|BRENNER, DAVID - Columbia University Medical Center|
|SHURYAK, IGOR - Columbia University Medical Center|
|BLATTNIG, STEVEN - National Aeronautics And Space Administration (NASA)|
|RABIN, BERNARD - University Of Maryland|
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 12/18/2020
Publication Date: 2/2/2021
Citation: Brenner, D.J., Shuryak, I., Blattnig, S.R., Shukitt Hale, B., Rabin, B.M. 2021. Mechanistically-based model development for space radiation risk assessment: Modeling space radiation induced cognitive dysfunction using targeted and non-targeted effects. [abstract] NASA Human Research Program IWS 2021 (online), Program #1105-002219.
Technical Abstract: Radiation-induced central nervous system (CNS) damage and consequent cognitive dysfunction are increasingly recognized as important risks for astronauts on long-distance space missions such as exploration of Mars [1-2]. These adverse cognitive deficits are similar to those seen in aging and are thought to be caused by similar mechanisms, i.e., persistent oxidative stress and neuroinflammation . Mechanistically-motivated mathematical modeling of this phenomenon can provide much needed insight into interpreting the growing amount of relevant experimental data in laboratory animals, generating and testing mechanistic hypotheses, and producing quantitative predictions for radiation quality effects and risk magnitudes for space mission scenarios. Here we developed and used several model variants based on two general categories of radiation-induced damage: targeted effects (TE), caused by traversal of cells by ionizing tracks, and non-targeted effects (NTE), caused by responses of nearby or even distant cells to signals released by traversed cells. The NTE-based terms used in these formalisms were motivated by our previous work , where we assumed that NTE signals cause sensitive cells to enter into a prolonged stressed state (e.g. persistent oxidative stress) which increases the risk of adverse health effects such as carcinogenesis or cognitive dysfunction. We compared the performances of 18 dose response model variants based on these concepts, fitted by robust nonlinear regression to a large published data set on novel object recognition testing in rats exposed to multiple space-relevant radiation types (H, C, O, Si, Ti and Fe ions), covering wide ranges of LET (0.22-181 keV/µm) and dose (0.001-2 Gy). The strongest support (by Akaike information criterion) was found for an NTE+TE model where NTE saturate at low doses (~0.01 Gy) and occur at all tested LETs, whereas TE depend on dose linearly with a slope that increases with LET. Importance of NTE was also found by additional analyses of the data using quantile regression and random forests. These results suggest that radiation effects on novel object recognition can be induced even at low doses of space radiations, and that the dose response in this space-relevant dose range is not linear (concave) and is likely dominated by NTE rather than TE. Importantly, the radiation effects were persistent over a substantial portion of the rat lifetime. This provides evidence that radiation- induced cognitive decline may not just occur during a space exploration mission, but can potentially last over a lifetime. Therefore, it is even more important that we study countermeasures to prevent these declines, and one that has had promising results is nutrition, specifically polyphenolic-rich berry diets, which also show promising results in aging animals by improving cognitive function. Our findings are based on a single (although large) data set in laboratory animals. However, we believe that they have potentially important implications for assessing CNS dysfunction risks for astronauts on interplanetary space missions.