Induction Of Dominant Lethals Research Articles

Dominant lethal effects of nocodazole in germ cells of male mice

The ability of the anticancer drug, nocodazole, to induce dominant lethal mutations in male germ cells was investigated by the in vivo dominant lethal test. Mice were treated with single doses of 15, 30 and 60 mg/kg nocodazole. These males were mated at weekly intervals to virgin females for 6 weeks. Nocodazole clearly induced dominant lethal mutations in the early spermatid stage with the highest tested dose. Mice treated with 60 mg/kg nocodazole showed an additional peak of dominant lethal induction in mature spermatozoa during the first week matings after treatment. The percentage sperm count and sperm motility were significantly decreased after treatment of males with 30 and 60 mg/kg nocodazole. Moreover, the middle and highest doses of nocodazole significantly increased the percentage of abnormal sperm. Our study provides evidence that nocodazole is a germ cell mutagen. Marked alteration in the spermiogram analysis after nocodazole treatment possibly confirms that nocodazole has a significant effect on sperm maturation and development during storage and transit. The demonstrated mutagenicity profile of nocodazole may support further development of effective chemotherapy with less mutagenicity. Moreover, the cancer patients and medical personnel exposed to this drug chemotherapy may stand a higher risk for abnormal reproductive outcomes.

Germ cell mutagenicity of topoisomerase I inhibitor topotecan detected in the male mouse-dominant lethal study

To investigate the ability of topotecan, a topoisomerase I-targeting anticancer drug, to induce dominant lethal mutations in male mouse germ cells, males were treated with single doses of 3, 6 and 12mg/kg topotecan. Each male was mated at 4-day intervals to virgin females for a total of nine 4-day mating intervals. The two highest doses of topotecan are shown to be mutagenic in post-meiotic cells. The greatest effect occurred in those cells which were in the early-spermatid stage at the time of exposure. Mice treated with 12mg/kg topotecan showed an additional peak of dominant lethal induction in mature sperm during the first 4-day matings after treatment. The mutagenic effects were directly correlated with free radicals accumulation as an obvious increase in the generation reactive oxygen species and 8-hydroxydeoxyguanosine was noted in animals treated with 6 and 12mg/kg topotecan. Treatment of male mice with N-acetylcysteine, a free radical scavenger, significantly protected mice from topotecan-induce dominant lethality. Moreover, N-acetylcysteine had no antagonizing effect on topotecan-induce topoisomerase-I inhibition. Our study provides evidence that topotecan is a germ cell mutagen and its effect is more pronounced during the post-meiotic stages through a mechanism that may involves increases in DNA oxidative stress.

Dominant lethal mutations of topoisomerase II inhibitors etoposide and merbarone in male mice: a mechanistic study

Two topoisomerase II inhibitors, etoposide and merbarone, were tested for the induction of dominant lethal mutations in male mice. Etoposide was administered at a dosage of 30 or 60 mg/kg. Merbarone was administered at a dosage of 40 or 80 mg/kg. These males were mated at weekly intervals to virgin females for 6 weeks. In the present experiments, regardless of the agent, spermatids appeared to be the most sensitive germ-cell stage to dominant lethal induction. Etoposide and merbarone clearly induced dominant lethal mutations in the early spermatid stage only with the highest tested doses. The mutagenic effects were also directly correlated with reactive oxygen species accumulation as an obvious increase in 2',7'-dichlorofluorescein fluorescence level was noted in the sperm of animals treated with higher doses of etoposide and merbarone. Treatment of male mice with N-acetylcysteine significantly protected mice from etoposide- and merbarone-induced dominant lethality. Moreover, N-acetylcysteine treatment had no antagonizing effect on etoposide- and merbarone-induced topoisomerase II inhibition. Overall, this study provides for the first time that etoposide and merbarone induce dominant lethal mutations in the early spermatid stage through a mechanism that involves increases in oxidative stress. The demonstrated mutagenicity profile of etoposide and merbarone may support further development of effective chemotherapy with less mutagenicity.

Comparative strain and hybrid investigation of dominant lethals and reciprocal translocations induced to mouse spermatogonia.

