Trp53 Deficiency Increases the Frequency of Hprt Mutant T Lymphocytes Following High-LET Iron Particle Irradiation of Mice

Abstract

Charged particles like iron-56 ions impose health risks in long-term manned space exploration. This study was designed to define the impact of Trp53 status upon the manifestation of mutations in the hypoxanthine-guanine phosphoribosyltransferase (Hprt) gene in splenic T-cells following exposure of Trp53 wild-type, hemizygous, and nullizygous lacZ transgenic mice to 1 Gy ⁵⁶Fe particles. In male and female mice necropsied at 2, 4, and 8 weeks postexposure, Hprt mutant frequencies in splenic T-cells (measured via the Hprt mutation cloning assay) increased significantly over time to peak at 4 weeks postexposure before decreasing to lower but still elevated levels. Mutagenic potency estimates based upon the change in mutant frequency over time in exposed versus respective control groups showed that the total mutagenic response depended upon the Trp53 genetic status, with the mutagenic burden of 1 Gy being threefold and 5.3-fold greater in Trp53^+/− and Trp53^−/− mice, respectively, compared to Trp53^+/+ mice.