Genomics assessment of the impact of ionising radiation on the human brain

Abstract

Ionising radiation (IR) is a pervasive environmental factor with known biological effects, yet its long-term impact on brain function and cognitive processes remains insufficiently understood. In recent years, evidence has emerged purporting IR as a possible risk factor for cognitive impairment, characterised by deficits in learning, memory, and information processing ability. While consequences of prenatal exposure has been more extensively studied, there is much more uncertainty about the effects of IR when exposure occurs in adolescents and adults, particularly at low to moderate doses. High-throughput technologies have highlighted changes in genes and pathways related to brain function secondary to radiation exposure. Consequently, individuals exposed through medical therapy, nuclear disasters, and occupation might be subject to such a risk. The aim of this thesis was to investigate the relationship between gene expression, genetic variation and IR exposure, with a specific focus on the molecular mechanisms that underlie the impact on the brain’s function and activity. A multi-tiered approach was employed integrating data from healthy and disease brain tissues, IR-exposed cell lines and a unique population of potentially exposed British nuclear test veterans (NTVs). Leveraging publicly available data, the gene expression profiles in normal brains, brain cancers and neurological disorders were investigated. Furthermore, the impact of exposure to IR at various levels was studied in human cell lines. Whole genome sequencing data from the NTVs were analysed and compared with a matched military control group, to reveal the potential impact of radiation in the context of brain function and cognition. The present work includes critical analysis of phenotypic, clinical, genomic and transcriptomic data to identify patterns of gene expression and variation. The findings revealed that the healthy brain is tightly regulated by gene specific expression patterns involved in synaptic transmission, cellular stress responses and metabolic processes. Brain cancers revealed upregulation in the cell cycle and proliferation pathways, whilst highlighting dysregulation of neuroinflammation and metabolic processes in the Alzheimer’s brain. Limited differential expression was noted in psychiatric disorders, suggesting complex, multifactorial origins in cognitive symptoms. Transcriptomics landscape analysis of IR-exposed human cells identified dose-responsive genes, with the number of differentially expressed genes increasing tenfold from low to high doses of exposure. While the effects of IR did not show a linear dependence on dose, the key pathways related to DNA repair, oxidative stress response and inflammatory pathways affected were observed across all exposure levels. These pathways were also found to be implicated in cognitive dysfunction and neurodegenerative diseases, suggesting a potential link between IR and CNS diseases. Moreover, the results pinpointed to several novel radiation exposure and dose-specific biomarkers, that showed good discriminatory power between irradiated and control samples. Genomic analyses in the military veteran population revealed no significant differences in the frequency of single nucleotide polymorphisms, indels, and the incidence of clustered mutations between the two cohorts. The lack of genetic variation between the groups appeared to be influenced by ageing. Several shared and cohort-specific mutations pinpointed genes potentially associated with ageing, underpinning some of the self-reported health challenges of the NTVs have and some known associations to CNS and cognitive functions. The findings elucidate the biological responses, mutations, genetic, and the adverse pathways that can lead to cognitive impairments. Additionally, it illustrates the limited association between the NTVs and potential IR exposure.