Abstract
High charge and energy (HZE) particles are a main hazard of the space radiation environment. Uncertainty regarding their health effects is a limiting factor in the design of human exploration-class space missions, that is, missions beyond low earth orbit. Previous work has shown that HZE exposure increases cancer risk and elicits other aging-like phenomena in animal models. Here, we investigate how a single exposure to HZE particle radiation, early in life, influences the subsequent age-dependent evolution of oxidative stress and appearance of degenerative tissue changes. Embryos of the laboratory model organism, Oryzias latipes (Japanese medaka fish), were exposed to HZE particle radiation at doses overlapping the range of anticipated human exposure. A separate cohort was exposed to reference γ-radiation. Survival was monitored for 750 days, well beyond the median lifespan. The population was also sampled at intervals and liver tissue was subjected to histological and molecular analysis. HZE particle radiation dose and aging contributed synergistically to accumulation of lipid peroxidation products, which are a marker of chronic oxidative stress. This was mirrored by a decline in PPARGC1A mRNA, which encodes a transcriptional co-activator required for expression of oxidative stress defense genes and for mitochondrial maintenance. Consistent with chronic oxidative stress, mitochondria had an elongated and enlarged ultrastructure. Livers also had distinctive, cystic lesions. Depending on the endpoint, effects of γ-rays in the same dose range were either lesser or not detected. Results provide a quantitative and qualitative framework for understanding relative contributions of HZE particle radiation exposure and aging to chronic oxidative stress and tissue degeneration.
Highlights
Exposure to fast-moving atomic nuclei, known as high charge and energy (HZE) particles, is a limiting factor in the design of exploration-class human space missions, defined as those that venture beyond low earth orbit and beyond the partial protection afforded by the earth’s magnetic field [1]
Prior work has shown that HZE particle radiation is associated with cancer and a number of other aging-like phenomena, including atherosclerosis, bone loss, and cognitive or behavioral impairment
Our results show that a single exposure to HZE particle radiation, in a dose range overlapping that of anticipated human exposure, significantly elevates the levels of lipid peroxidation products in liver, when measured months or years following initial irradiation
Summary
Exposure to fast-moving atomic nuclei, known as high charge and energy (HZE) particles, is a limiting factor in the design of exploration-class human space missions, defined as those that venture beyond low earth orbit and beyond the partial protection afforded by the earth’s magnetic field [1]. Persistent oxidative stress is suspected to be an underlying factor in many of these degenerative effects observed at the organ level Elevated levels of reactive oxygen species or their reaction products have been measured following HZE particle radiation exposure of both cells and animals [14,15,16,17,18]. HZE particles appear to be effective, other DNA damaging agents induce oxidative stress. Possible mechanisms leading to generation or release of reactive oxygen species include mitochondria injury [19,20], DNA damagemediated activation of NADPH oxidases [21,22], and p53mediated repression of PGC-1a, a master regulator of mitochondrial function and antioxidant gene expression [23]. Oxidative stress propagates from cell to cell, in part by signaling mechanisms [16,24], and is a target for countermeasure development [14,25]
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