreement between the sensitivity to somatic damage, as measured by LD5o(30), and the induction of genetic damages in spermatozoa.