Abstract
Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses risk to stem cells that are key to intestinal homeostasis. Currently, the molecular spectrum of heavy ion radiation-induced perturbations in intestinal stem cells (ISCs), that could trigger intestinal pathologies, remains largely unexplored. The Lgr5-EGFP-IRES-creERT mice were exposed to 50 cGy of iron radiation. Mice were euthanized 60 d after exposure and ISCs were sorted using fluorescence activated cell sorting. Reactive oxygen species (ROS) and mitochondrial superoxide were measured using fluorescent probes. Since DNA damage is linked to senescence and senescent cells acquire senescence-associated secretory phenotype (SASP), we stained ISCs for both senescence markers p16, p21, and p19 as well as SASP markers IL6, IL8, and VEGF. Due to potential positive effects of SASP on proliferation, we also stained for PCNA. Data show increased ROS and ongoing DNA damage, by staining for γH2AX, and 53BP1, along with accumulation of senescence markers. Results also showed increased SASP markers in senescent cells. Collectively, our data suggest that heavy-ion-induced chronic stress and ongoing DNA damage is promoting SASP in a fraction of the ISCs, which has implications for gastrointestinal function, inflammation, and carcinogenesis in astronauts and patients.
Highlights
Heavy ion radiation is a major concern in outer space and represents an appreciable dose equivalent of the galactic cosmic radiation (GCR) [1,2,3]
Radiation exposure is linked to increased Reactive oxygen species (ROS) production and oxidative stress and our previous studies have demonstrated chronic oxidative and inflammatory stress in intestinal epithelial cells (IECs) after heavy ion radiation [15]
Since www.aging-us.com oxidative stress and accompanied increased oxidative DNA damage and DNA double stand breaks (DSBs) were observed in these live sorted intestinal stem cells (ISCs), the current data suggest that levels of cellular stress and DNA damage in these cells were below apoptotic threshold
Summary
Heavy ion radiation is a major concern in outer space and represents an appreciable dose equivalent of the galactic cosmic radiation (GCR) [1,2,3]. Cumulative doses of heavy ion radiation from such missions remain a major concern for astronauts’ health. Mathematical modeling approaches indicate that during a Mars mission ~30% of the cells in astronauts will be traversed by either primary or secondary tracts generated by heavy ion radiation [1,2,3]. Considering that ~15% of the GCR is heavy ions, astronauts would be expected to receive 0.05 to 0.07 Gy of heavy ion radiation during a Mars mission [6,7,8]. Current spacecraft shielding technology is unable to block incoming energetic heavy ion radiation rather heavy ions are expected to generate additional harmful secondary radiation from traversed materials. Uncertainty remains about the long-term effects of low dose heavy ion radiation on intestinal stem cells (ISCs), which are important for maintaining astronauts’ gastrointestinal (GI) health during long duration space missions
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