Molecular analyses of in vivo hprt mutant T cells from atomic bomb survivors

Abstract

In vivo-derived hprt-deficient mutant T cells isolated from three nonirradiated controls and two atomic bomb survivors were studied by Southern blot analysis to investigate the molecular spectra of the mutations. Mutant frequencies for the three controls were 1.8, 2.3, and 7.3 x 10(-6), and those for the two survivors (who had received radiation doses of 2.46 and 2.15 Gy, based upon the revised atomic bomb shielded kerma estimates) were 9.3 and 14.4 x 10(-6), respectively. Fourteen (13%) of 105 mutant T-cell colonies from the controls showed various structural changes in the hprt gene. The frequency of mutants with hprt gene structural changes in one atomic bomb survivor, who exhibited a mutant frequency of 9.3 x 10(-6), was 26% (16/61), which was significantly higher than that of the controls. However, the frequency of structural changes in the other survivor (14%, 8/59) was not higher than that of the controls. Two sets of mutants (in total, eight mutants) from the survivor, who showed a significantly higher frequency of mutants with hprt gross alterations than did the controls, had the same hprt changes and the same rearrangements of T-cell receptor (TcR) beta- and gamma-chain genes, indicating a clonal expansion from one progenitor mutant. This phenomenon may reflect an in vivo recovery process of T cells in the periphery after exposure to atomic bomb radiation. However, when comparing the frequency of mutations, these two sets of mutants should be reduced. After reducing the total number of mutants from the number of gross hprt changes, the frequency was not significantly higher than that of the controls.

Mutagenesis after cancer therapy.

“…One HD patient underwent a significant clonal expansion, which greatly affected the MF. This also has been observed previously in two other studies (40,41). Therefore, we believe it is likely that the treatments induced persistently elevated mutation frequencies in only a subset of patients.…”

“…Similarly, a study on atomic bomb survivors showed that when the clonal mutants are enumerated and the number of actual independent mutational events determined, those with elevated MFs had normal mutation frequencies when compared to controls (41). Thus, it is possible that all patients have a similar level of mutagenic damage induced in the hprt gene, but that the damage is visible as hprt mutants in only a subset, based on the probability of a particular T-cell responding to an antigenic stimulus later.…”

Sensitivity of somatic mutations in human umbilical cord blood to maternal environments

“…Each of these assays can detect, quantitate, and partially characterize somatic mutation and segregation events that have occurred in vivo during the development of lymphocytes or erythrocytes. Both have proven to be useful biodosimeters of mutagenesis in animals and adult humans [Hakoda et al, 1989;Albertini et al, 1990;Thilly, 1990;Grant and Jensen, 19931.…”

Mutant Frequency of Radiotherapy Technicians Appears to Be Associated With Recent Dose of Ionizing Radiation

“…Some proportion even of those chromosomal aberrations which would be expected to be unstable persist with time (Bender and Gooch 1963 ). Using the same assay as our laboratory, Hakoda et al (1989) found that atomic bomb survivors had a significantly higher mutant frequency than controls 43 y after the event. Since radiotherapy technicians are not exposed to radiation in discrete doses but rather continuously, we could not examine persistence of mutants after cessation of exposure.…”