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which dose responses (0.2-1 Gy) were similar among the groups of rats irradiated at 1, 3 and 7 weeks after
birth. Relative biological effectiveness (RBE) values were calculated based on linear fitting of the dose-
hazard relationship. The effect of neutrons increased along with the age at irradiation, indicating RBE
values of 7, 7 and 18 for animals that were 1, 3 and 7 weeks of age, respectively. Carcinogenesis after
irradiation at 1 week of age was characterized by a small effect at 1 Gy and concomitant early cessation
of the estrous cycle, implying that premature ovarian failure changed the hormonal milieu and led to
attenuated cancer development. Our findings offer RBE information for use in the risk assessment of
radiotherapy of childhood tumors. The unexpected observation of age-dependent RBE values necessitates
further clarification of underlying mechanisms.
(PS2-38) Cell Death and Autosomal Mutation in Mouse Splenocytes in Vivo Caused by HZE ions. Dmytro
1
1
1
2
2
Grygoryev ; Anna Ohlrich ; Michael Lasarev ; Stacey Gauny ; Amy Kronenberg ; and Mitchell Turker, 1
1
Oregon Health & Science University, Portland, OR and Lawrence Berkeley National Laboratory, Berkeley,
CA
2
High-energy charged particles (HZE ions) found in the space environment can significantly affect
human health as a result of space travel by inducing mutations and related cancers. To better understand
the relation between HZE ion exposure and somatic mutation, we examined cell survival fraction, mutant
frequency, and the types of induced mutations for mouse splenic T cells exposed in vivo to different doses
48
56
of densely ionizing Ti (1 GeV/amu, LET = 107 keV/µm, 0.2 – 1.4 Gy) and Fe (1 GeV/amu, LET = 151
keV/µm, 0.25 – 2.0 Gy) ions. The lowest doses were equivalent to a fluence of 1 or 2 particle hits per
nucleus. We used an assay that selects for mutations affecting the chromosome 8-encoded Aprt locus in
mouse splenocytes isolated from spleen T cell suspensions. For this assay, spleens were removed from
Aprt heterozygous mice 3-4 months after exposure, T cell suspensions prepared, and the cells plated for
selection for loss of Aprt expression. As part of this assay, we also obtained data showing relative cell
survival as a function of a given exposure. To confirm the mutagenic effects of the exposures, we used a
PCR based assay for loss of heterozygosity (LOH) events on chromosome 8 to identify radiation signature
mutations in the Aprt T cell mutants from exposed mice. The data showed increased mutant frequencies
and decreased T cell survival only at the highest dose tested for each NZE ion. However, the molecular
data clearly showed the induction of radiation signature mutations that varied as a function of dose. At
the high doses for Ti (1.4 Gy) and Fe (2.0 Gy), the major difference was the induction of apparent mitotic
recombination events when compared with Aprt mutant T cells obtained from unexposed mice. At the
lower doses for Ti and Fe ions, the induction of other types of radiation signature mutations (interstitial
deletions and more complex chromosomal rearrangements) was apparent. Interestingly, the radiation
signature mutations observed at the low doses were not observed in the Aprt mutant T cells induced at
high doses. In tota, l the results show that HZE ions with high LET readily induce mutations in splenic T
cells, even at low fluence.
155 | P a g e
birth. Relative biological effectiveness (RBE) values were calculated based on linear fitting of the dose-
hazard relationship. The effect of neutrons increased along with the age at irradiation, indicating RBE
values of 7, 7 and 18 for animals that were 1, 3 and 7 weeks of age, respectively. Carcinogenesis after
irradiation at 1 week of age was characterized by a small effect at 1 Gy and concomitant early cessation
of the estrous cycle, implying that premature ovarian failure changed the hormonal milieu and led to
attenuated cancer development. Our findings offer RBE information for use in the risk assessment of
radiotherapy of childhood tumors. The unexpected observation of age-dependent RBE values necessitates
further clarification of underlying mechanisms.
(PS2-38) Cell Death and Autosomal Mutation in Mouse Splenocytes in Vivo Caused by HZE ions. Dmytro
1
1
1
2
2
Grygoryev ; Anna Ohlrich ; Michael Lasarev ; Stacey Gauny ; Amy Kronenberg ; and Mitchell Turker, 1
1
Oregon Health & Science University, Portland, OR and Lawrence Berkeley National Laboratory, Berkeley,
CA
2
High-energy charged particles (HZE ions) found in the space environment can significantly affect
human health as a result of space travel by inducing mutations and related cancers. To better understand
the relation between HZE ion exposure and somatic mutation, we examined cell survival fraction, mutant
frequency, and the types of induced mutations for mouse splenic T cells exposed in vivo to different doses
48
56
of densely ionizing Ti (1 GeV/amu, LET = 107 keV/µm, 0.2 – 1.4 Gy) and Fe (1 GeV/amu, LET = 151
keV/µm, 0.25 – 2.0 Gy) ions. The lowest doses were equivalent to a fluence of 1 or 2 particle hits per
nucleus. We used an assay that selects for mutations affecting the chromosome 8-encoded Aprt locus in
mouse splenocytes isolated from spleen T cell suspensions. For this assay, spleens were removed from
Aprt heterozygous mice 3-4 months after exposure, T cell suspensions prepared, and the cells plated for
selection for loss of Aprt expression. As part of this assay, we also obtained data showing relative cell
survival as a function of a given exposure. To confirm the mutagenic effects of the exposures, we used a
PCR based assay for loss of heterozygosity (LOH) events on chromosome 8 to identify radiation signature
mutations in the Aprt T cell mutants from exposed mice. The data showed increased mutant frequencies
and decreased T cell survival only at the highest dose tested for each NZE ion. However, the molecular
data clearly showed the induction of radiation signature mutations that varied as a function of dose. At
the high doses for Ti (1.4 Gy) and Fe (2.0 Gy), the major difference was the induction of apparent mitotic
recombination events when compared with Aprt mutant T cells obtained from unexposed mice. At the
lower doses for Ti and Fe ions, the induction of other types of radiation signature mutations (interstitial
deletions and more complex chromosomal rearrangements) was apparent. Interestingly, the radiation
signature mutations observed at the low doses were not observed in the Aprt mutant T cells induced at
high doses. In tota, l the results show that HZE ions with high LET readily induce mutations in splenic T
cells, even at low fluence.
155 | P a g e
