William Sheridan

The effects of acute single or fractionated X-ray treatment on mouse spermatogonia

A group of CBA male mice were irradiated with a total dose of 275-R X-rays to the spermatogonia in 55 daily fractions of 5 R. A second group received 275 R in one acute irradiation. A control group was kept. In studies of the dominant lethality among ofsspring measured as intra-uterine death the acute single dose males had a significantly higher rate than the control. The fraction irradiated males did not differ significantly from the control. F1 females from the irradiated groups showed no significant effects on productivity or fertility when compared to the control. There were no indications of increased mutation rates for sex-linked recessives among offspring to either irradiated group. Investigation of the rates of intra-uterine death in back-crosses between F1 males and their F2 daughters did not reveal any significant increase in the frequency of recessive lethals in the irradiation groups as compared to the control. This indicates that the rates of induction of recessive lethals are quite low. It was concluded that there was no evidence that the administration of an irradiation dose in many small fractions leads to an increased mutation frequency.

The relationship between the number of implantations and the rate of intra-uterine death in mice.

Abstract Our attention has been called to a possible source of error in studies of mutations manifested as intra-uterine death, namely exaggeration of the rate of death by litter-mate correlation. Examination of data from several experiments has shown that in our CBA strain we have no indication of litter-mate correlation. A model is presented based on the supposition that the probabilities for different death rates are themselves normally distributed. It is shown that with a standard error of ± 2%, the hypothetical distribution fits the observed data better than the assumption of a constant rate of death.

The effects of the time interval in fractionated x-ray treatment of mouse spermatogonia.

Abstract Male CBA strain mice were submitted to fractionated radiation treatment of spermatogonia. Effects of doses of 300 R + 300 R, 400 R + 400 R and 500 R + 500 R with time intervals of 24, 48, 72 and 144 h between irradiations were studied. Intervals of 24, 48 or 72 h prolonged the post-irradiation sterile period compared with doses given in a single treatment or with an interval of 144 h. This was interpreted as an indication that the shorter intervals led to a greater amount of cell killing. In matings with CBA females all irradiated groups gave higher rates of intrauterine death and lower implantation rates than controls. Differences between irradiated groups within series imply that even the rate of dominant lethals may be increased by application of the dose in fractions. The results lead to the conclusion that time intervals of up to 72 h between irradiation doses may increase the amount of genetic damage compared with the same total dose given as a single treatment.

Expression of TEM-induced damage to postmeiotic stages of spermatogenesis of the mouse during early embryogenesis I. Investigations with in vitro embryo culture

After treatment of postmeiotic stages of spermatogenesis of the mouse with TEM, dose and stage of spermatogenesis-dependent disturbances of the early embryonic development can be observed both in vivo and after in vitro culture of the embryos. The observations in both systems can be correlated. The embryo-culture system thereby enables analysis of the expression of mutagen-induced damage more accurately than the in vivo dominant lethal test. With the doses used (0.2 and 0.4 mg/kg) TEM-treatment of the fathers did not affect the rate of fertilized and cleaving eggs during the first three weeks post-treatment but severely disturbed the further development of the embryos at all stages up to implantation, exhibiting a maximum effect on morulae.

The induction by x-irradiation of dominant lethal mutations in spermatogonia of mice.

Abstract Investigation was made of the amount of dominant lethality found among offspring of male mice after irradiation of the spermatogonia with 550 R X-rays. A significantly greater rate of death was observed in the X-ray group when compared with the corresponding controls. The effects were constant and continued over a long period of time. The effect was also evident in outcrosses to another strain. No evidence of fluctuations in the results which might indicate intra-tissue selection or clustering was noted. Tests of F 1 sons of the irradiated and control groups presented no differences between the groups. There were no indications of chromosomal effects leading to semi-sterility, or dominant lethal genes with incomplete penetrance producing higher death rates. A higher rate of intra-uterine death was observed among F 1 females of the X-ray group when compared to the control.

