An analytical approach to the induction of translocations in the spermatogonia of the mouse

doi:10.1016/0027-5107(81)90160-3

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

Volume 82, Issue 2, July 1981, Pages 305-321

https://doi.org/10.1016/0027-5107(81)90160-3 Get rights and content

Abstract

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An analysis of a series of data providing a comprehensive impression of the effect of radiation on the induction of translocations in the spermatogonia of the mouse is presented. It is assumed that the spermatogonial stem-cell population is made up of a sensitive and resistant compartment, tha the same type of basic lesion can lead to either translocation induction or cell inactivation, and that the basic lesion has a linear-quadratic dose relationship.
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The same set of parameter values is used to provide a quantitative description of the acute dose-response relationship and the effects of dose-rate and short-term, 24-h and long-term fractionation. The unusual effect of 24-h fractionation can be explained by proposing that the first dose blocks the progression of sensitive cells into the resistant compartment whilst the progression of the resistant cells into the sensitive compartment is unaffected.
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The analysis indicates that (1) the majority of the spermatogonial stem cells in the mouse are in the sensitive compartment; (2) that the yield of translocations is proportional to accumulated dose for chronic radiation schedules; (3) the biology of spermatogenesis should be taken into account when extrapolations are made from one animal species to another.

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The induction of chromosomal damage and cell killing in mouse spermatogonial stem cells following combined treatments with hydroxyurea, 3-aminobenzamide and X-rays
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To analyze in more detail the relation between the sensitivity of spermatogonial stem cells to killing and the induction of genetic damage, mature male mice received combined treatments with hydroxyurea (HU), 3-aminobenzamide (3-AB) and X-rays. Stem cell killing was determined using the repopulation index method and translocations were studied via spermatocyte analysis. HU was administered at 16 or at 48 h before further treatment in order to create stem cell populations with different sensitivities in whic the translocation induction and stem cell killing could be studied and compared. The sensitivities for cell death and genetic damage appeared to be strongly correlated: at 16 h after HU significantly higher values were found than at 48 h or in controls without HU pretreatment.
By using 3-AB in the treatment schedules we were able to investigate whether the sensitization of stem cells towards cell death and genetic damage is the outcome of a radiation- or drug-induced G₁ delay. The effect of 3-AB was most pronounced at 16 h after HU. This confirms that at this interval a large fraction of stem cells is in G₁. Our data therefore indicate that all treatments that induce an enrichment of G₁ cells also result in a sensitization of stem cells to cell killing or the induction of mutagenic damage.
Enhanced specific-locus mutation response of 101/H male mice to single, acute X-irradiation
1994, Mutation Research Regular Papers
The specific-locus mutation yield from 101/H mice following single, acute 6 Gy spermatogonial X-irradiation was significantly higher than both a concurrent C3H/HeH × 101/H F₁ hybrid control and historical data obtained with mice of equivalent genotype. There is therefore discord with the reduced translocation response to single X-ray doses previously identified in this strain.
By contrast, the mutation yield following a 24-h interval 3 + 3 Gy fractionated X-ray dose was not significantly different from that of its concurrent hybrid control, nor from results obtained by others with mice of the equivalent or different genotypes. Here there is no discord with the translocation response obtained with a 1 + 5 Gy 24-h interval fractionated regime.
Appraisal of comparable specific-locus and translocation data indicates that the differing results obtained with and two genetic end-points are not without precedence. This, together with the observation that the responses for cytologically visible deletions and specific-locus mutations are similar, suggests that the latter two events predominantly derive from one-hit events, with translocations deriving from two-hit events and that the probabilities of induction of each type of lesion vary according to the organisation of the nucleus in different phases of the cell cycle.
The radiosensitivity of spermatogonial stem cells in C3H/101 F<inf>1</inf> hybrid mice
