title: Short- and long-term effects of56Fe irradiation on cognition and hippocampal DNA methylation and gene expression.
abstract: Astronauts are exposed to56Fe ions that may pose a significant health hazard during and following prolonged missions in deep space. We showed previously that object recognition requiring the hippocampus, a structure critical for cognitive function, is affected in 2-month-old mice irradiated with56Fe ions. Here we examined object recognition in 6-month-old mice irradiated with56Fe ions, a biological age more relevant to the typical ages of astronauts. Moreover, because the mechanisms mediating the detrimental effects of56Fe ions on hippocampal function are unclear, we examined changes in hippocampal networks involved in synaptic plasticity and memory, gene expression, and epigenetic changes in cytosine methylation (5mC) and hydroxymethylation (5hmC) that could accompany changes in gene expression. We assessed the effects of whole body56Fe ion irradiation at early (2 weeks) and late (20 weeks) time points on hippocampus-dependent memory and hippocampal network stability, and whether these effects are associated with epigenetic changes in hippocampal DNA methylation (both 5mC and 5hmC) and gene expression.
  
  
  
  At the two-week time point, object recognition and network stability were impaired following irradiation at the 0.1 and 0.4 Gy dose, but not following irradiation at the 0.2 Gy dose. No impairments in object recognition or network stability were seen at the 20-week time point at any irradiation dose used. Consistent with this pattern, the significance of pathways for gene categories for 5hmC was lower, though not eliminated, at the 20-week time point compared to the 2-week time point. Similarly, significant changes were observed for 5mC gene pathways at the 2-week time point, but no significant gene categories were observed at the 20-week time point. Only the 5hmC changes tracked with gene expression changes.
  
  
  
  Dose- and time-dependent epigenomic remodeling in the hippocampus following56Fe ion exposure correlates with behavioral changes.
authors: Oregon Stem Cell Center and Department of Pediatrics, Oregon Health and Science University, Portland, OR, 97239, USA. impeys@ohsu.edu.|Department of Cell, Developmental Biology, and Cancer Biology, Oregon Health and Science University, Portland, OR, 97239, USA. impeys@ohsu.edu.
authors: Soren
authors: S
authors: Impey
authors: Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, CA, 94110, USA.|Departments of Physical Therapy Rehabilitation Science, University of California, San Francisco, San Francisco, CA, 94110, USA.|Neurological Surgery, University of California San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, CA, 94110, USA.
authors: Timothy
authors: T
authors: Jopson
authors: Oregon Stem Cell Center and Department of Pediatrics, Oregon Health and Science University, Portland, OR, 97239, USA.
authors: Carl
authors: C
authors: Pelz
authors: Oregon Stem Cell Center and Department of Pediatrics, Oregon Health and Science University, Portland, OR, 97239, USA.
authors: Amanuel
authors: A
authors: Tafessu
authors: Oregon Stem Cell Center and Department of Pediatrics, Oregon Health and Science University, Portland, OR, 97239, USA.
authors: Fatema
authors: F
authors: Fareh
authors: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA.
authors: Damian
authors: D
authors: Zuloaga
authors: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA.
authors: Tessa
authors: T
authors: Marzulla
authors: Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, CA, 94110, USA.|Departments of Physical Therapy Rehabilitation Science, University of California, San Francisco, San Francisco, CA, 94110, USA.|Neurological Surgery, University of California San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, CA, 94110, USA.
authors: Lara-Kirstie
authors: LK
authors: Riparip
authors: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA.
authors: Blair
authors: B
authors: Stewart
authors: Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, CA, 94110, USA.|Departments of Physical Therapy Rehabilitation Science, University of California, San Francisco, San Francisco, CA, 94110, USA.|Neurological Surgery, University of California San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, CA, 94110, USA.
authors: Susanna
authors: S
authors: Rosi
authors: Oregon Institute of Occupational Health Sciences and Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, 97239, USA.
authors: Mitchell S
authors: MS
authors: Turker
authors: Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA. raberj@ohsu.edu.|Departments of Neurology and Radiation Medicine, Oregon Health and Science University, Portland, OR, 97239, USA. raberj@ohsu.edu.|Division of Neuroscience ONPRC, Oregon Health and Science University, Portland, OR, 97239, USA. raberj@ohsu.edu.
authors: Jacob
authors: 0000-0002-9861-9893
authors: J
authors: Raber
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000528:radiation effects; D016000:Cluster Analysis; D003071:Cognition / Q000528:radiation effects*; D019175:DNA Methylation / Q000528:radiation effects*; D044127:Epigenesis, Genetic / Q000528:radiation effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000528:radiation effects*; D063990:Gene Ontology; D006624:Hippocampus / Q000378:metabolism* / Q000528:radiation effects*; D007150:Immunohistochemistry; D007501:Iron; D008297:Male; D018782:Maze Learning; D051379:Mice; D011597:Psychomotor Performance / Q000528:radiation effects; D011839:Radiation, Ionizing
chemical_list: D007501:Iron
keywords: Cognition; DNA methylation; Gene expression; Hippocampus; Network stability