Effects of HZE particle exposure location and energy on brain inflammation and oxidative stress in rats

Authors: CAHOON, DANIELLE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; RABIN, BERNARD - University Of Maryland; Fisher, Derek; Shukitt-Hale, Barbara

Submitted to: Radiation Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/24/2023
Publication Date: 9/27/2023
Citation: Cahoon, D., Rabin, B., Fisher, D.R., Shukitt Hale, B. 2023. Effects of HZE particle exposure location and energy on brain inflammation and oxidative stress in rats. Radiation Research. 200(5):431-443. https://doi.org/10.1667/RADE-22-00041.1.
DOI: https://doi.org/10.1667/RADE-22-00041.1

Interpretive Summary: Astronauts in deep space will be exposed to radiation particles which have been shown to negatively affect the brain as well as performance. Recent research using animal models has shown that the head/brain does not have to be directly hit by these radiation particles to cause performance deficits. Damage to the brain caused by radiation hits to the body are called non-targeted effects (NTEs) and recent research has shown that NTEs are primarily responsible for changes in cognitive function following radiation exposure. The present experiment was designed to further explore the role of targeted and non-targeted effects on radiation-induced inflammation and oxidative stress (OS). Forty-six male Sprague-Dawley rats received head-only or body-only exposures of two different energies of iron radiation, and two different energies of titanium radiation. Twenty-four hours following irradiation, the brain was removed and two areas involved in cognition were dissected out for analysis. Results showed that exposure to both iron and titanium produced changes in measures of brain inflammation and OS in these brain areas. However, radiation effects varied depending upon the specific measure, brain region, and exposure location. Although overall exposures of the head produced more detrimental changes in inflammation and OS than exposures of the body, body-only exposures also produced changes relative to no irradiation. Because particle energy did not contribute to the changes, results suggest that NTEs are likely the primary cause of changes in the brain, even when only the rat head is radiated. Therefore, these findings, although in an animal model, suggest that NTEs should be considered in the estimation of risk to astronauts and in the development of countermeasures.

Technical Abstract: Astronauts on exploratory missions will be exposed to radiation particles of high energy and charge (HZE particles), which have been shown to produce neurochemical and performance deficits in animal models. Exposure to HZE particles can produce both targeted effects, resulting from direct ionization of atoms along the particle track and non-targeted effects (NTEs) in cells that are distant from the track, extending the range of potential damage beyond the site of irradiation. While recent work suggests that NTEs are primarily responsible for changes in cognitive function following HZE exposures, the relative contributions of targeted and non-targeted effects to neurochemical changes following HZE exposures are unclear. The present experiment was designed to further explore the role of targeted and non-targeted effects on HZE-induced neurochemical changes (inflammation and oxidative stress, OS) by evaluating the effects of exposure location and particle energy/linear energy transfer (LET). Forty-six male Sprague-Dawley rats received head-only or body-only exposures to 56Fe particles (600 MeV/n [75 cGy] or 1000 MeV/n [100 cGy]) or 48Ti particles (500 MeV/n [50 cGy] or 1100 MeV/n [75 cGy]) or no irradiation (0 cGy). Twenty-four hours following irradiation, rats were euthanized and the brain was dissected for analysis of HZE particle-induced neurochemical changes in the hippocampus and frontal cortex. Results showed that exposure to 56Fe and 48Ti produced changes in measures of brain inflammation (glial fibrillary astrocyte protein, GFAP), oxidative stress (NADPH-oxidoreductase-2, NOX2) and antioxidant enzymes (superoxide dismutase SOD, glutathione S-transferase GST, nuclear factor erythroid 2-related factor 2 Nrf2). However, radiation effects varied depending upon the specific measure, brain region, and exposure location. Although overall exposures of the head produced more detrimental changes in neuroinflammation and OS than exposures of the body, body-only exposures also produced changes relative to no irradiation, and the effect of particle energy/LET on neurochemical changes was minimal. Results suggest that NTEs are likely the proximal cause of neurochemical changes, even when only the rat head is exposed. Therefore, these findings, although in an animal model, suggest that NTEs should be considered in the estimation of risk to the CNS and development of countermeasures.