Dominant lethals and translocation induction were assayed in mice after 276 R spermatogonial X-irradiation. Inbred A/Jax strain matings showed a much higher foetal mortality than did the CBA strain matings both in controls and in irradiated groups. No significant irradiation induction of dominant lethals was found. No strain-by-treatment interaction in embryonic death was found for males of either strain when mated to CBA females. Neither did the dominant lethal study reveal any differences between the two types of reciprocal hybrids between the strains, mated to CBA females, albeit the irradiated F1 (A/Jax x CBA) group showed a significant increase of foetal mortality compared to its control. The frequencies of spermatocytes with translocations after spermatogonial irradiation of CBA, A/Jax, F1 (CBA x A/Jax) and F1 (A/Jax x CBA) males were 0.040, 0.044, 0.047 and 0.047 respectively. No translocations were found in the control males. The estimates of the amount of dominant lethals expected from these frequencies seem to be somewhat higher than the actual results. The variances for the means of spermatocytes with translocations were significantly higher for both types of hybrids than for both strains.

Chlornaphazine and chlorambucil induce dominant lethal mutations in male mice.

Two antineoplastic agents, chlornaphazine (CN) and chlorambucil (CHL), were tested for the induction of dominant lethal mutations in male mice. Both compounds are nitrogen mustard derivatives and have been shown to be genotoxic in a variety of organisms. CN was administered intraperitoneally to DBA/2J male mice at a dosage of 0, 500, 1000, or 1500 mg/kg body weight (bw). Immediately following treatment, each male was mated at 4-day intervals to two virgin C57BL/6J females. CHL was administered intraperitoneally to C3H/HeJ and DBA/2J males at a dosage of 0, 2.5, or 5.0 mg/kg bw. These males were mated at weekly intervals to two virgin T-stock females. CN and CHL clearly induced dominant lethal mutations. CN induced dominant lethal effects in all post-meiotic germ-cell stages of treated DBA males, with a clear dose-response relationship. The results with CHL-treated DBA males indicated that all post-meiotic germ-cell stages, except late-spermatids, were affected by CHL treatment, while in C3H males, CHL induced dominant lethal effects in all post-meiotic germ-cell stages. A dose-response relationship was also observed with CHL in C3H male mice. In the present experiments, regardless of the agent or the mouse strain used, spermatids appeared to be the germ-cell stage most sensitive to dominant lethal induction.

Induction of dominant lethals in progeny of male CBA mice after pheromonal action

The inhibiting effect of pheromone 2,5-dimethylpyrazine of house mouse females on the reproductive function of the CBA male mice was studied. The mutagenic effect of six-day pheromonal effect was assessed by dominant lethal test. Analysis for the frequency of dominant lethals showed that the pheromonal effect results in an increased death rate of the progeny of the treated males. This is probably explained by implantation failure and is expressed in a reduced average number of the implantation sites and low live embryos per female. The proportion of females with live embryos decreased significantly. The implication of the effect of female mouse pheromone 2,5-dimethylpyrazine on the genetic processes in germ cells of male mice is discussed.

The Interaction of the rad201Gene with Genes mei-9and mei-41in Germline Cells of DrosophilaFemales

The effect of Drosophilamutation rad201G1together with mutations mei-41D5and mei-9aon the sensitivity of oocytes to induction of dominant lethals (DLs) was studied. To this end, the frequencies of spontaneous and gamma-radiation-induced DLs in consecutive egg batches of females carrying double or single mutations were estimated. Since the effects of the mutations examined are expressed only at the previtellogenetic stages of oogenesis, only newly hatched (0–5-hour-old) females, whose oocytes did not develop farther than stage 7, were irradiated. The results obtained indicated that in intact and irradiated oocytes of double mutants mei-9arad201G1and mei-41D5rad201G1, mutation rad201G1epistatically suppresses the mutations of the both meigenes.

Reproductive toxicity of 1,3-butadiene in the mouse: cytogenetic analysis of chromosome aberrations in first-cleavage embryos and flow cytometric evaluation of spermatogonial cell killing

