Short- and long-term effects of 56Fe irradiation on cognition and hippocampal DNA methylation and gene expression

Soren Impey; Timothy Jopson; Carl Pelz; Amanuel Tafessu; Fatema Fareh; Damian Zuloaga; Tessa Marzulla; Lara-Kirstie Riparip; Blair Stewart; Susanna Rosi; Mitchell S Turker; Jacob Raber

doi:10.1186/s12864-016-3110-7

Short- and long-term effects of ⁵⁶Fe irradiation on cognition and hippocampal DNA methylation and gene expression

BMC Genomics. 2016 Oct 24;17(1):825. doi: 10.1186/s12864-016-3110-7.

Authors

Soren Impey^{1

2}, Timothy Jopson^{3

4

5}, Carl Pelz⁶, Amanuel Tafessu⁶, Fatema Fareh⁶, Damian Zuloaga⁷, Tessa Marzulla⁷, Lara-Kirstie Riparip^{3

4

5}, Blair Stewart⁷, Susanna Rosi^{3

4

5}, Mitchell S Turker⁸, Jacob Raber^{9

10

11}

Affiliations

¹ Oregon Stem Cell Center and Department of Pediatrics, Oregon Health and Science University, Portland, OR, 97239, USA. impeys@ohsu.edu.
² Department of Cell, Developmental Biology, and Cancer Biology, Oregon Health and Science University, Portland, OR, 97239, USA. impeys@ohsu.edu.
³ Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, CA, 94110, USA.
⁴ Departments of Physical Therapy Rehabilitation Science, University of California, San Francisco, San Francisco, CA, 94110, USA.
⁵ Neurological Surgery, University of California San Francisco, Zuckerberg San Francisco General Hospital, San Francisco, CA, 94110, USA.
⁶ Oregon Stem Cell Center and Department of Pediatrics, Oregon Health and Science University, Portland, OR, 97239, USA.
⁷ Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA.
⁸ Oregon Institute of Occupational Health Sciences and Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, 97239, USA.
⁹ Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA. raberj@ohsu.edu.
¹⁰ Departments of Neurology and Radiation Medicine, Oregon Health and Science University, Portland, OR, 97239, USA. raberj@ohsu.edu.
¹¹ Division of Neuroscience ONPRC, Oregon Health and Science University, Portland, OR, 97239, USA. raberj@ohsu.edu.

Abstract

Background: Astronauts are exposed to ⁵⁶Fe 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 with ⁵⁶Fe ions. Here we examined object recognition in 6-month-old mice irradiated with ⁵⁶Fe ions, a biological age more relevant to the typical ages of astronauts. Moreover, because the mechanisms mediating the detrimental effects of ⁵⁶Fe 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 body ⁵⁶Fe 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.

Results: 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.

Conclusions: Dose- and time-dependent epigenomic remodeling in the hippocampus following ⁵⁶Fe ion exposure correlates with behavioral changes.

Keywords: Cognition; DNA methylation; Gene expression; Hippocampus; Network stability.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
CA1 Region, Hippocampal / metabolism
CA1 Region, Hippocampal / radiation effects
Cluster Analysis
Cognition / radiation effects*
DNA Methylation / radiation effects*
Epigenesis, Genetic / radiation effects*
Gene Expression Profiling
Gene Expression Regulation / radiation effects*
Gene Ontology
Hippocampus / metabolism*
Hippocampus / radiation effects*
Immunohistochemistry
Iron*
Male
Maze Learning
Mice
Psychomotor Performance / radiation effects
Radiation, Ionizing*

Substances

Iron

Grants and funding

T32 DA007262/DA/NIDA NIH HHS/United States