While the cystic degeneration was a very notable feature of the HZE-exposed group, we do not at this time have a clear understanding of its etiology; perhaps it is an emergent phenomenon reflecting the various kinds of stress imposed by HZE exposure. To investigate differences between the effects of HZE Fulvestrant particle radiation and c-rays, we exposed a separate cohort of medaka embryos to c-radiation. It was necessary to establish the two cohorts sequentially, rather than simultaneously, because of the logistical difficulty in handling large numbers of embryos simultaneously. The c-ray cohort was established about six weeks after the HZE cohort and was drawn from the same stocks. The two cohorts had approximately the same median lifespan and showed a similar age-dependent increase in 4-HNE levels and agedependent decline in PPARGC1A mRNA. Thus, we regard them as biologically comparable. There was some radiation dependent increase in 4-HNE levels in the c-ray cohort, but it was not statistically significant in the regression analysis. There were also radiation-dependent declines in PPARGC1A and CDKN1A, although these were smaller than for the HZE radiation-exposed cohort. Quantitative and qualitative differences in HZE particle radiation and c-rays presumably reflect the distinctive physics of tissue interaction. HZE particles produce a dense burst of reactive oxygen species along a nanometer-scale core track, whereas c-rays, at the same dose, deposit energy along more numerous but less densely ionizing tracks. Dense ionization along the core HZE track leads to potentially irreparable DNA damage. At the same time, radial propagation of secondary electrons produces damage at sites elsewhere in the target cell or in neighboring cells. Thus, a single encounter with an HZE particle thus creates damage that is simultaneously denser and more widespread, potentially affecting DNA and the mitochondria simultaneously and in different ways. We speculate that this may produce a sufficient burst of damage from which cells never fully recover – an initial burst of reactive oxygen species leads to a self-perpetuating cycle of mitochondrial injury, leakage of endogenous reactive oxygen species, and further damage to mitochondria or other cellular components. The medaka model has some limitations, notably the paucity of species cross-reactive antibodies. We were thus not able to measure levels of TP53 or phosphorylated ATM proteins, which would have provided direct information regarding the presence of a chronic DNA damage response. We were not able to measure 8oxodeoxyguanosine, a major base oxidation product, because of high background staining. We were not able to detect c-H2AX, a marker of unrepaired DNA double-strand breaks. It may be that examination of mRNA expression profiles in greater depth.