Reproductive effects of 1,3 butadiene inhalation have been evaluated in male mice by reduction of post-meiotic germ cells, alteration of sperm chromatin structure and transmission of chromosome aberrations to one-cell embryos. Animals were exposed for 5 consecutive days for 6 h per day to butadiene concentrations of 130, 500 or 1300 ppm. The testicular fraction of post-meiotic germ cells was measured by flow cytometric analysis on the basis of their DNA content. Round spermatids were discriminated from mature, elongated spermatids by their different degree of chromatin condensation. Butadiene-induced cytotoxic effects on differentiating spermatogonia were shown by a concentration-dependent decrease of round spermatids occurring 21 days after chemical exposure, confirmed by a similar decrease of elongated spermatids measured in testes sampled 7 days later. Statistically significant effects were seen already at 130 ppm. An incomplete repopulation of the elongated spermatid compartment observed 35 days after exposure to 1300 ppm suggested that, at the highest concentration tested, butadiene toxicity extended to stem cells. Alterations of sperm chromatin were revealed by its increased sensitivity to acidic denaturation in situ. The percentage of abnormal sperm was significantly increased after butadiene exposure of differentiating spermatogonia and spermatocytes. This suggested the induction of persistent effects interfering with chromatin remodelling during spermiogenesis. Chromosome-type structural aberrations were significantly elevated in first-cleavage embryos conceived by males mated during the first and second week after the end of exposure. The lowest effective tested concentration was 500 ppm, the same reported for dominant lethal induction under identical exposure conditions. As in the dominant lethal assay, the effect of this dose was confined to exposed sperm, while both sperm and late spermatids were affected by the inhalation of 1300 ppm. A quantitative comparison between the effects induced by intraperitoneal injections of diepoxybutane or butadiene inhalations suggested that other reactive intermediates, in addition to diepoxybutane, might contribute to mediate butadiene-induced reproductive toxicity.

Male-mediated F 1 effects in mice exposed to 1,3-butadiene

We examined the effects on dominant lethality, the incidence of fetal abnormalities and tumour incidence in surviving offspring of acute and subchronic exposure of male mice by inhalation to the industrial monomer, 1,3-butadiene. In the acute study, CD-1 mice were exposed to atmospheres containing 0 ( n = 25), 1250 ( n = 25) or 6250 ppm ( n = 50) for 6 h, and each male was caged 5 days later for 1 week with two untreated virgin females. One of the females was killed humanely on day 17 of gestation. The other was allowed to deliver and rear her litter and the litters were monitored throughout adulthood. The killed female was examined for the number of live foetuses, the number of post implantation deaths (early and late) and the number and type of any gross malformations. In the subchronic study, males were exposed to 0 ( n = 25), 12.5 ( n = 25) or 1250 ( n = 50) for 6 h per day on 5 days per week for 10 weeks and then mated the next morning. Mating and observation details were as for the acute study. Acute exposure to butadiene resulted in only a small decrease in implantations; after 10 weeks' subchronic exposure with either the high or low concentration, however, a wide variety of statistically significant effects was seen. At 1250 ppm, the number of implantations was reduced, dominant lethal mutations were induced, and the incidences of early and late deaths were increased; some of the live foetuses were malformed. The low dose also increased the frequency of malformations and late deaths but it did not affect the number of early deaths. Skeletal examination of malformed foetuses, randomly selected normal litter mates and controls confirmed the abnormalities seen at necropsy in malformed foetuses. However, karyotypic analysis of foetal liver from malformed foetuses, randomly selected normal litter mates and controls showed no karyotypic abnormalities. The number of gross suspected tumours in the F 1 adults did not appear to reveal an increase over control values. Thus, butadiene is mutagenic in the germ cells of male mice, as shown by the induction of dominant lethality at 1250 ppm, and the frequencies of late deaths and congenital malformations appear to be increased at the subchronic level of 12.5 ppm and skeletal examination of malformed foetuses confirmed the macroscopic abnormalities.

Chlorambucil and bleomycin induce mutations in the specific-locus test in female mice

Specific-locus studies have shown chlorambucil (CHL) and bleomycin (BLE) to be mutagenic in mouse oocytes, almost doubling the number of chemicals previously known to induce mutations in females. The overall CHL-induced mutation rate in oocytes is, however, one order of magnitude below that for male meiotic and postmeiotic stages, and only 1 50 that for early spermatids. For BLE, no specific-locus data for males are available for comparison, but the chemical had earlier been found negative for dominant-lethal induction in males. Both BLE and CHL were significantly mutagenic only in mature and maturing oocytes. In keeping with an earlier report, BLE produced a high incidence of dominant lethals in these stages. CHL failed to induce dominant lethals, indicating that for mature and maturing oocytes, in contrast with results for males, sensitivity to dominant-lethal mutations is not a prerequisite for induction of specific-locus mutations. Exposure of immature oocytes to either BLE or CHL produced neither dominant lethals nor significant induction of specific-locus mutations; however, CHL gave evidence of killing immature oocytes. By contrast, BLE, which has been considered a radiomimetic chemical, does not appear to kill immature oocytes and thus differs markedly from radiation exposures equivalent for dominant-lethal induction. Therefore, the failure to recover specific-locus mutations cannot be ascribed to cell selection resulting from oocyte killing, as has sometimes been done for radiation. Adding results on the nature of the CHL- and BLE-induced mutations to prior information, the estimated minimum proportion of large DNA lesions induced in oocytes by chemicals becomes 35.3%, significantly different from the corresponding figure (∼ 70%) for radiations. For chemical treatments, the oocyte proportion is highly significantly above the 3.6% induced in spermatogonia, but only on the borderline of statistically significant difference from that induced in postspermatogonial stages.

