Relative Biological Effectiveness of Energetic Heavy Ions for Intestinal Tumorigenesis Shows Male Preponderance and Radiation Type and Energy Dependence in APC1638N/+ Mice

Suman, Shubhankar; Kumar, Santosh; Moon, Bo Hyun; Strawn, Steve J.; Thakor, Hemang; Fan, Ziling; Shay, Jerry W.; Fornace, Albert J.; Datta, Kamal

doi:10.1016/j.ijrobp.2015.10.057

Cited by 43 publications

(56 citation statements)

References 44 publications

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“…Reduced IGFBP3 along with increased pro-proliferative Ki67 staining in intestine and colon is in agreement with earlier observations reporting anti-proliferative and pro-apoptotic effects of IGFBP37677. Our observations in this study could act as the prelude necessary for future studies on contribution of leptin/IGF1 signaling axis to some of the heavy ion radiation’s long-term consequences such as premature senescence, metabolic alterations, and GI carcinogenesis we have reported previously413577879. The current study performed in wild type mice irradiated with a non-lethal dose of 56 Fe radiation is an initial step towards understanding GI tract related long-term hormonal alterations after heavy ion space radiation exposure especially after low dose exposures.…”

Section: Discussionsupporting

confidence: 93%

“…Although we have shown long-term activation of leptin signaling, additional experiments will be required to understand its impact on metabolic functions such as regulation of energy expenditure and glucose metabolism2466. Importantly, increased leptin signaling including Jak2/Stat3 has been demonstrated to accompany pathogenesis of CRC65 and we have already demonstrated in mouse models increased frequency of intestinal tumorigenesis after heavy ion radiation exposure413. Additionally, leptin true to its multimodal pro-growth effects has also been reported to activate mTOR via Akt68 and interestingly, our study demonstrated increased levels of both the phospho-mTOR as well as phospho-Akt after 56 Fe radiation.…”

Section: Discussionmentioning

confidence: 87%

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

Suman

Kumar

Fornace

et al. 2016

Sci Rep

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Travel into outer space is fraught with risk of exposure to energetic heavy ion radiation such as 56Fe ions, which due to its high linear energy transfer (high-LET) characteristics deposits higher energy per unit volume of tissue traversed and thus more damaging to cells relative to low-LET radiation such as γ rays. However, estimates of human health risk from energetic heavy ion exposure are hampered due to lack of tissue specific in vivo molecular data. We investigated long-term effects of 56Fe radiation on adipokines and insulin-like growth factor 1 (IGF1) signaling axis in mouse intestine and colon. Six- to eight-week-old C57BL/6J mice were exposed to 1.6 Gy of 56Fe ions. Serum and tissues were collected up to twelve months post-irradiation. Serum was analyzed for leptin, adiponectin, IGF1, and IGF binding protein 3. Receptor expressions and downstream signaling pathway alterations were studied in tissues. Irradiation increased leptin and IGF1 levels in serum, and IGF1R and leptin receptor expression in tissues. When considered along with upregulated Jak2/Stat3 pathways and cell proliferation, our data supports the notion that space radiation exposure is a risk to endocrine alterations with implications for chronic pathophysiologic changes in gastrointestinal tract.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 87%

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

Suman

Kumar

Fornace

et al. 2016

Sci Rep

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“…3 and Table 2, that the uncertainty bounds surrounding the RER estimates are somewhat wider than those surrounding the corresponding RBE estimates, even though the underlying data set was the same for both estimates. To an extent, this is a function of the design of the experimental mouse study (7), which was optimized for RBE estimation. Thus, for example in the 28 Si ion experiment, 20 mice were used for each of the four heavy-ion doses and the four gamma-ray doses, a total of 160 animals.…”

Section: Discussionmentioning

confidence: 99%

“…The data set analyzed was radiation-induced intestinal tumorigenesis in APC 1638N/þ mice, as previously reported by Suman et al (7). Male mice (females were also used in the experimental study, but for illustrative purposes we analyzed the male data only because they showed more tumors) were exposed at age 6 to 8 weeks to 12 C ions (doses: 0.1, 0.5 and 2.0 Gy; energy: 290 MeV/n; LET: 13 keV/lm), 28 Si ions (doses: 0.1, 0.5 and 1.4 Gy; energy: 300 MeV/n; LET: 69 keV/lm) and 56 Fe ions (doses: 0.1, 0.5 and 1.6 Gy; energy: 1000 MeV/n; LET: 148 keV/lm) at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory.…”

Section: Mouse Carcinogenesis Data Setmentioning

confidence: 99%

Scaling Human Cancer Risks from Low LET to High LET when Dose-Effect Relationships are Complex

et al. 2017

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“…This range of doses has been chosen to Y.G. Shckorbatov determine possible cell response to low and very low doses (a low dose is <100 mGy delivered acutely [18]), while in the most of articles published before and analyzed in this paper were used the doses from low [5,6,19] to medium [8,10,19,20] and high [11].…”

Section: Methodsmentioning

confidence: 99%

Human buccal epithelium cell response to low intensive neutron radiation

2018

Biophysical Bulletin

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Background: The investigation of the low doses of ionizing radiation is still a great importance for identification of the threshold of harmful effect and potential hormetic effect of low doses. Objectives: The purpose of investigation was to evaluate the stress response in human buccal epithelium cells induced by low intensive neutron radiation. Materials and Methods: The level of chromatin condensation in interphase nuclei was applied for assessment of the cell reaction to stress. Exfoliated human buccal epithelium cells were collected, placed in the 3.03 mM phosphate buffer solution (pH=7.0) with addition of 2.89 mM CaCl2 and exposed to neutron radiation from 2 Pu-Be sources IBN-17. The heterochromatin granule quantity (HGQ) assessments were done after orcein staining that had been immediately performed after cell exposure to neutron radiation in the dose range from 2.3 mSv to 146.0 mSv. Also the effect of fast neutron radiation in the dose of 11.4 mSv on human buccal epithelium cells was investigated in 1-64 min after exposure. The HGQ in every variant of experiment was assessed in 30 nuclei in 3 separate experiments. The mean HGQ and standard error of mean were assessed in every experiment. Results: Neutron radiation induced the increase of HGQ. Partially slowed neutrons have less influence on neutron-induced HGQ increase than only fast neutrons especially with 1 min delay after exposure. Fast neutrons induce heterochromatinization in cell samples irradiated with doses 4.6–36.5 mSv. Further increase of dose has led to return of HGQ to control levels. After cell exposure to fast neutron flow (11.4 mSv) the peaks of chromatin condensation were observed for time intervals 2–8 and 32–64 min after cell exposure to radiation. Conclusions: Qualitative characteristic of neutron radiation (slow/fast neutrons) influences the rate of cell stress response as revealed by chromatin condensation in cell nuclei. It was demonstrated that there is a threshold dose above which cells are able to develop stress response to neutron radiation. The dose-response dependence is non-monotonous and is of wave-like form. Described phenomena may be explained by the effect of hormesis.

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Relative Biological Effectiveness of Energetic Heavy Ions for Intestinal Tumorigenesis Shows Male Preponderance and Radiation Type and Energy Dependence in APC1638N/+ Mice

Cited by 43 publications

References 44 publications

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

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

Scaling Human Cancer Risks from Low LET to High LET when Dose-Effect Relationships are Complex

Human buccal epithelium cell response to low intensive neutron radiation

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