title: 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.
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Munjal M
authors.initials: MM
authors.lastname: Acharya
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Al Anoud D
authors.initials: AA
authors.lastname: Baddour
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kawashita
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Barrett D
authors.initials: BD
authors.lastname: Allen
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Amber R
authors.initials: AR
authors.lastname: Syage
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Thuan H
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Yoon
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Erich
authors.initials: E
authors.lastname: Giedzinski
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Vipan K
authors.initials: VK
authors.lastname: Parihar
authors.affiliation: University of California Irvine, CA 92697, USA.
authors.forename: Janet E
authors.initials: JE
authors.lastname: Baulch
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000528:radiation effects; D001921:Brain / Q000378:metabolism / Q000528:radiation effects*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000528:radiation effects; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D057890:Epigenomics; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology; D014916:Whole-Body Irradiation
chemical_list: D004268:DNA-Binding Proteins; C000715535:Dnmt3a protein, mouse; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; C034214:5-iodotubercidin; D044503:5-Methylcytosine; D049308:Dioxygenases; C551915:Tet3 protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D000248:Adenosine Kinase; D014372:Tubercidin