title: Charged particle mutagenesis at low dose and fluence in mouse splenic T cells.
abstract: High-energy heavy charged particles (HZE ions) found in the deep space environment can significantly affect human health by inducing mutations and related cancers. To better understand the relation between HZE ion exposure and somatic mutation, we examined cell survival fraction, Aprt mutant frequencies, and the types of mutations detected for mouse splenic T cells exposed in vivo to graded doses of densely ionizing (48)Ti ions (1GeV/amu, LET=107 keV/μm), (56)Fe ions (1GeV/amu, LET=151 keV/μm) ions, or sparsely ionizing protons (1GeV, LET=0.24 keV/μm). The lowest doses for (48)Ti and (56)Fe ions were equivalent to a fluence of approximately 1 or 2 particle traversals per nucleus. In most cases, Aprt mutant frequencies in the irradiated mice were not significantly increased relative to the controls for any of the particles or doses tested at the pre-determined harvest time (3-5 months after irradiation). Despite the lack of increased Aprt mutant frequencies in the irradiated splenocytes, a molecular analysis centered on chromosome 8 revealed the induction of radiation signature mutations (large interstitial deletions and complex mutational patterns), with the highest levels of induction at 2 particles nucleus for the (48)Ti and (56)Fe ions. In total, the results show that densely ionizing HZE ions can induce characteristic mutations in splenic T cells at low fluence, and that at least a subset of radiation-induced mutant cells are stably retained despite the apparent lack of increased mutant frequencies at the time of harvest.
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Grygoryev
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, United States.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gauny
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Lasarev
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Ohlrich
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Kronenberg
authors.affiliation: Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States; Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States. Electronic address: turkerm@ohsu.edu.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Turker
mesh_terms: D000228:Adenine Phosphoribosyltransferase / Q000235:genetics; D000818:Animals; D002872:Chromosome Deletion; D003359:Cosmic Radiation / Q000009:adverse effects*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D018499:Linear Energy Transfer; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009154:Mutation / Q000528:radiation effects*; D059645:Mutation Rate; D011868:Radioisotopes; D013154:Spleen / Q000473:pathology / Q000528:radiation effects*; D013601:T-Lymphocytes / Q000473:pathology / Q000528:radiation effects*; D014916:Whole-Body Irradiation
chemical_list: D011868:Radioisotopes; D000228:Adenine Phosphoribosyltransferase
keywords: Aprt mutation; Charged particle mutagenesis; Radiation signature mutations; Splenic T cells