Mice Exposed to Combined Chronic Low-Dose Irradiation and Modeled Microgravity Develop Long-Term Neurological Sequelae

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.

Immunological and hematological outcomes following protracted low dose/low dose rate ionizing radiation and simulated microgravity

“…1 A–C), indicating distinct transcriptomic profiles are generated following each condition. Similar outcomes were also observed in our previous report that analyzed brain tissues at 4-months post-exposure 18 , indicating LDR, HLU, and simSpace independently trigger divergent pathways post-exposure. Interestingly, post-HLU appears to produce a large number of transcriptional changes compared to post-LDR alone, indicating altered gravity may cause pronounced physiological impairments.…”

“…Therefore, spleens and blood of mice were analyzed by RNAseq and hematological analyses, respectively, at 7-days post-simSpace. Previous studies in our lab have developed a simSpace model of low-dose radiation (LDR, 0.04 Gy) and hindlimb unloading (HLU) that mimics astronauts in-orbit on the International Space Station (ISS) 18 . Analyses at 7-days post-simSpace provide insight into the immediate early responses similarly experienced by crew during Earth readaptation, a critical time point of equalizing homeostasis.…”

“…Ground-based models of spaceflight are developed to easily explore the impacts of the spaceflight environment on physiology. Indeed, we previously reported that a 21-day, protracted exposure of 0.04 Gy low dose/low dose rate gamma radiation (LDR), combined with hindlimb unloading (HLU), can have neurological impacts on blood–brain barrier integrity, the oxidative stress response, and neuroplasticity 18 – 22 . Here, we expand on this work, using RNA-sequencing of splenic tissues and complete blood cell (CBC) counts to characterize relevant immune and hematological pathways engaged after 1-week readaptation following simulated spaceflight conditions.…”

Spaceflight influences gene expression, photoreceptor integrity, and oxidative stress-related damage in the murine retina

“…However, the space environment is fundamentally different from Earth. Microgravity and ionizing radiation compose a unique set of physiological stressors, the effects of which remain to be fully characterized 2,3 .…”

Understanding the Effects of Deep Space Radiation on Nervous System: The Role of Genetically Tractable Experimental Models

“…Irradiation produced many different neurophysiological alterations, which have been well-measured in the perirhinal cortex, including changes in both intrinsic and extrinsic neuronal properties [69]. Studies in rodents also showed that the effects of irradiation on CNS transcriptional activity and epigenetic state can be potentiated by simulated microgravity [70].…”