title: Accelerated (48)Ti Ions Induce Autosomal Mutations in Mouse Kidney Epithelium at Low Dose and Fluence.
abstract: Exposure to high-energy charged particles (HZE ions) at low fluence could significantly affect astronaut health after prolonged missions in deep space by inducing mutations and related cancers. We tested the hypothesis that the mutagenic effects of HZE ions could be detected at low fluence in a mouse model that detects autosomal mutations in vivo. Aprt heterozygous mice were exposed to 0.2, 0.4 and 1.4 Gy of densely ionizing (48)Ti ions (1 GeV/amu, LET = 107 keV/μm). We observed a dose-dependent increase in the Aprt mutant fraction in kidney epithelium at the two lowest doses (an average of 1 or 2 particles/cell nucleus) that plateaued at the highest dose (7 particles/cell nucleus). Mutant cells were expanded to determine mutation spectra and translocations affecting chromosome 8, which encodes Aprt. A PCR-based analysis for loss of heterozygosity (LOH) events on chromosome 8 demonstrated a significant shift in the mutational spectrum from Ti ion exposure, even at low fluence, by revealing "radiation signature" mutations in mutant cells from exposed mice. Likewise, a cytogenetic assay for nonreciprocal chromosome 8 translocations showed an effect of exposure. A genome-wide LOH assay for events affecting nonselected chromosomes also showed an effect of exposure even for the lowest dose tested. Considered in their entirety, these results show that accelerated (48)Ti ions induce large mutations affecting one or more chromosomes at low dose and fluence.
authors.affiliation: a  Oregon Institute of Occupational Health Sciences and.
authors.forename: Gwen
authors.initials: G
authors.lastname: Hryciw
authors.affiliation: a  Oregon Institute of Occupational Health Sciences and.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Grygoryev
authors.affiliation: a  Oregon Institute of Occupational Health Sciences and.
authors.forename: Michael
authors.initials: M
authors.lastname: Lasarev
authors.affiliation: a  Oregon Institute of Occupational Health Sciences and.
authors.forename: Anna
authors.initials: A
authors.lastname: Ohlrich
authors.affiliation: a  Oregon Institute of Occupational Health Sciences and.
authors.forename: Cristian
authors.initials: C
authors.lastname: Dan
authors.affiliation: a  Oregon Institute of Occupational Health Sciences and.
authors.forename: Ravi
authors.initials: R
authors.lastname: Madhira
authors.affiliation: a  Oregon Institute of Occupational Health Sciences and.
authors.forename: Bradley
authors.initials: B
authors.lastname: Eckelmann
authors.affiliation: c  Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gauny
authors.affiliation: c  Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720.
authors.forename: Amy
authors.initials: A
authors.lastname: Kronenberg
authors.affiliation: a  Oregon Institute of Occupational Health Sciences and.|b  Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon 97239; and.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Turker
mesh_terms: D000228:Adenine Phosphoribosyltransferase / Q000235:genetics; D000818:Animals; D004848:Epithelium / Q000528:radiation effects; D007668:Kidney / Q000528:radiation effects*; D019656:Loss of Heterozygosity; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011868:Radioisotopes; D014025:Titanium; D014178:Translocation, Genetic
chemical_list: D011868:Radioisotopes; D014025:Titanium; D000228:Adenine Phosphoribosyltransferase