Abstract
Spaceflight poses many challenges for humans. Ground-based analogs typically focus on single parameters of spaceflight and their associated acute effects. This study assesses the long-term transcriptional effects following single and combination spaceflight analog conditions using the mouse model: simulated microgravity via hindlimb unloading (HLU) and/or low-dose γ-ray irradiation (LDR) for 21 days, followed by 4 months of readaptation. Changes in gene expression and epigenetic modifications in brain samples during readaptation were analyzed by whole transcriptome shotgun sequencing (RNA-seq) and reduced representation bisulfite sequencing (RRBS). The results showed minimal gene expression and cytosine methylation alterations at 4 months readaptation within single treatment conditions of HLU or LDR. In contrast, following combined HLU+LDR, gene expression and promoter methylation analyses showed multiple altered pathways involved in neurogenesis and neuroplasticity, the regulation of neuropeptides, and cellular signaling. In brief, neurological readaptation following combined chronic LDR and HLU is a dynamic process that involves pathways that regulate neuronal function and structure and may lead to late onset neurological sequelae.
Highlights
The central nervous system (CNS) is vulnerable to irradiation [1] and fluid shifts [2] experienced during short- and long-term spaceflight
We found minimal gene alterations at 4 months of readaptation within single treatment conditions of hindlimb unloading (HLU) or low-dose ionizing radiation (LDR), namely, in pathways related to the reduced expression of translational machinery, while the combination of HLU+LDR resulted in a wide panel of altered differentially expressed genes (DEG) and differentially methylated promoters (DMP) profiles for tight junctions, aquaporins, neurogenesis markers and neuropeptides
We identified that chronic exposure (21 days) to single or combined HLU and LDR resulted in long-term transcriptional alterations in CNS brain tissue in female mice at 4 months post-exposure
Summary
The central nervous system (CNS) is vulnerable to irradiation [1] and fluid shifts [2] experienced during short- and long-term spaceflight. During missions beyond low-earth orbit (LEO), astronauts will be continuously exposed to low-dose ionizing radiation (LDR). While high linear energy transfer (LET) galactic cosmic radiation (GCR) and low LET solar particle event (SPE) radiation contribute large portions of the radiation dose accumulated by astronaut crew members [3], interactions between GCR and SPE particles and spacecraft release secondary radiation including γ-rays that can deliver a significant fraction of the total mission does [4]. Studies examining readaptation to Earth’s gravity are of equal importance, as recovery from spaceflight exposure may require medical intervention, in particular within organs known to be sensitive to irradiation and fluid shifts
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