title: Defining the Biological Effectiveness of Components of High-LET Track Structure.
abstract: During space travel, astronauts are exposed to a wide array of high-linear energy transfer (LET) particles, with differing energies and resulting biological effects. Risk assessment of these exposures carries a large uncertainty predominantly due to the unique track structure of the particle's energy deposition. The complex damage elicited by high charge and energy (HZE) particles results from both lesions along the track core and from energetic electrons, δ rays, generated as a consequence of particle traversal. To better define how cells respond to this complex radiation exposure, a normal hTERT immortalized skin fibroblast cell line was exposed to a defined panel of particles carefully chosen to tease out track structure effects. Phosphorylation kinetics for several key double-strand break (DSB) response proteins (γ-H2AX, pATF2 and pSMC1) were defined after exposure to ten different high-LET radiation qualities and one low-LET radiation (X ray), at two doses (0.5-2 Gy) and time points (2 and 24 h). The results reveal that the lower energy particles (Fe 300, Si 93 and Ti 300 MeV/u), with a narrower track width and higher number and intensity of δ rays, cause the highest degree of persistent damage response. The persistent γ-H2AX signal at lower energies suggests that damage from these exposures are more difficult to resolve, likely due to the greater complexity of the associated DNA lesions. However, different kinetics were observed for the solely ATM-mediated phosphorylations (pATF2 and pSMC1), revealing a shallow induction at early times and a higher level of residual phosphorylation compared to γ-H2AX. The differing phospho-protein profiles exhibited, compared to γ-H2AX, suggests additional functions for these proteins within the cell. The strong correspondence between the predicted curves for energy deposition per nucleosome for each ion/energy combination and the persistent levels of γ-H2AX indicates that the nature of energy distribution defines residual levels of γ-H2AX, an indicator of unrepaired DSBs. Our results suggest that decreasing the energy of a particle results in more complex damage that may increase genomic instability and increase the risk of carcinogenesis.
authors.affiliation: a  Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, California 94710;
authors.forename: Deepa M
authors.initials: DM
authors.lastname: Sridharan
authors.affiliation: b  NASA, Lyndon B. Johnson Space Center, Houston, Texas 77058; and.
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Chappell
authors.affiliation: a  Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, California 94710;
authors.forename: Mary K
authors.initials: MK
authors.lastname: Whalen
authors.affiliation: c  University of Nevada, Las Vegas, Health Physics and Diagnostic Sciences, Las Vegas, Nevada 89154.
authors.forename: Francis A
authors.initials: FA
authors.lastname: Cucinotta
authors.affiliation: a  Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, California 94710;
authors.forename: Janice M
authors.initials: JM
authors.lastname: Pluth
mesh_terms: D051698:Activating Transcription Factor 2 / Q000032:analysis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology; D002453:Cell Cycle / Q000528:radiation effects; D002478:Cells, Cultured; D003359:Cosmic Radiation; D004249:DNA Damage; D005347:Fibroblasts / Q000528:radiation effects; D006657:Histones / Q000032:analysis; D006801:Humans; D018499:Linear Energy Transfer; D009707:Nucleosomes / Q000528:radiation effects
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C468783:H2AX protein, human; D006657:Histones; D009707:Nucleosomes; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins