Effects of 28Si Ions, 56Fe Ions, and Protons on the Induction of Murine Acute Myeloid Leukemia and Hepatocellular Carcinoma

Abstract

Estimates of cancer risks posed to space-flight crews by exposure to high atomic number, high-energy (HZE) ions are subject to considerable uncertainty because epidemiological data do not exist for human populations exposed to similar radiation qualities. We assessed the carcinogenic effects of 300 MeV/n 28Si or 600 MeV/n 56Fe ions in a mouse model for radiation-induced acute myeloid leukemia and hepatocellular carcinoma. C3H/HeNCrl mice were irradiated with 0.1, 0.2, 0.4, or 1 Gy of 300 MeV/n 28Si ions, 600 MeV/n 56Fe ions or 1 or 2 Gy of protons simulating the 1972 solar particle event (1972SPE) at the NASA Space Radiation Laboratory. Additional mice were irradiated with 137Cs gamma rays at doses of 1, 2, or 3 Gy. All groups were followed until they were moribund or reached 800 days of age. We found that 28Si or 56Fe ions do not appear to be substantially more effective than gamma rays for the induction of acute myeloid leukemia. However, 28Si or 56Fe ion irradiated mice had a much higher incidence of hepatocellular carcinoma than gamma ray irradiated or proton irradiated mice. These data demonstrate a clear difference in the effects of these HZE ions on the induction of leukemia compared to solid tumors, suggesting potentially different mechanisms of tumorigenesis. Also seen in this study was an increase in metastatic hepatocellular carcinoma in the 28Si and 56Fe ion irradiated mice compared with those exposed to gamma rays or 1972SPE protons, a finding with important implications for setting radiation exposure limits for space-flight crew members.

Late-occurring chromosome aberrations and global DNA methylation in hematopoietic stem/progenitor cells of CBA/CaJ mice exposed to silicon (28Si) ions

“…Further, translocations involving mouse chromosome 2 have been detected in a few cells from some cases of mouse rML [76,[78][79][80], in particular those induced by neutron exposure. Hence, the detection of cells with an abnormal chromosome 2 in some mice exposed to 300 MeV/n 28 Si ions may reflect the ability of 300 MeV/n 28 Si ions to induce ML [12].…”

“…Such increases persisted up to 6 mos postirradiation, indicating (for the first time) the induction of chronic inflammatory responses in BM and heart tissues of mice exposed to 300 MeV/n 28 Si ions. Recently, it was found that 300 MeV/n 28 Si ions (in the dose range of 0.1-0.4 Gy) are capable of inducing ML in C3H/HeNCrl mice, a strain of mouse known to be susceptible to radiation-induced ML [12]. However, cellular/molecular mechanisms potentially occurring during 28 Si-ion-induced ML have not been investigated.…”

Safe days in space with acceptable uncertainty from space radiation exposure

“…Hepatocellular carcinoma in male C3H/HeNCrl mice (Weil et al, 2014) Dose response for Si and Fe particles was qualitatively different from γ -rays. Incidence of metastatic tumors significantly increased with Si and Fe particles compared to γ -rays or simulated solar protons.…”

“…Several reports (Fry et al, 1985;Alpen et al, 1993;Dicello et al, 2004;Weil et al, 2009Weil et al, , 2014Grahn et al, 1992;Imaoka et al, 2007;Trani et al, 2010;Datta et al, 2013;Illa-Bochaca et al, 2014;Wang et al, 2015) have suggested that HZE particles and neutrons could produce more lethal tumors compared to tumors produced by low LET radiation or background tumors, which is a qualitative difference not accounted for in current risk estimates. Table 3 summarizes these findings from animal studies with HZE particle beams.…”

High-Energy Particle-Induced Tumorigenesis Throughout the Gastrointestinal Tract

“…Indirect information on HZE risk, obtained from radiation studies of rodents, has therefore been considered [e.g., (8)(9)(10)(11)(12)(13)]. One set of experiments, on murine Harderian gland (HG) tumorigenesis, has been influential in astronaut risk analysis [reviewed in ref.…”