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Non-Targeted Effects Models Predict Significantly Higher Mars Mission Cancer Risk than Targeted Effects Models.

ABSTRACT: Cancer risk is an important concern for galactic cosmic ray (GCR) exposures, which consist of a wide-energy range of protons, heavy ions and secondary radiation produced in shielding and tissues. Relative biological effectiveness (RBE) factors for surrogate cancer endpoints in cell culture models and tumor induction in mice vary considerable, including significant variations for different tissues and mouse strains. Many studies suggest non-targeted effects (NTE) occur for low doses of high linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. Using the mouse Harderian gland tumor experiment, the only extensive data-set for dose response modelling with a variety of particle types (>4), for the first-time a particle track structure model of tumor prevalence is used to investigate the effects of NTEs in predictions of chronic GCR exposure risk. The NTE model led to a predicted risk 2-fold higher compared to a targeted effects model. The scarcity of data with animal models for tissues that dominate human radiation cancer risk, including lung, colon, breast, liver, and stomach, suggest that studies of NTEs in other tissues are urgently needed prior to long-term space missions outside the protection of the Earth's geomagnetic sphere.

SUBMITTER: Cucinotta FA

PROVIDER: S-EPMC5431989 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Interplanetary human spaceflight represents a formidable medical challenge, but also provides a unique platform for investigating human adaptation to extreme environmental changes. Understanding the long-term effects of isolation has relevance in a range of scenarios and it is well recognized that a better understanding of the relationship between environmental exposure and the epigenome can lead to more effective preventive measures. Here we conduct a longitudinal epigenetic, mood state and biochemical profiling of 6 crew members in an experiment simulating a 520-day mission to Mars. Illumina HumanMethylation450 BeadChip was used to obtain DNA methylation profiles. Firstly, we found that long-term isolation can induce global DNA methylation remodeling, and this change seems to be an active adaptation (rather than a random process or a by-product of the isolation). This study is the first to demonstrate the dynamic relationship between global epigenetic remodeling and isolation-induced mood state and biochemical changes. Secondly, by considering the location of methylation sites within the genome and using gene-pathway annotation, we were able to identify pathways that were significantly enriched in methylation events and consider their association with specific function and the timeline of the mission. Thirdly, via our definition of epi-entropy, a measure of entropy adapted to methylation events, we observed that the methylation remodeling produced a marked reduction in epi-entropy. Results suggest that DNA methylation change is an indicator of change rather than its by-product, i.e., there is a psychology-epigenome-metabolism model of long-term depression; DNA methylation programs the environment signal into the epigenome, which is subsequently transformed into the biochemical output and health outcome. Thus, longitudinal epigenetic profiling could code the effect of isolation and act as early indicators of latent health outcome. A longitudinal epigenetic, mood state and biochemical profiling of 6 crew members in an experiment simulating a 520-day mission to Mars. 36 samples of blood cell DNA methylation profiling were obtained by Illumina HumanMethylation450 BeadChip, across 6 sampling points during the 520 days mission for all of the 6 crew members.

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Non-Targeted Effects Models Predict Significantly Higher Mars Mission Cancer Risk than Targeted Effects Models.

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