Study Of Persistent Oxidative Stress And Possible Mechanism Elicited By Exposure To HZE Particle Radiation

BackgroundHigh charge and energy (HZE) particles are a major component of galactic cosmic rays, and uncertainty over their biological effects is a limiting factor in human space exploration. HZE particles deliver concentrated energy along relatively few radiation tracks, creating complex damage that is difficult to repair. HZE radiation causes cancer in rodents. It also causes various non-cancer effects, including cognitive and behavioral changes, neuroinflammation, bone loss, chronic vascular injury, and persistent oxidative stress in intestinal tissue. It unclear whether there is a simple unifying explanation for these effects, and to what extent they are a concern at mission-relevant doses of0.3Gy or less.ObjectiveHere we address these questions in a large-scale, lifetime experiment using a laboratory model organism, the Japanese medaka fish (Oryzias latipes).Materials and methodsWe exposed stage28medaka embryos to1GeV/nucleon56Fe ion radiation. We used a wide dose range of0.1to9Gy, in3-fold increments, with?250individuals per dose group. We exposed a separate cohort to reference y-rays over a0.1to27Gy range.ResultsWe observed acute mortality only in the highest dose groups, whereas the others showed no significant difference in overall survival for at least600d post-irradiation. We sampled the populations at250d post-irradiation and analyzed livers for pathological changes. Steatosis, spongiosis hepatis and ballooning degeneration were elevated in HZE-exposed groups, and to a lesser extent in y-ray exposed groups. We classify these changes as "aging-like" as they occur normally in non-irradiated fish, but only at much more advanced ages. A lipid peroxidation product,4-hydroxy-2-nonenal (4-HNE) was significantly elevated (1.8to5-fold) in HZE particle irradiated groups, but only slightly elevated in y-ray groups. Changes in mRNA expression included:repression of PGC-1?, a key regulator of mitochondrial biogenesis and maintenance, induction of cyclin dependent protein kinase inhibitor, p21, induction of the inflammatory biomarker, PTGES. There was also variable induction of superoxide dismutase2(SOD2) and catalase (CAT), which are oxidative stress defense genes. These changes were not seen in ?-ray exposed groups.ConclusionsResults here support the hypothesis that a developmental exposure to mission relevant doses HZE particle radiation induces long-lasting oxidative stress and associated responses, which lead to aging-like changes in adult liver.