Novel Double-Hit Model of Radiation and Hyperoxia-Induced Oxidative Cell Damage Relevant to Space Travel
Open accessAbstract
Spaceflight occasionally requires multiple extravehicular activities (EVA) that potentially subject astronauts to repeated changes in ambient oxygen superimposed on those of space radiation exposure. We thus developed a novel in vitro model system to test lung cell damage following repeated exposure to radiation and hyperoxia. Non-tumorigenic murine alveolar type II epithelial cells (C10) were exposed to >95% O2 for 8 h only (O2), 0.25 Gy ionizing γ-radiation (IR) only, or a double-hit combination of both challenges (O2 + IR) followed by 16 h of normoxia (ambient air containing 21% O2 and 5% CO2) (1 cycle = 24 h, 2 cycles = 48 h). Cell survival, DNA damage, apoptosis, and indicators of oxidative stress were evaluated after 1 and 2 cycles of exposure. We observed a significant (p < 0.05) decrease in cell survival across all challenge conditions along with an increase in DNA damage, determined by Comet analysis and H2AX phosphorylation, and apoptosis, determined by Annexin-V staining, relative to cells unexposed to hyperoxia or radiation. DNA damage (GADD45α and cleaved-PARP), apoptotic (cleaved caspase-3 and BAX), and antioxidant (HO-1 and Nqo1) proteins were increased following radiation and hyperoxia exposure after 1 and 2 cycles of exposure. Importantly, exposure to combination challenge O2 + IR exacerbated cell death and DNA damage compared to individual exposures O2 or IR alone. Additionally levels of cell cycle proteins phospho-p53 and p21 were significantly increased, while levels of CDK1 and Cyclin B1 were decreased at both time points for all exposure groups. Similarly, proteins involved in cell cycle arrest was more profoundly changed with the combination challenges as compared to each stressor alone. These results correlate with a significant 4- to 6-fold increase in the ratio of cells in G2/G1 after 2 cycles of exposure to hyperoxic conditions. We have characterized a novel in vitro model of double-hit, low-level radiation and hyperoxia exposure that leads to oxidative lung cell injury, DNA damage, apoptosis, and cell cycle arrest.
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In mouse lung cancer, the combination of hyperoxia and radiation increased cell death and DNA damage compared to hyperoxia or radiation alone.
“In mouse lung cancer, the combination of hyperoxia and radiation increased cell death and DNA damage compared to hyperoxia or radiation alone. 351”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [351]
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- Authors
- Pietrofesa, R., Velalopoulou, A., Lehman, S., Arguiri, E., Solomides, P., Koch, C., Mishra, O., Koumenis, C., Goodwin, T., & Christofidou-Solomidou, M.
- Affiliations
- University of Pennsylvania (US)
- National Aeronautics and Space Administration (US)
- Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3450 Hamilton Walk, Edward J. Stemmler Hall 2nd Floor, Office Suite 227, Philadelphia, PA 19104, USA
- ORCID
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2016-06-16
- Volume
- 17
- Issue
- 6
- Pages
- 953
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC4926486
- OpenAlex
- W2435274812
- Cited by
- 13
- References
- 53
- Citations by year
- 2026: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 1
- FWCI
- 2.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- NASA (#NNX12AK19G)
- National Institutes of Health (R01CA133470, 1R21NS087406-01, R03CA180548, 1P42ES023720-01, 1P30ES013508-02)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Physiology › Spaceflight effects on biology
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
- Keywords
- hyperoxia, ionizing radiation, oxidative stress, alveolar type II cells, DNA damage, apoptosis, cell cycle arrest, p53, H2AX phosphorylation, heme oxygenase-1, NQO1, spaceflight, extravehicular activity, astronaut health
- MeSH terms
- Animals, Antioxidants, Cell Cycle, Cell Survival, DNA Damage, Gene Expression Regulation, Histones, Humans, Models, Biological, Oxidation-Reduction, Phosphorylation, Radiation, Ionizing, Space Flight, Signal Transduction, Gene Expression Regulation, Enzymologic, Apoptosis, Reactive Oxygen Species, Oxidative Stress, Hyperoxia, Mice, Alveolar Epithelial Cells
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