SPECIFIC-LOCUS MUTATION RESPONSE TO UNEQUAL, 1 + 9 GY X-RAY FRACTIONATIONS AT 24-H AND 4-DAY FRACTION INTERVALS

The specific-locus mutation frequency obtained from mouse spermatogonial stem cells following unequal, 1 + 9 Gy[Gray] X-ray fractionation with a 24-h fractionation interval is low, and consistent with the 2 fractions acting additively. The response is therefore markedly different from the augmented mutation frequencies obtained with 500 + 500 R and 100 + 500 R, 24-h fractionations. The lower yield compared with the 100 + 500 R response also indicates a clear difference from the translocation data which demonstrate increases in yield with increasing 2nd dose over the same dose range. The decline in specific locus mutation yield with the increase in the 2nd dose from 500 R to 9 Gy suggests that the stem cells surviving the 1st fraction are heterogeneous in their sensitivities to this class of genetic damage. A similar, additive specific locus mutation frequency is obtained with unequal, 1 + 9 Gy X-irradiation when the interval between fractions is 4 days. This is consistent with 500 + 500 R, 4-day and 7-day interval responses obtained previously but again differs from the sub-additive translocation responses obtained with such X-ray fractionation. Taken together with the data from previous studies the present results suggest that 24 h after the first fraction, the surviving stem cell have 2 components; survivors of the formerly radiosensitive, cycling component of the normal stem cell population and the formerly radioresistant, G0 or arrested G1 cells which are being triggered into a rapid cell cycle to achieve repopulation of the testis; these 2 components are of near-equal sensitivity to translocation induction and cell killing, hence the additive translocation yields with equal X-ray fractionations and yields consistent with those extrapolated from lower doses with higher,unequal fractionations, e.g., 1 + 7 Gy, 1 + 9 Gy; but the formerly radioresistant, triggered component is much more sensitive than the surviving cycling component to specific locus mutation and cell killing, hence the augmented mutation response with 500 + 500 R fractionation and the drop in yield with 1 + 9 Gy compared with 100 + 500 R X-irradiation. Four days after the 1st fraction, the stem cell population has changed but still comprises 2 populations; rapidly-dividing cells which are highly sensitive to killing and newly-established radioresistant cells equivalent to those of a normal stem cell population; translocations recovered from the 2nd fraction derive primarily from the G1 phase of the cell cycle of the rapidly-dividing cells; hence, since G1 is shorter in these cells than in the cycling cells of a normal cell population, the translocation yield is lower; specific-locus mutations recovered from the 2nd fraction derive primarily from the more constant S, G2, M phases of the cell cycle of the rapidly-dividing cells that are common to the cycling component of a normal stem cell population; hence, the additive response for this class of genetic damage.