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Single-cell transcriptomic profiling reveals sex-specific microglial responses to simulated galactic cosmic radiation without classical inflammatory activation

ABSTRACT: Long‑duration deep space missions expose astronauts to galactic cosmic radiation (GCR), a complex mixture of high‑ and low‑LET ions that can compromise central nervous system (CNS) health. Microglia, the resident immune cells of the brain, are highly sensitive to radiation, yet their cell‑state adaptations to space‑relevant mixed‑field exposure remain poorly defined. Here, we performed single‑cell RNA sequencing (scRNA‑seq) of hippocampal microglia isolated from male and female C57BL/6J mice 53 days after acute 100 cGy 5‑ion GCR simulation. Behavioral testing showed no overt deficits, but scRNA‑seq revealed subtle, sex‑specific transcriptional remodeling. Male microglia engaged a stress‑adaptive program characterized by upregulation of Fkbp5, Rtp4, Creb5, and metabolic regulators, with concurrent downregulation of ER chaperone and ribosomal genes. Female microglia displayed a transcriptionally blunted phenotype with selective induction of Fkbp5, Ccnd3, and Tnfaip3, and broad downregulation of inflammatory and NOD/TNF pathways. Canonical inflammatory or disease‑associated microglia signatures were absent and homeostatic markers (P2ry12, Cx3cr1) were preserved. These findings define a non‑inflammatory, sex‑specific microglial response to space‑relevant GCR and provide a cellular framework for sex‑informed CNS risk assessment and countermeasure development for deep space travel.

ORGANISM(S): Mus musculus

PROVIDER: GSE315315 | GEO | 2025/12/31

REPOSITORIES: GEO

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Project description:Human deep space and planetary travel is limited by uncertainties regarding the health risks associated with exposure to galactic cosmic radiation (GCR), and in particular the high linear energy transfer (LET), heavy ion component. Here we assessed the impact of two high-LET ions 56Fe and 28Si, and low-LET X rays on genome-wide methylation patterns in human bronchial epithelial cells. We found that all three radiation types induced rapid and stable changes in DNA methylation but at distinct subsets of CpG sites affecting different chromatin compartments. The 56Fe ions induced mostly hypermethylation, and primarily affected sites in open chromatin regions including enhancers, promoters and edges (“shores”) of CpG islands. The 28Si ion-exposure had mixed effects, inducing both hyper and hypomethylation and affecting sites in more repressed heterochromatic environments, whereas X rays induced mostly hypomethylation, primarily at sites in gene bodies and intergenic regions. Significantly, the methylation status of 56Fe ion irradiation sensitive sites, but not those affected by X ray or 28Si ions, could discriminate tumor from normal tissue for human lung adenocarcinomas and squamous cell carcinomas. Thus, high LET radiation exposure leaves a lasting imprint on the epigenome, and affects sites relevant to human lung cancer. The 56Fe ion signature may prove useful in monitoring the cumulative biological impact and associated cancer risks encountered by astronauts in deep space. Genome wide DNA methylation profiling of normal human bronchial epithelial cells irradiated with varying doses of 28Si-ion radiation ( 300 MeV/u at 0, 0.3, 1.0 Gy) , 56Fe-ion radiation (600 MeV/u at 0, 0.1, 0.3, 1.0 Gy) or X rays (320 kV at 0, 1.0 Gy). Triplicate control and irradiated samples were incubated and sampled at 4 timepoints between 2 and 62 days. The Illumina Infinium 450k Human DNA methylation Beadchip was used to obtain DNA methylation profiles across >485,000 CpGs from collected samples. Samples include: 56Fe ions, 4 doses x 4 time points x 3 replicates (4 removed in QC) = 44 samples; 28Si ions = 3 doses x 4 time points x 3 replicates = 36 samples; X ray, 2 doses x 4 time points x 3 replicates (2 removed in QC)= 22 samples.

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Single-cell transcriptomic profiling reveals sex-specific microglial responses to simulated galactic cosmic radiation without classical inflammatory activation

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