Abstract
Among the dangers to astronauts engaging in deep space missions such as a Mars expedition is exposure to radiations that put them at risk for severe cognitive dysfunction. These radiation-induced cognitive impairments are accompanied by functional and structural changes including oxidative stress, neuroinflammation, and degradation of neuronal architecture. The molecular mechanisms that dictate CNS function are multifaceted and it is unclear how irradiation induces persistent alterations in the brain. Among those determinants of cognitive function are neuroepigenetic mechanisms that translate radiation responses into altered gene expression and cellular phenotype. In this study, we have demonstrated a correlation between epigenetic aberrations and adverse effects of space relevant irradiation on cognition. In cognitively impaired irradiated mice we observed increased 5-methylcytosine and 5-hydroxymethylcytosine levels in the hippocampus that coincided with increased levels of the DNA methylating enzymes DNMT3a, TET1 and TET3. By inhibiting methylation using 5-iodotubercidin, we demonstrated amelioration of the epigenetic effects of irradiation. In addition to protecting against those molecular effects of irradiation, 5-iodotubercidin restored behavioral performance to that of unirradiated animals. The findings of this study establish the possibility that neuroepigenetic mechanisms significantly contribute to the functional and structural changes that affect the irradiated brain and cognition.
Highlights
NASA and other space agencies are currently developing the technologies necessary to allow manned missions to a near-Earth asteroid, the Moon and to Mars by the 2030’s
A series of studies have demonstrated through the use of viral-mediated, localized gene knockdown that several writers and erasers of DNA methylation, including DNMT3a, and ten-eleven translocation methylcytosine dioxygenase (TET) enzymes TET1 and TET3 are involved in memory formation and addiction behavior[6,17,18]
DNA methylation status depends on enzymatic reactions by DNA methyltransferases (DNMTs) that add methyl groups to cytosine bases in DNA to form 5mC and on the ten-eleven-translocation (TET) enzymes that perform oxidative reactions to convert 5mC to 5hmC (Fig. 1a)[32]
Summary
NASA and other space agencies are currently developing the technologies necessary to allow manned missions to a near-Earth asteroid, the Moon and to Mars by the 2030’s. In concordance with the finding that 5hmC is an active epigenetic mark in neuronal tissue where it is found predominantly in euchromatin[20], the dynamic accumulation of 5hmC has been shown to play an important role in learning and memory[17,18,21] These reversible epigenetic regulators might represent a dynamic mechanism for cellular plasticity in the response to external stimuli[22,23], where radiation exposure may confound cognitive function during deep space exploration[24]. A recent study demonstrated that low dose space radiation exposure affected persistent changes in 5hmC levels that were associated with significantly altered expression of genes involved in neurodegenerative diseases and with cognitive impairment[25]
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