Effects of gamma-radiation on mature pupae of maize borer, Chilo partellus (Swinhoe) (Lepidoptera: Pyralidae)

Mature (5- to 6-day-old) male and female pupae of C. partellus were irradiated at 5 to 20 kilo-Roentgen (kR) and 5 to 10 kR respectively. Emergence of normal appearing moths, pupal periods and adult longevities remained statistically unaffected. Fecundity of normal (nonirradiated) females mated with males irradiated as pupae was nonsignificantly different from control, but fecundity of females irradiated as pupae at 10 kR was significantly reduced when they were mated with normal mates. Dominant lethals of varying intensities were induced at 5–20 kR. However, induction of dominant lethality was sex- as well as dose-dependent. Radiation doses inducing 100% dominant lethals in sperm (20 kR) and ova (5 kR) did not mitigate the mating ability of males and receptivity of females. However, receptivity of females was reduced significantly when they were irradiated as pupae at 10 kR. Rates of embryonation in F1 eggs were significantly reduced when normal females were crossed with males irradiated as pupae at 20 kR, but similar effect was observed at 10 kR in reversed crosses. Embryonic development was delayed in eggs obtained from crosses, where male or female parent was irradiated in pupal stage, but in both cases most of the dominant lethals acted late in embryonic development.

Dominant lethality in mice--a test for mutagenicity of influenza X-31 virus.

The induction of dominant lethal mutation in germ cells is the cause of embryonic death resulting in the reduction of litter size in the F1 progeny. Dominant lethal mutations were induced when male mice were infected with live A2 influenza virus. The chromosomal aberrations induced in the germ cells were shown to be responsible for the dominant lethality. Killed influenza virus was also potent in inducing chromosomal aberrations in spermatocytes of mice. In light of these observations, the UV-inactivated virus was tested for its potency in induction of dominant lethality in both female and male germ cells. The virus-inoculated females were mated with uninjected males and vice versa. Both the inactivated and live virus were found to induce dominant lethality in both female and male mice, indicating that not only the live virus but also the inactivated virus is capable of bringing about chromosomal damage resulting in dominant lethality.

Studies of the induction of dominant lethals and translocations in male mice after chronic exposure to microwave radiation.

Male C3H mice were exposed to 100 W m-2 of 2.45 GHz continuous-wave microwave radiation for 6 h per day for a total of 120 h over an 8-week period. The exposure level was chosen so that the specific energy absorption rate (SAR) would be approximately equal to the level of 4 W kg-1 which is considered by a number of organizations to be a threshold for adverse biological effects. At the end of the treatment period the mice were mated with a different group of (C3H x 101) F1 hybrid females each week for the following 8 weeks. There was no significant reduction in pregnancy rate, preimplantation survival or postimplantation survival in the exposed group compared to sham-exposed controls. At the end of the mating period a cytogenetic analysis was carried out of meiotic chromosome preparations of testicular tissue, thus sampling cells that were stem cell spermatogonia during the treatment regime. The results showed no difference in the frequency of reciprocal translocations between the sham and treated groups, or in the frequency of cells with autosome or sex chromosome univalents. Low levels of fragments and exchanges were found in both groups. It is concluded that there is no evidence in this experiment to show that chronic exposure of male mice to 2.45 GHz microwave radiation induces a mutagenic response in male germ cells. This conclusion is in agreement with the observations of Berman et al. (1980), who reported a lack of male germ cell mutagenesis after repetitive or chronic exposure of rats to 2.45 GHz.