The frequency of recessive lethals in an irradiated mouse population.

Abstract Male offspring of the 14th generation of a mouse population in which the males of each generation were given 276 R X-rays to the spermatogonia were mated in back-crosses to their daughters in order to determine the rate of recessive lethals. They were also outcrossed to females of the CBA strain for studies of dominant effects. Male offspring of the corresponding control population were tested in a similar way. The rate of induced recessive lethals among the offspring to the irradiated population was calculated to be 8.46%. Comparisons of results in the dominance tests for males assumed to be lethal-free and those suspected of being heterozygous for recessive lethals gave no indications of overall dominant deleterious effects which might have led to selection against lethal bearers. It is concluded that the low frequency of induced recessive lethals is probably due to a low rate of induction.

The dominant effects of a recessive lethal in the mouse.

Abstract A presumably new mutant occured spontaneously in the CBA strain. The mutant is a recessive lethal with a dominant spotting effect. The fertility and productivity of mutant-bearing males and females was compared with that of non-mutant sibs in matings to CBA strain animals. Mutant males had a significantly lower mating prowess than their normal brothers. They also gave a somewhat increased rate of intra-uterine death and a slightly reduced implantation rate. Mutant females showed a lower litter-size at birth than their normal sisters. They also exhibited tendencies to more often lose litters completely. It is concluded that due to the dominant deleterious effects a mutant of this type might be more rapidly eliminated from a population. However, no general conclusions concerning recessive lethals can be drawn since studies of other lethals which do not have dominant morphological characteristics have given no indications of the existence of overall dominant deleterious effects.

The radiosensitivity of offspring of an irradiated mouse population: I. Effects on the reproductive capacity of irradiated female offspring

Abstract Female offspring to the 13th generation of a population in which the males have been irradiated with 276 R X-rays to the spermatogonia in each generation, and offspring from the corresponding control population were irradiated with doses of 65 R or 100 R and their production studied. No significant differences between the groups at either dose level were found in numbers of litters or in litter size. An increase in length of the gestation period was noted in all groups. The feasibility of using reproductive capacity as an alternative to mortality in determining differences in radiosensitivity is considered. It is concluded that offspring to unirradiated groups do not stand a lesser risk from irradiation than offspring to previously irradiated groups.

GENETIC EFFECTS OF SUPRA-LETHAL X-RAY TREATMENT OF MALE MICE

Abstract The F1 sons of male mice (CBA) which had been irradiated with 1092 R X-rays were studied. (The fathers had received bone marrow injections following irradiation and regained fertility after some months, thus the F1 animals had one genome irradiated in the spermatogonial stage.) Dominant lethality and dominant subviability effects were studied for each individual F1 male in backcrosses to females of the CBA strain. The frequency of recessive lethals was estimated from the results of matings of the F1 males with their daughters compared with crosses with daughters of other F1 males. Three males of the total 110 tested showed semi-sterility. The suspected presence of dominant subviability mutations in 10 other males could not be verified in retests. The rate of recessive lethals was calculated to be approximately 10 per cent.

THE RADIOSENSITIVITY OF OFFSPRING OF AN IRRADIATED MOUSE POPULATION. II. THE EFFECTS OF ACUTE OR FRACTIONATED DOSES OF X RAYS ON MALE OFFSPRING.

Abstract The LD 50 value for male offspring of a mouse population in which the sires of each generation have received 276 R X-irradiation to the spermatogonia was determined. The LD 50 values for the corresponding control populations offspring, and the CBA strain from which the populations derive, were also determined. Offspring of the 3 groups were also submitted to fractional doses of X-rays totalling 1400 R, and the survival time observed. No differences in LD 50 , or survival after fractionated exposures, were observed between the irradiated population offspring and offspring of the control. The CBA strain mice showed a greater radiosensitivity than either population in all experiments. It is concluded that ancestral irradiation does not necessarily lead to a decrement which will be manifested as a difference in response to irradiation.