High-Energy Particle-Induced Tumorigenesis Throughout the Gastrointestinal Tract

Trani, Daniela; Nelson, Scott A.; Moon, Bo‐Hyun; Swedlow, Jan J.; Williams, Evelyn W.; Strawn, Steven J.; Appleton, Paul L.; Kallakury, Bhaskar; Näthke, Inke; Fornace, Albert J.

doi:10.1667/rr13502.1

Cited by 22 publications

(27 citation statements)

References 32 publications

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“…Proton is ~ 50%, helium is ~25% and HZE particles with high-LET is ~25% of a given GCR simulation dose. Combining such information with previously published data that showed high-versus low-LET radiation induced a higher incidence of tumorigenesis in different mouse models (Fry et al, 1983;Trani et al, 2014;Ullrich et al, 1987;Wang et al, 2015;Weil et al, 2009), and the real risk of space radiation-induced tumorigenesis might be lower than previously estimated since high-LET radiation takes ~1/4 of total space radiation. Such a prediction needs further experiments to verify.…”

Section: Accepted Manuscriptsupporting

confidence: 61%

“…However, due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the risk of lung carcinogenesis is for astronauts following exposure to space radiation (Durante and Cucinotta, 2008), and evaluating the space radiation risk depends primarily on animal experiments. Previously, different groups using different mouse models demonstrated that high-LET radiation versus low-LET radiation has a higher risk of generating tumorigenesis in the Harderian gland (Fry et al, 1983), lung (Ullrich et al, 1987), mammary (Ullrich et al, 1987), liver (Weil et al, 2009) and colon (Trani et al, 2014). These data provide valuable information for estimating the risk of space radiation with high-LET HZE particle-induced tumorigenesis.…”

Section: Introductionmentioning

confidence: 95%

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Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

Wang

Zhang

Wang

et al. 2016

Life Sciences in Space Research

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Section: Accepted Manuscriptsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 95%

Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

Wang

Zhang

Wang

et al. 2016

Life Sciences in Space Research

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Laiakis¹,

Trani

Moon³

et al. 2015

Radiation Research

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As space travel is expanding to include private tourism and travel beyond low-Earth orbit, so is the risk of exposure to space radiation. Galactic cosmic rays and solar particle events have the potential to expose space travelers to significant doses of radiation that can lead to increased cancer risk and other adverse health consequences. Metabolomics has the potential to assess an individual’s risk by exploring the metabolic perturbations in a biofluid or tissue. In this study, C57BL/6 mice were exposed to 0.5 and 2 Gy of 1 GeV/nucleon of protons and the levels of metabolites were evaluated in urine at 4 h after radiation exposure through liquid chromatography coupled to time-of-flight mass spectrometry. Significant differences were identified in metabolites that map to the tricarboxylic acid (TCA) cycle and fatty acid metabolism, suggesting that energy metabolism is severely impacted after exposure to protons. Additionally, various pathways of amino acid metabolism (tryptophan, tyrosine, arginine and proline and phenylalanine) were affected with potential implications for DNA damage repair and cognitive impairment. Finally, presence of products of purine and pyrimidine metabolism points to direct DNA damage or increased apoptosis. Comparison of these metabolomic data to previously published data from our laboratory with gamma radiation strongly suggests a more pronounced effect on metabolism with protons. This is the first metabolomics study with space radiation in an easily accessible biofluid such as urine that further investigates and exemplifies the biological differences at early time points after exposure to different radiation qualities.

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“…Another testable prediction is that tumors arising after a low fluence exposure to densely ionizing heavy ions may appear earlier or be more aggressive than spontaneous tumors due to the complexity of the initial damage. This has been observed in some types of tumors induced by densely ionizing Fe ions [47, 48]. We note that mutant load in the kidney can be affected somewhat by toxicity because cells that lose mitotic capacity cannot form mutant clones (or cancer if this endpoint is studied).…”

Section: Discussionmentioning

confidence: 56%

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

et al. 2017

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Exposure to a small number of high-energy heavy charged particles (HZE ions), as found in the deep space environment, could significantly affect astronaut health following prolonged periods of space travel if these ions induce mutations and related cancers. In this study, we used an in vivo mutagenesis assay to define the mutagenic effects of accelerated 56Fe ions (1 GeV/amu, 151 keV/μm) in the mouse kidney epithelium exposed to doses ranging from 0.25 to 2.0 Gy. These doses represent fluences ranging from 1 to 8 particle traversals per cell nucleus. The Aprt locus, located on chromosome 8, was used to select induced and spontaneous mutants. To fully define the mutagenic effects, we used multiple endpoints including mutant frequencies, mutation spectrum for chromosome 8, translocations involving chromosome 8, and mutations affecting non-selected chromosomes. The results demonstrate mutagenic effects that often affect multiple chromosomes for all Fe ion doses tested. For comparison with the most abundant sparsely ionizing particle found in space, we also examined the mutagenic effects of high-energy protons (1 GeV, 0.24 keV/μm) at 0.5 and 1.0 Gy. Similar doses of protons were not as mutagenic as Fe ions for many assays, though genomic effects were detected in Aprt mutants at these doses. Considered as a whole, the data demonstrate that Fe ions are highly mutagenic at the low doses and fluences of relevance to human spaceflight, and that cells with considerable genomic mutations are readily induced by these exposures and persist in the kidney epithelium. The level of genomic change produced by low fluence exposure to heavy ions is reminiscent of the extensive rearrangements seen in tumor genomes suggesting a potential initiation step in radiation carcinogenesis.

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High-Energy Particle-Induced Tumorigenesis Throughout the Gastrointestinal Tract

Cited by 22 publications

References 32 publications

Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

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

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

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