The relationship between radiation-induced and transposon-induced genetic damage during Drosophila spermatogenesis

The combined effect of transposon mobility and X-rays on X-linked recessive lethals and dominant lethals was measured in the germ line of F 1 male hybrids in the P-M system of hybrid dysgenesis. X-linked lethal mutation rate was measured in the chromosome derived from the P-strain father of the M × P cross. Mutations induced in irradiated dysgenic males were compared to those of unirradiated males, as well as to irradiated nondysgenic males derived from M × M crosses. Three four-day broods of sperm were tested for both X-linked lethals and dominant lethals. X-linked lethal mutation rate in dysgenic control males was 6.38%, 6.36% and 4.55% in broods 1, 2 and 3 respectively, thus showing a decrease in older males. The mutation rate in the same broods of irradiated, nondysgenic control males was 3.66%, 4.46% and 6.38%, respectively. The rate obtained in dysgenic irradiated males was 10.33, 11.16 and 7.97 in the same 3 broods. These results demonstrate that when X-rays and P element mobility were and 7.97 in the same 3 broods. These results demonstrate that when X-rays and P element mobility were combined as a source of mutagenesis, a strickly additive effect on genetic damage was observed in the first two broods of sperm which represent primarily mature sperm and spermatids respectively. The third brood, representing mostly spermatocytes showed a less than additive effect, probably due to germinal selection. In contrast, the induction of dominant lethals showed a clearly synergistic effect in the last two Broods of sperm tested, when X-rays and transposon mobility were combined. The X-ray component of dominant lethlity in brood 1, representing mostly mature spermatozoa, was negative, indicating a lower than expected lethality induced by X-irradiation in the presence of P element mobility. The X-ray-induced component of dominant lethality, was expressed as the per cent of embryo lethality after adjusting the results obtained with each brood of sperm from nondysgenic and dysgenic males to their respective unirradiated controls. These values were 32.3%, 30.5% and 64.7% for brood 1, 2 and 3 respectively from nondysgenic males, and 14.1%, 56.1% and 71.4% for the same broods from dysgenic males. Thus the differential effect of X-rays in sperm broods 1, 2 and 3 was −18.2, +25.6 and +6.7% respectively. These results suggest that the synergistic effect may be due to the common component of X-ray and P element-induced genetic damage, namely chromosome breaks, and that the interaction of these lesions resulted in a greater than additive number of of unrestitude chromosome breaks and nonviable chromosomal rearrangements.

Frequency of congenital defects and dominant lethals in the offspring of male mice treated with methylnitrosourea

ICR strain male mice injected intraperitoneally with daily doses of MNU (5–25 mg/kg) for 5 days and mated to untreated virgin females of the same strain on days 1–7, 8–14, 15–21 and 64–80 after the last dose. Copulations during these periods involve, respectively, spermatozoa, late spermatids, early spermatids, and spermatogonial stem cells at the time of the last treatment. The uterine contents were examined on day 18 of pregnancy for post-implantation losses (dominant lethality). Fetuses were examined for exteranal and skeletal abnormalities. In contrast to the results reproted for specific-locus mutations, MNU treatment of either postmeiotic cells or spermatogonial stem cells caused dose-dependent significant increases in the incidence of congenital defects and of dominant lethals over the control levels. The relative sensitivity of germ cells sampled on days 1–7, 8–21 and 64–80 to MNU-induced congenital defects was 1:1.6:2. For the induction of dominant lethals, the sensitivity ratio was 1:1.8:0.5. It is proposed that congenital defects in the offspring of mice following paternal treatment with MNU may represent mostly chromasomal rather than genic changes. Cleft palate was the most frequent of the external abnormalities, which were significantly induced in every treatment series; fused ribs were the most frequent of the skeletal abnormalities, which were significatly induced in the treatment series for spermatogonial stem cells.

The use of a battery of strains of mice in a factorial design to study the induction of dominant lethal mutations

The induction of dominant lethality following oral dosing of males with 200 mg/kg of cyclophosphamide was investigated using a factorial experimental design. Males from 3 genotypes, BALB/c, CBA/Ca and CBA/Ca × C57BL/6JF 1 hybrid (CBB6F 1) were mated to 6 females of the same genotype as the males over 3 weeks. Cyclophosphamide reduced the mating frequency of the BALB/c and CBA/Ca males. The total number of implants/female was reduced in all 3 genotypes with the greatest effect in the first 2 weeks after the males were treated. The proportion of early deaths/litter was significantly increased in CBA/Ca and CBB6F 1 but the increase was smaller and non-significant with BALB/c. There was a high incidence (29.8%) of early deaths in the control BALB/c females. Statistical analysis of the ratio of early deaths to total implants in a litter using either the Freeman-Tukey binomial or the arc-sine transformation gave similar and satisfactory results. Analysis of early death data rather then the ratio of early deaths: total implants would have led to misleading conclusions. The implications of the use of a factorial design in dominant lethal assays for the detection of strain variation in mutagenic response without an increase in animal usage is discussed.

