Heavy Ion Radiation Exposure Triggered Higher Intestinal Tumor Frequency and Greater β-Catenin Activation than γ Radiation in APCMin/+ Mice

Abstract

Risk of colorectal cancer (CRC) after exposure to low linear energy transfer (low-LET) radiation such as γ-ray is highlighted by the studies in atom bomb survivors. On the contrary, CRC risk prediction after exposure to high-LET cosmic heavy ion radiation exposure is hindered due to scarcity of in vivo data. Therefore, intestinal tumor frequency, size, cluster, and grade were studied in APCMin/+ mice (n = 20 per group; 6 to 8 wks old; female) 100 to 110 days after exposure to 1.6 or 4 Gy of heavy ion 56Fe radiation (energy: 1000 MeV/nucleon) and results were compared to γ radiation doses of 2 or 5 Gy, which are equitoxic to 1.6 and 4 Gy 56Fe respectively. Due to relevance of lower doses to radiotherapy treatment fractions and space exploration, we followed 2 Gy γ and equitoxic 1.6 Gy 56Fe for comparative analysis of intestinal epithelial cell (IEC) proliferation, differentiation, and β-catenin signaling pathway alterations between the two radiation types using immunoblot, and immunohistochemistry. Relative to controls and γ-ray, intestinal tumor frequency and grade was significantly higher after 56Fe radiation. Additionally, tumor incidence per unit of radiation (per cGy) was also higher after 56Fe radiation relative to γ radiation. Staining for phospho-histone H3, indicative of IEC proliferation, was more and alcian blue staining, indicative of IEC differentiation, was less in 56Fe than γ irradiated samples. Activation of β-catenin was more in 56Fe-irradiated tumor-free and tumor-bearing areas of the intestinal tissues. When considered along with higher levels of cyclin D1, we infer that relative to γ radiation exposure to 56Fe radiation induced markedly reduced differentiation, and increased proliferative index in IEC resulting in increased intestinal tumors of larger size and grade due to preferentially greater activation of β-catenin and its downstream effectors.

Metabolomic Profiling of Urine Samples from Mice Exposed to Protons Reveals Radiation Quality and Dose Specific Differences

“…As long term effects of exposure to space radiation persist and can lead to carcinogenesis and central nervous system effects, as has been previously demonstrated in mouse models (4, 5, 16, 17, 23–25), it is imperative to understand the early effects of radiation exposure and the metabolic changes that can contribute to genetic alterations through persistent inflammatory or oxidative responses. Urinary metabolomics can rapidly provide a snapshot of the metabolic state of an individual and as shown this first study of exposure to protons identify a significant number of metabolites that are involved in important biochemical processes.…”

Safe days in space with acceptable uncertainty from space radiation exposure

“…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.…”

“…Intestinal tumors in APC Min/+ mice (Trani et al, 2010, Datta et al, 2013 Heavy ions increased tumor multiplicity and grade compared to protons or γ -rays.…”

Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine

“…Epidemiological observations linking radiation and colorectal cancer (CRC) are also well supported by studies in animal models43536. Apart from carcinogenesis, radiation exposure has also been reported to cause metabolic and hormonal alterations related to growth and proliferation in human as well as in animal studies373839404142434445.…”