Antioxidants Ameliorates Ionizing Radiation-Induced Microcephaly in Cerebral Organoid Derived from Human-induced Pluripotent Stem Cells

Ionizing radiation exposure induces DNA damage and chromosome aberrations through both direct and indirect effect. The indirect effects are primarily mediated by the generation of hydroxyl radicals, a process attributed to radiation. Dimethyl sulfoxide (DMSO) and ascorbic acid (AA) are known as radical scavengers and have radioprotective effects. Radiation therapy is widely employed in the treatment of malignant tumors such as glioblastoma; however, its side effects, including cognitive impairments resulting from damage to healthy neurons, pose significant challenges. To ameliorate these effects, radioprotective reagents have been sought. In this study, we used cerebral organoids derived from human-induced pluripotent stem cells to address the radioprotective effect of radical scavengers, DMSO and AA in brain exposure. Although exposure to radiation for 20-day-old cerebral organoids results in DNA double-strand breaks and apoptosis leading to microcephaly phenotype, treatment with DMSO or AA not only before but also after radiation alleviated DNA damage, cell death, and the microcephaly phenotype. Our results suggest that DMSO and AA are candidates for the radioprotective reagents for brain tumor therapy.