Comparative Analysis of Cell Killing and Autosomal Mutation in Mouse Kidney Epithelium Exposed to 1 GeV/nucleon Iron IonsIn VitroorIn Situ

Abstract

Astronauts receive exposures to high-energy heavy ions from galactic cosmic radiation. Although high-energy heavy ions are mutagenic and carcinogenic, their mutagenic potency in epithelial cells, where most human cancers develop, is poorly understood. Mutations are a critical component of human cancer, and mutations involving autosomal loci predominate. This study addresses the cytotoxic and mutagenic effects of 1 GeV/nucleon iron ions in mouse kidney epithelium. Mutant fractions were measured for an endogenous autosomal locus (Aprt) that detects all types of mutagenic events contributing to human cancer. Results for kidneys irradiated in situ are compared with results for kidney cells from the same strain exposed in vitro. The results demonstrate dose-dependent cell killing in vitro and for cells explanted 3-4 months postirradiation in situ, but in situ exposures were less likely to result in cell death than in vitro exposures. Prolonged incubation in situ (8-9 months) further attenuated cell killing at lower doses. Iron ions were mutagenic to cells in vitro and for irradiated kidneys. No sparing was seen for mutant frequency with a long incubation period in situ. In addition, the degree of mutation induction (relative increase over background) was similar for cells exposed in vitro or in situ. We speculate that the latent effects of iron-ion exposure contribute to the maintenance of an elevated mutation burden in an epithelial tissue.

Genotoxicity of charged particles of importance in space flight using murine kidney epithelial cells

“…Si ions were also quite mutagenic with evidence for a linear dose–response for Aprt mutations in kidney cells exposed in vitro or in kidneys harvested from mice irradiated several months earlier. These results are consistent with the linear dose–response data obtained previously for Aprt mutation induction following Fe ion exposure in vitro or in vivo , but the results for Si ions differ from the curvilinear dose–response data we recently published following similar exposures to energetic protons [ 1, 2]. Our most recent studies examined the molecular characteristics of Si ion-induced Aprt mutants following in vitro exposure.…”

Galactic cosmic ray simulation at the NASA Space Radiation Laboratory

“…It may be useful if GCR simulation addresses both cell and animal studies and it may be feasible to design some experiments that allow direct comparison of the in vitro and in vivo (Kronenberg et al, 2009, 2013) systems. In some cases, the less expensive cell culture experiments may mimic what happens in the body.…”

Simulated space radiation-induced mutants in the mouse kidney display widespread genomic change

“…Most mutagenesis studies with charged particles use cell culture systems [5–11] and/or mouse models [12–18] to identify mutagenic effects. The main advantages of cell culture systems are reduced time and cost for the complete assay because cultured cells are actively dividing.…”

“…We use an in vivo system to study charged particle mutagenesis in the intact kidney epithelium in which the selectable autosomal mouse Aprt gene, located on chromosome 8, detects the full spectrum of mutations, from small intragenic changes to whole chromosome loss [12–15, 19]. Charged particle exposure induces Aprt mutant cells, which persist for extended times in the kidney [12, 13] until isolated from the dispersed kidney via selection of the primary cells in culture.…”