Abstract
ABSTRACTChildren undergoing cranial radiation therapy (CRT) for pediatric central nervous system malignancies are at increased risk for neurological deficits later in life. We have developed a model of neurotoxic damage in adult Drosophila following irradiation during the juvenile stages with the goal of elucidating underlying neuropathological mechanisms and of ultimately identifying potential therapeutic targets. Wild-type third-instar larvae were irradiated with single doses of γ-radiation, and the percentage that survived to adulthood was determined. Motor function of surviving adults was examined with a climbing assay, and longevity was assessed by measuring lifespan. Neuronal cell death was assayed by using immunohistochemistry in adult brains. We also tested the sensitivity at different developmental stages by irradiating larvae at various time points. Irradiating late third-instar larvae at a dose of 20 Gy or higher impaired the motor activity of surviving adults. A dose of 40 Gy or higher resulted in a precipitous reduction in the percentage of larvae that survive to adulthood. A dose-dependent decrease in adult longevity was paralleled by a dose-dependent increase in activated Death caspase-1 (Dcp1) in adult brains. Survival to adulthood and adult lifespan were more severely impaired with decreasing larval age at the time of irradiation. Our initial survey of the Drosophila Genetic Reference Panel demonstrated that differences in genotype can confer phenotypic differences in radio-sensitivity for developmental survival and motor function. This work demonstrates the usefulness of Drosophila to model the toxic effects of radiation during development, and has the potential to unravel underlying mechanisms and to facilitate the discovery of novel therapeutic interventions.
Highlights
Cranial radiation therapy (CRT) is a mainstay of treatment for brain tumors, along with surgery and chemotherapy
First-instar larvae feed, grow and undergo two successive molts to become third-instar larvae over the two days. After another 2.5-3 days, metamorphosis begins with dose of radiation tested, we observed substantial adult mortality (>40% for Canton-S and Oregon-R) within 48 h of eclosion (Fig. 1B). Because this very early adult mortality is likely to be the result of residual developmental defects caused by radiation exposure, we excluded flies that died within 48 h of eclosion from subsequent lifespan measurement
These results indicate that radiation during larval development has a greater effect on the lifespan of surviving adults than it does on the survival of irradiated larvae to adulthood
Summary
Cranial radiation therapy (CRT) is a mainstay of treatment for brain tumors, along with surgery and chemotherapy. As therapy has become more effective and affected individuals live longer, the long-term sequelae of this treatment, in children, have received increasing attention. Individuals who undergo CRT before the age of 18 have a increased incidence of many neurological and cognitive side effects, including impairments of memory, attention, visuo-spatial processing, learning ability, and motor control and dexterity, in addition to increased prevalence of seizure disorders (Armstrong et al, 2009; Edelstein et al, 2011b; Ellenberg et al, 2009; Mulhern et al, 2005; Packer et al, 2003; Redmond et al, 2013). As increasingly effective therapy results in more pediatric brain tumor survivors, there is an increasing need for radioprotective strategies to reduce the damage to healthy tissue during treatment
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