1993, Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
The radiosensitivity of spermatogonial stem cells of C3H/HeH × 101/H F₁ hybrid mice was determined by counting undifferentiated spermatogonia at 10 days after X-irradiation. During the spermatogenic cycle, differences in radiosensitivity were found, which were correlated with the proliferative activity of the spermatogonial stem cells. In stage VIII_irr, during quiescence, the spermatogonial stem cells were most radiosensitive with a D₀ of 1.4 Gy. In stages XI_irr−V_irr, when the cells were proliferatively active, the D₀ was about 2.6 Gy. Based on the D₀ values for sensitive and resistant spermatogonia and on the D₀ for the total population, a ratio of 45:55% of sensitive to resistant spermatogonial stem cells was estimated for cell killing.
When the present data were compared with data on translocation induction obtained in mice of the same genotype, a close fit was obtained when the translocation yield (Y; in % abnormal cells) after a radiation dose D was described by Y = e^τD, with τ = 1 for the sensitive and τ = 0.1 for the resistant spermatogonial stem cells, with a maximal e^τD of 100.
A quantitative study of spermatogonial multiplication and stem cell renewal in the C3H/101 F<inf>1</inf> hybrid mouse
1993, Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
In whole mounts of seminiferous tubules of C3H/101 F₁ hybrid mice, spermatogonia were counted in various stages of the epithelial cycle. Furthermore, the total number of Sertoli cells per testis was estimated using the disector method. Subsequently, estimates were made of the total numbers of the different spermatogonial cell populations per testis.
The results of the cell counts indicate that the undifferentiated spermatogonia are actively proliferating from stage XI until stage IV. Three divisions of the undifferentiated spermatogonia are needed to obtain the number of A₁ plus undifferentiated spermatogonia produced each epithelial cycle. Around stage VIII almost two-thirds of the A_pr and all of the A_al spermatogonia differentiate into A₁ spermatogonia. It was estimated that there are 2.5 × 10⁶ differentiating spermatogonia and 3.3 × 10⁵ undifferentiated spermatogonia per testis. There are about 35,000 stem cells per testis, constituting about 0.03% of all germ cells in the testis. It is concluded that the undifferentiated spermatogonia, including the stem cells, actively proliferate during about 50% of the epithelial cycle.
X-ray induced translocations in premeiotic germ cells of monkeys
1991, Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
The induction of reciprocal translocations by various X-ray exposures was studied in spermatogonial stem cells of rhesus monkeys (Macaca mulatta) and stump-tailed macaques (Macaca arctoides) by means of spermatocyte analysis many cell generations after irradiation. The yields of translocations recovered from irradiated stump-tailed macaques were lower than those observed in rhesus monkeys and represent in fact the lowest induction rates per Gy ever recorded for experimental mammals. In the rhesus monkey a humped dose-effect relationship was found with (a) a homogeneous response with (pseudo-)linear kinetics below 1 Gy, (b) much more variability at higher doses, and (c) no induction at all at doses of 4 Gy and above. It is suggested that the post-irradiation proliferation differention pattern of surviving rhesus monkey spermatogonial stem cells is mainly responsible for these characteristics of the dose-response curve.
The relationship between induced reciprocal translocations and cell killing of rhesus monkey spermatogonial stem cells after combined treatments with follicle-stimulating hormone and X-rays
1991, Mutation Research Letters
The induction of reciprocal translocations in spermatogonial stem cells of monkeys (rhesus and crabeating), visualized in dividing primary spermatocytes, was studied after combined treatments with folliclestimulating hormone (FSH, 54 IU/kg/week) and X-rays (1 Gy). No clear differences in the frequencies of induced translocations between FSH-pretreated and non-pretreated animals were recorded. Comparison of these translocation data with studies on cell killing in the same monkeys shows that the ratio between the probabilities that radiation-induced basic lesions kill a cell or produce translocations (the p/c ratio) is of the same order of magnitude as that observed for the mouse. Consequently the well documented differences in radiation response between the rhesus monkey and the mouse cannot be explained by differences in the p/c ratio. It is concluded that differences in multiplication-differentiation patterns of surviving stem-cell spermatogonia after irradiation are probably responsible for the observed differences between mice and rhesus monkeys.

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