Study of the base analog 6-mercaptopurine in the mouse specific-locus test

The base analog 6-mercaptopurine (6MP) was studied in the mouse specific-locus test in various male germ-cell stages. The overall finding of 3 mutations in 65 376 offspring rules out (at the 5% significance level) and induced mutation rate greater than 1.22 times the historical control rate. For spermatogonial stem cells alone, the multiple ruled out is 3.7; and for postspermatogonial stages, it is 0.7. For late differentiating spermatogonia and preleptotene spermatocytes, stages that had earlier been found sensitive to dominant-lethal induction (a result confirmed in the present experiment), tthe results (0 mutations in 5214 offspring) do not rule out a positive effect; they indicate only that the induced rate is unlikely to be greater than 9.8 times the historical control rate. There is evidence that 6MP (or an active metabolite) reaches all germ-cell stages of concern. Because spermatogonial stem cells are not killed, the negative mutation mutation-rate results cannot be attributed to cell selection.

Efficiency of different methods of EMS application for the induction of dominant lethals in germ cells of medfly, Ceratitis capitata (Wied.), males

EMS (ethyl methanesulfonate) fed to adult Mediterranean fruit flies in 10% sugar water was found to be the most effective treatment for the induction of dominant lethals in male germ cells. This application procedure showed a direct regression between the log concentration of EMS and the probit F1 egg lethality, provided a reasonably uniform uptake of EMS by the exposed males, and was non-toxic at the relevant concentrations. The same application procedure, but employing 1% sugar water, was also non-toxic to the treated males but resulted in large variations in the rate of uptake of the mutagen, thus producing no clear correlation between the concentration of EMS and dominant lethality. Injection of adult males with EMS caused high parental mortality and caused a severe reduction in mating propensity at concentrations below that causing dominant lethality. Dominant lethality was observed in all treatment procedures as a reduction in egg hatchability, whereas adult emergence from surviving pupae was never affected. A small, but significant, reduction in pupal production from hatched eggs was observed in the treatment involving “egg/larval feeding” and in all adult treatments, but in no case could this be correlated to the concentration of EMS. The high levels of radioactivity, observed in the testes of males treated with 14C-labelled EMS through feeding of adults (10% sugar), in spermathecase of females mated to these males and in resultant F1 eggs, suggest that a major portion of the label reaching the testes was associated with the sperm itself rather than with other parts of the testes or the seminal fluid.

Relative genetic efficiency of some radionuclides in mammals

ICR strain male mice injected intraperitoneally with daily doses of MNU (5–25 mg/kg) for 5 days and mated to untreated virgin females of the same strain on days 1–7, 8–14, 15–21 and 64–80 after the last dose. Copulations during these periods involve, respectively, spermatozoa, late spermatids, early spermatids, and spermatogonial stem cells at the time of the last treatment. The uterine contents were examined on day 18 of pregnancy for post-implantation losses (dominant lethality). Fetuses were examined for exteranal and skeletal abnormalities. In contrast to the results reproted for specific-locus mutations, MNU treatment of either postmeiotic cells or spermatogonial stem cells caused dose-dependent significant increases in the incidence of congenital defects and of dominant lethals over the control levels. The relative sensitivity of germ cells sampled on days 1–7, 8–21 and 64–80 to MNU-induced congenital defects was 1:1.6:2. For the induction of dominant lethals, the sensitivity ratio was 1:1.8:0.5. It is proposed that congenital defects in the offspring of mice following paternal treatment with MNU may represent mostly chromasomal rather than genic changes. Cleft palate was the most frequent of the external abnormalities, which were significantly induced in every treatment series; fused ribs were the most frequent of the skeletal abnormalities, which were significatly induced in the treatment series for spermatogonial stem cells.

Discrimination between the effects of X-ray irradiation of the mouse oocyte and uterus on the induction of dominant lethals and congenital anomalies: II. Localised irradiation experiments

In order to evaluate whether irradiation of the postimplantation maternal environment contributed to the induction of postimplantation mortality or congenital anomalies, mouse ovaries were surgically exteriorised and selectively irradiated or shielded in a specially constructed apparatus. The results show that exposure of the mouse abdomen and uterus to 3.70 Gy X-rays, 15–21 days prior to conception, has no significant effect on the incidence of either postimplantation mortality or congenital anomalies. Exposure of the ovaries to 3.27 Gy X-rays during the same period, however, increased the frequency of both postimplantation mortality and congenital anomalies.