Translocation yield from the immature mouse testis and the nature of spermatogonial stem cell heterogeneity

Abstract

The response of the immature mouse testis to X-irradiation was found to differ from the adult in three respects. 1. (1) Treatment of 5-day old mice with 300 R or 500 R produced no clear sterile period and even with a 1000 R exposure some animals became fertile at maturity. However, others showed a temporary sterile period or were permanently sterilized. 10-day old mice showed a response which more clearly approximated that of the adult. Comparison with histological observations on rats irradiated when immature suggested that the spermatogonia present at this age are not more radioresistant than those of the adult testis but that surviving cells can procede directly into spermatogenesis rather than first repopulating their numbers as in the adult. 2. (2) Testis weights on reaching adulthood were severely reduced and the degree of effect was found to be dependent upon both radiation dose and age at time of treatment. This was attributed largely to the failure of compensatory repopulation in the immature testis but greater cell killing or lower cell numbers in the immature testis could be contributory factors. 3. (3) Translocation yields from mice irradiated at 5 days of age approximated half that of the adult yield with both 300 R and 500 R treatments. This agrees well with Selby's specific locus mutation data from immature mice. Yields from animals exposed to 1000 R at 3 or 5 days of age were extremely low. Translocation yield from these immature mice thus showed a humped dose-response curve as in the adult. The response from 10-day old mice generally approximated that of the adult, this also agreeing with Selby's findings. It is concluded that the low yields are attributable to the presence of proliferating stem cell populations. As in the adult several days after radiation exposure, the stem cells may have a short cell cycle, be sensitive to radiation killing and yield low levels of genetic damage. A model to account for the heterogeneity in radio-sensitive of spermatogonial stem cell populations both in the adult and immature testis is proposed, this based on Smith and Martin's concept of the cell cycle. The heterogeneity is attributed to a variation in cell cycle times within a single stem cell type. Those in a long G 1 (A state) would be the most radioresistant having greater time available for repair of pre-mutational or pre-breakage lesions before the onset of S, those with a shorter A state, leaving the A state, or in other stages of the cell cycle (SG 2M) would be more radiosensitive and contribute most to the total yield of genetic damage at lower (<600 R) X-ray doses. Under normal conditions most cells will be in G 1 and this will account for most of the genetic damage recovered. However, proliferating cells with a much shorter cell cycle must spend a much higher proportion of their time in S and G 2 and the recovery of both translocations and point mutations from these stages should approximate only one-half of that from G 1 due to chromatid segregation. Yields from short cycling cells such as in the immature testis or in the adult following earlier acute (or chronic) radiation exposure will be lower.