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Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine.

ABSTRACT: Proliferative gastrointestinal (GI) tissue is radiation-sensitive, and heavy-ion space radiation with its high-linear energy transfer (high-LET) and higher damaging potential than low-LET ?-rays is predicted to compromise astronauts' GI function. However, much uncertainty remains in our understanding of how heavy ions affect coordinated epithelial cell migration and extrusion, which are essential for GI homeostasis. Here we show using mouse small intestine as a model and BrdU pulse labeling that cell migration along the crypt-villus axis is persistently decreased after a low dose of heavy-ion ⁵⁶Fe radiation relative to control and ?-rays. Wnt/?-catenin and its downstream EphrinB/EphB signaling are key to intestinal epithelial cell (IEC) proliferation and positioning during migration, and both are up-regulated after ⁵⁶Fe radiation. Conversely, factors involved in cell polarity and adhesion and cell-extracellular matrix interactions were persistently down-regulated after ⁵⁶Fe irradiation-potentially altering cytoskeletal remodeling and cell extrusion. ⁵⁶Fe radiation triggered a time-dependent increase in ?H2AX foci and senescent cells but without a noticeable increase in apoptosis. Some senescent cells acquired the senescence-associated secretory phenotype, and this was accompanied by increased IEC proliferation, implying a role for progrowth inflammatory factors. Collectively, this study demonstrates a unique phenomenon of heavy-ion radiation-induced persistently delayed IEC migration involving chronic sublethal genotoxic and oncogenic stress-induced altered cytoskeletal dynamics, which were seen even a year later. When considered along with changes in barrier function and nutrient absorption factors as well as increased intestinal tumorigenesis, our in vivo data raise a serious concern for long-duration deep-space manned missions.

SUBMITTER: Kumar S

PROVIDER: S-EPMC6196540 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine.

Kumar Santosh S Suman Shubhankar S Fornace Albert J AJ Datta Kamal K

Proceedings of the National Academy of Sciences of the United States of America 20181001 42

Proliferative gastrointestinal (GI) tissue is radiation-sensitive, and heavy-ion space radiation with its high-linear energy transfer (high-LET) and higher damaging potential than low-LET γ-rays is predicted to compromise astronauts' GI function. However, much uncertainty remains in our understanding of how heavy ions affect coordinated epithelial cell migration and extrusion, which are essential for GI homeostasis. Here we show using mouse small intestine as a model and BrdU pulse labeling that ...[more]

PMID: 30275302

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Project description:Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 exhibit similar features to patients with hypoparathyroidism, including reduced serum parathyroid hormone (PTH) and Ca with low bone turnover. Although persistent suppression of bone turnover may increase bone fragility, bone strength in ADH1 patients has been unclear. We created knock-in mice harboring the A843E activating mutation of CaSR, mimicking severe features of ADH1 patients. The severe form of ADH1 model mice showed smaller body and bone size with lower bone mineral density (BMD) and cortical area of the femur compared with age-matched wild-type (WT) mice. Bone strength in the femur was lower in ADH1 mice even after correction by bone geometry and/or BMD. Microcracks were markedly increased in ADH1 mice, but were rarely detected in WT mice. There was a negative correlation between bone strength corrected by bone geometry and/or BMD and microcrack number or density in ADH1 and WT mice. Among ADH1 mice, negative correlation was still observed between bone strength and microcrack number or density. Microcracks increased with age in ADH1 mice, and were negatively correlated with bone strength. Treatment with PTH(1-34) or a calcilytic, JTT-305, increased bone turnover, reduced microcracks, and increased bone strength to similar levels to those in WT mice. The increase in microcracks was associated with a reduction in bone strength in ADH1 mice, and aging aggravates these changes. These results demonstrate that activating mutation of CaSR causes reduction in PTH secretion with suppressed bone turnover, that reduced bone turnover is associated with an age-dependent increase in microcracks with a reduction in bone strength, and that both PTH(1-34) and calcilytic ameliorate all these changes in bone turnover and strength. It is suggested that fracture susceptibility may be increased in severe types of ADH1 patients especially in the elderly. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Dataset Information

Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine.

Publications

Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine.

Similar Datasets

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