High-Dose Gestational Irradiation Disrupts Fetal Mouse Brain Structure and Region-Specific Transcriptomic Profiles

Background/Objectives: Prenatal exposure to ionizing radiation can disrupt neurodevelopment, yet the region-specific structural and molecular responses of the developing brain remain incompletely understood. In particular, how gestational irradiation alters transcriptional programs across distinct fetal brain regions and whether these responses differ by sex has not been fully characterized. This study examined the structural and transcriptomic responses in the fetal mouse brain following high-dose gestational irradiation. Methods: Pregnant BALB/c mice were exposed to 1.8 Gy of X-ray irradiation on gestational day (GD) 14.5, and fetal brains were collected on GD 18.5. Results: Using a previously characterized model of radiation-induced fetal growth restriction, H&E-stained sagittal fetal brain sections revealed reduced hippocampal volume and enlargement of the lateral ventricle, while cerebellar volume and optical density were not significantly altered. RNA-seq analysis of the telencephalon, diencephalon, midbrain, and hindbrain revealed region-specific transcriptional dysregulation enriched for genes associated with immune and inflammatory signalling, neurogenesis, gliogenesis, cell migration, and neurotransmitter signalling, with the strongest response observed in the telencephalon and differing DEG profiles between males and females in sex-stratified analyses. Conclusions: These findings indicate that high-dose gestational irradiation is associated with region-specific structural alterations and transcriptional changes in the fetal brain, generating hypotheses regarding the mechanisms of radiation-induced neurodevelopmental disruption.