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Title: Exposure to O-16 particle irradiation causes age-like decrements in rats through increased oxidative stress, inflammation and loss of autophagy

Author
item Poulose, Shibu
item BIELINSKI, DONNA - Tufts University
item CARRIHILL-KNOLL, KIRSTY - University Of Maryland
item RABIN, BERNARD - University Of Maryland
item Shukitt-Hale, Barbara

Submitted to: Radiation Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/29/2011
Publication Date: 12/1/2011
Citation: Poulose, S.M., Bielinski, D., Carrihill-Knoll, K., Rabin, B.M., Shukitt Hale, B. 2011. Exposure to O-16 particle irradiation causes age-like decrements in rats through increased oxidative stress, inflammation and loss of autophagy.Radiation Research. 176:761-769.

Interpretive Summary: On manned missions to outer space astronauts will be exposed to various forms of radiation which may have long term consequences on their health. In our previous studies, exposure of young laboratory animals to some of these radiations has caused significant declines in memory and cognitive functions similar to that of aged animals. Most of these studies are done with one or two types of radiation, and information on other charged radiation particles is limited. In this study we exposed young rats to high energy oxygen radiation and measured its effect on inflammation, stress response and housekeeping function in the brain known as autophagy. We studied short term or immediate effects (36 hours) and long term effects (75 days) after the exposure to the radiation. We observed significant differences between radiated and unexposed rats in terms of their inflammation and stress response. Even though some of the damage was recovered after a longer period of time, we noticed some permanent damage in terms of the molecular changes, indicating a non-recoverable function in the brain. Similarly autophagy, the natural housekeeping process in the brain by which toxic debris and proteins are degraded and recycled, also decreased, similar to what we see in aged animals. Overall both inflammation and loss of autophagy which increased as a result of oxygen radiation caused excessive oxidative damage, which in turn caused excessive toxic protein buildup. Also radiation exposure caused activation of immune cells in brain called microglia, which can respond to neuronal distress signals, secrete neurotoxic intermediates and damage neurons. Therefore, this study provides insights on how oxygen radiation produces age-like decrements that may impair the ability of astronauts to perform critical tasks during long-term space travel.

Technical Abstract: Exposing young rats to particles of high energy and charge (HZE particles) enhances indices of oxidative stress and inflammation, disrupts the functioning of neuronal communication, and alters cognitive behaviors. Even though exposure to these highly charged particles occurs at low fluence rates, previous reports indicate that the cumulative effects of long duration flights could possibly manifest in molecular changes similar to those seen in aged animals. In the present study, we assessed stress and inflammatory responses, as well as autophagy, a dynamic process for intracellular degradation and recycling of toxic proteins and organelles, in the brains of young Sprague-Dawley rats (2 months old) exposed to 0, 5, 50 and 100 cGy of 1000MeV/n ionizing oxygen (16O) radiation. Exposure to 16O significantly (P<0.05) inhibited autophagy function in the hippocampus as measured by accumulation of ubiquitin inclusion bodies such as P62/SQSTM1, autophagosome marker MAP1B-LC3 and regulator proteins such as mTOR. The molecular changes measured at short term (36 hours) and long term (75 days) intervals after the 16O exposure indicate that certain losses in function were recovered in terms of autophagy. However, inflammatory and oxidative stress markers remained elevated even after 75 days, possibly potentiating harmful cascading effects. Immunohistochemical analyses of the irradiated brain sections showed substantial increases in the levels of NF-kB and glial fibrillary acidic protein (GFAP), indicating activated glial cells even after 75 days of exposure, a condition known to be deleterious. The results also indicated a significant decrease in PKC-a., a key G protein modulator involved in neuronal survival and functions of neuronal trophic factors as well as motor behavior, suggesting long term effects of 16O radiation. These results provide evidence regarding molecular effects following exposure to oxygen radiation, which may lead to oxidative stress, inflammation, and non-recoverable function in the brain of young rats and possibly following manned missions to outer space.