Epigenetic determinants of space radiation-induced cognitive dysfunction

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.

Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance

“…Further studies would be required to confirm to what extent this reflects causal or consequential changes [ 98 ]. Epigenetic DNA methylation is very relevant for space travel, since an irradiation response in brain tissue and inhibition of DNA methylation can be an effective neuroprotective strategy to avoid radiation-induced cognitive deficits [ 99 ].…”

Sex-Specific Effects of a Wartime-Like Radiation Exposure on Cognitive Function

“…Previously published work performed by others and by us has suggested that radiation affects changes in DNA methylation profiles that correlate with cognitive impair-ments (34)(35)(36). In some cases, these changes have been implicated not just as biomarkers of exposure, but also as a functionally relevant epigenetic mechanism underlying the CNS effects of irradiation.…”

“…However, systematic studies need to be conducted to critically evaluate the link between radiationinduced CNS effects and hormone cycles. Finally, the observed epigenetic changes have been posited to be a potential epigenetic mechanism that ultimately contributes to radiation-induced cognitive dysfunction (34)(35)(36). If a causative link could be established between alterations in DNA methylation and cognitive changes, it may provide a logical avenue for the development of radiation protection and mitigation strategies.…”

Assessment of Radiosensitivity and Biomonitoring of Exposure to Space Radiation

“…Another study investigated the correlation between 56 Fe-induced cognitive decline and changes in DNA methylation and hydroxymethylation (hmC) in the hippocampus, showing that especially hmC could be correlated to cognitive impairments (Impey et al 2016). Interestingly, treatment of mice with the DNA methylation inhibitor 5-iodotubercidin partially restored DNA methylation levels and could improve cognitive function of mice exposed to a space-relevant dose of 28 Si-ions (Acharya et al 2017).…”