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This research investigates the radiobiological response of human peripheral blood leukocytes (PBLs) exposed to laser-driven very high-energy electrons (VHEEs) delivered at an instantaneous ultra-high dose rate exceeding 10¹² Gy/s. PBLs serve as a valuable in vitro model for studying radiation-induced effects due to their high radiosensitivity, largely non-proliferative state in vivo, and widespread use in radiobiological assessments. Their well-characterized response to ionizing radiation provides critical insights into DNA damage and repair mechanisms, as well as overall cellular stress responses in normal human cells, making them an essential model for both mechanistic and translational research. PBLs are particularly suitable for examining radiation-induced chromosomal damage because they are inherently synchronized in the G0 phase of the cell cycle, ensuring uniform radiosensitivity. The micronucleus (MN) assay is a sensitive cytogenetic method used to detect and quantify chromosomal damage by measuring the formation of small extranuclear bodies—micronuclei—arising from acentric chromosome fragments or whole chromosomes excluded during cell division, making it a robust marker of radiation exposure.
Moreover, telomere length has emerged as a novel and sensitive endpoint of cellular radiation response. Telomeres, the protective caps at the ends of chromosomes, are essential for maintaining genome stability, and their excessive shortening can lead to genomic instability. Since mitochondrial DNA lacks protective histones and has limited repair capacity compared to nuclear DNA, it is particularly vulnerable to reactive oxygen species generated by ionizing radiation. mtDNA copy number, which reflects mitochondrial content per cell, serves as an indirect indicator of mitochondrial health and radiation-induced cellular damage.
Ionizing radiation affects not only directly irradiated cells but also neighboring non-irradiated cells through the bystander effect. This phenomenon includes increased apoptosis, micronucleus formation, DNA strand breaks, altered regulatory protein expression, and reduced clonogenic survival. These responses are mediated by intercellular communication via gap junctions and soluble factors released into the extracellular environment and may have important clinical implications, particularly for tissues outside the primary radiation field during radiotherapy.
In this study, we analyzed the biological effects of VHEE bunches on both nuclear and mitochondrial DNA, considering direct and bystander responses. Our findings demonstrate that laser-plasma-accelerated VHEEs elicit distinct radiobiological responses, with evidence of micronuclei formation and telomere shortening, yet induce less chromosomal damage and telomere reduction compared to conventional X-rays at equivalent doses. These results provide an important reference for evaluating the radiobiological properties and therapeutic potential of VHEEs in preclinical studies, particularly in the context of their ultra-high instantaneous dose rates.
