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Interest in deep space exploration underlines the needs to investigate the effects of exposure to combined sources of space radiation. The lung is a target organ for radiation, and exposure to protons and heavy ions as radiation sources may lead to the development of degenerative disease and cancer. In this study, we evaluated the pro-fibrotic and epigenetic effects of exposure to protons (150 MeV/nucleon, 0.1 Gy) and heavy iron ions ((56)Fe, 600 MeV/nucleon, 0.5 Gy) alone or in combination (protons on Day 1 and (56)Fe on Day 2) in C57BL/6 male mice 4 weeks after irradiation. Exposure to (56)Fe, proton or in combination, did not result in histopathological changes in the murine lung. At the same time, combined exposure to protons and (56)Fe resulted in pronounced molecular alterations in comparison with either source of radiation alone. Specifically, we observed a substantial increase in the expression of cytokine Il13, loss of expression of DNA methyltransferase Dnmt1, and reactivation of LINE-1, SINE B1 retrotransposons, and major and minor satellites. Given the deleterious potential of the observed effects that may lead to development of chronic lung injury, pulmonary fibrosis, and cancer, future studies devoted to the investigation of the long-term effects of combined exposures to proton and heavy ions are clearly needed.

Intracellular oxygen concentration ([O2]i.c.) regulates key biological functions such as HIF-1α activation, glucose transport, potassium pumps, intracellular calcium concentration, P450 family enzymes and HMGR expression. However, the mechanisms regulating [O2]i.c remain to be defined. Here, we provide direct evidence of the mitochondrion's role in [O2]i.c. regulation. We used bis(2-(2′-benzothienyl)-pyridianto-N,C3’irridium(acetylacetonate) (BTP) to measure [O2]i.c. in living cells via microscopy.5 Well-differentiated cancers, LNCaP and MCF-7 showed intracellular hypoxia without exogenous hypoxia. In contrast, poorly-differentiated cancers exhibited intracellular normoxia, and exogenous hypoxia could induce hypoxia. The specific complex I inhibitor, rotenone, and the reduction of mitochondrial DNA (mtDNA) content increased in [O2]i.c,, indicating that [O2]i.c. is regulated by mitochondrial respiratory activity. [O2]i.c. is additionally regulated by glucose, but the dose-dependent relationship is parabolic. The no glucose condition induced normoxia, and the low concentration glucose condition (0.045mg/ml) induced strong hypoxia. [O2]i.c. was found to be additionally determined by the presence of FCS in the growth medium, and this effect was mimicked by an androgen analog, R1881, suggesting that androgen, glucose concentration and respiratory function are important regulators of [O2]i.c.. Citation Format: Sara Prior, Ara Kim, Seiji Tobita, Toshiyuki Takeuchi, Masahiro Higuchi. Intracellular hypoxia is dominantly determined by mitochondrial respiratory activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1693. doi:10.1158/1538-7445.AM2013-1693