title: Characterizing low dose and dose rate effects in rodent and human neural stem cells exposed to proton and gamma irradiation.
abstract: Past work has shown that exposure to gamma rays and protons elicit a persistent oxidative stress in rodent and human neural stem cells (hNSCs). We have now adapted these studies to more realistic exposure scenarios in space, using lower doses and dose rates of these radiation modalities, to further elucidate the role of radiation-induced oxidative stress in these cells. Rodent neural stem and precursor cells grown as neurospheres and human neural stem cells grown as monolayers were subjected to acute and multi-dosing paradigms at differing dose rates and analyzed for changes in reactive oxygen species (ROS), reactive nitrogen species (RNS), nitric oxide and superoxide for 2 days after irradiation. While acute exposures led to significant changes in both cell types, hNSCs in particular, exhibited marked and significant elevations in radiation-induced oxidative stress. Elevated oxidative stress was more significant in hNSCs as opposed to their rodent counterparts, and hNSCs were significantly more sensitive to low dose exposures in terms of survival. Combinations of protons and γ-rays delivered as lower priming or higher challenge doses elicited radioadaptive changes that were associated with improved survival, but in general, only under conditions where the levels of reactive species were suppressed compared to cells irradiated acutely. Protective radioadaptive effects on survival were eliminated in the presence of the antioxidant N-acetylcysteine, suggesting further that radiation-induced oxidative stress could activate pro-survival signaling pathways that were sensitive to redox state. Data corroborates much of our past work and shows that low dose and dose rate exposures elicit significant changes in oxidative stress that have functional consequences on survival.
authors.affiliation: Department of Internal Medicine, Duke University Medical Center, Durham, NC 27710, United States.
authors.forename: Bertrand P
authors.initials: BP
authors.lastname: Tseng
authors.forename: Mary L
authors.initials: ML
authors.lastname: Lan
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Tran
authors.forename: Munjal M
authors.initials: MM
authors.lastname: Acharya
authors.forename: Erich
authors.initials: E
authors.lastname: Giedzinski
authors.forename: Charles L
authors.initials: CL
authors.lastname: Limoli
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000528:radiation effects*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects*; D017785:Photons; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D013481:Superoxides; D009569:Nitric Oxide; D000111:Acetylcysteine
keywords: CM-H2DCFDA (or CM), 5-(and 6-) Chloromethyl-2,7-dichlorodihydrofluorescein diacetate; DAF, 4-Amino-5methylamino-2′,7′-difluorescein diacetate; DNA damage; Dose rate; GCR, Galactic cosmic rays; HDR, High dose rate; LDR, Low dose rate; LET, Linear energy transfer; MS, Mitosox; NAC, N-acetylcysteine; Neural stem cells; Oxidative stress; Protons; RNS, Reactive nitrogen species; ROS, Reactive oxygen species; Radiation
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