Modeling Reveals the Dependence of Hippocampal Neurogenesis Radiosensitivity on Age and Strain of Rats

Cognitive dysfunction following radiation treatment for brain cancers in both children and adults have been correlated to impairment of neurogenesis in the hippocampal dentate gyrus. Various species and strains of rodent models have been used to study radiation-induced changes in neurogenesis and these investigations have utilized only a limited number of doses, dose-fractions, age and time after exposures conditions. In this paper, we have extended our previous mathematical model of radiation-induced hippocampal neurogenesis impairment of C57BL/6 mice to delineate the time, age, and dose dependent alterations in neurogenesis of a diverse strain of rats. To the best of our knowledge, this is the first predictive mathematical model to be published about hippocampal neurogenesis impairment for a variety of rat strains after acute or fractionated exposures to low linear energy transfer (low LET) radiation, such as X-rays and γ-rays, which are conventionally used in cancer radiation therapy. We considered four compartments to model hippocampal neurogenesis and its impairment following radiation exposures. Compartments include: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN), and (4) glioblasts (GB). Additional consideration of dose and time after irradiation dependence of microglial activation and a possible shift of NSC proliferation from neurogenesis to gliogenesis at higher doses is established. Using a system of non-linear ordinary differential equations (ODEs), characterization of rat strain and age-related dynamics of hippocampal neurogenesis for unirradiated and irradiated conditions is developed. The model is augmented with the description of feedback regulation on early and late neuronal proliferation following radiation exposure. Predictions for dose-fraction regimes compared to acute radiation exposures, along with the dependence of neurogenesis sensitivity to radiation on age and strain of rats are discussed. A major result of this work is predictions of the rat strain and age dependent differences in radiation sensitivity and sub-lethal damage repair that can be used for predictions for arbitrary dose and dose-fractionation schedules

Cellular repair/misrepair track model

A repair/misrepair cell kinetics model is superimposed onto the track structure model of Katz to provide for a repair mechanism. The model is tested on the repair-dependent data of Yang et al. and provides an adequate description of that data. The misrepair rate determines the maximum relative biological effectiveness (RBE), but similar results could arise from indirect X-ray lethality not include in the present model

Nitric Oxide Is Involved in Heavy Ion-Induced Non-Targeted Effects in Human Fibroblasts

Previously, we investigated the dose response for chromosomal aberration (CA) for exposures corresponding to less than one particle traversal per cell nucleus by high energy and charge (HZE) particles, and showed that the dose responses for simple exchanges for human fibroblast irradiated under confluent culture conditions were best fit by non-linear models motivated by a non-targeted effect (NTE). Our results suggested that the simple exchanges in normal human fibroblasts have an important NTE contribution at low particle fluence. Nitric oxide (NO) has been reported as a candidate for intercellular signaling for NTE in many studies. In order to estimate the contribution of NTE components in induced CA, we measured CA with and without an NO scavenger in normal skin fibroblasts cells after exposure to 600 MeV/u and 1 GeV/u 56Fe ions, less than one direct particle traversal per cell nucleus. Yields of CA were significantly lower in fibroblasts exposed to the NO scavenger compared to controls, suggesting involvement of NO in cell signaling for induction of CA. Media transferred from irradiated cells induced CA in non-irradiated cells, and this effect was abrogated with NO scavengers. Our results strongly support the importance of NTE contributions in the formation of CA at low-particle fluence in fibroblasts. View Full-Tex

Uncertainty Analysis in Space Radiation Protection

Space radiation is comprised of high energy and charge (HZE) nuclei, protons, and secondary radiation including neutrons. The uncertainties in estimating the health risks from galactic cosmic rays (GCR) are a major limitation to the length of space missions, the evaluation of potential risk mitigation approaches, and application of the As Low As Reasonably Achievable (ALARA) principle. For long duration space missio ns, risks may approach radiation exposure limits, therefore the uncertainties in risk projections become a major safety concern and methodologies used for ground-based works are not deemed to be sufficient. NASA limits astronaut exposures to a 3% risk of exposure induced death (REID) and protects against uncertainties in risks projections using an assessment of 95% confidence intervals in the projection model. We discuss NASA s approach to space radiation uncertainty assessments and applications for the International Space Station (ISS) program and design studies of future missions to Mars and other destinations. Several features of NASA s approach will be discussed. Radiation quality descriptions are based on the properties of radiation tracks rather than LET with probability distribution functions (PDF) for uncertainties derived from radiobiology experiments at particle accelerators. The application of age and gender specific models for individual astronauts is described. Because more than 90% of astronauts are never-smokers, an alternative risk calculation for never-smokers is used and will be compared to estimates for an average U.S. population. Because of the high energies of the GCR limits the benefits of shielding and the limited role expected for pharmaceutical countermeasures, uncertainty reduction continues to be the optimal approach to improve radiation safety for space missions

DNA Damage Signals and Space Radiation Risk

Space radiation is comprised of high-energy and charge (HZE) nuclei and protons. The initial DNA damage from HZE nuclei is qualitatively different from X-rays or gamma rays due to the clustering of damage sites which increases their complexity. Clustering of DNA damage occurs on several scales. First there is clustering of single strand breaks (SSB), double strand breaks (DSB), and base damage within a few to several hundred base pairs (bp). A second form of damage clustering occurs on the scale of a few kbp where several DSB?s may be induced by single HZE nuclei. These forms of damage clusters do not occur at low to moderate doses of X-rays or gamma rays thus presenting new challenges to DNA repair systems. We review current knowledge of differences that occur in DNA repair pathways for different types of radiation and possible relationships to mutations, chromosomal aberrations and cancer risks

Theory of Alpha-Nucleus Collisions at High Energies

The interaction of high energy alpha particles with atomic nuclei is considered using multiple scattering theories. Semi-classical solutions to coupled-channel equations derived from Watson\u27s form of the nucleus-nucleus multiple scattering series are shown to be equivalent to the Glauber multiple scattering series. Second-order solutions for the elastic amplitude are developed and used to study the effects of short-range correlations in nuclear scattering. The Jastrow method is used to model the two-particle density for 4He and to construct one and two particle form factors. Excellent agreement with experimental data for angular distributions, and total and reaction cross sections is found. The inclusive momentum distribution for projectile fragmentation is developed in terms of Lorentz invariant three-particle phase space. The participant-spectator description of the fragmentation of alpha particles is formulated using direct reaction theory. Overlap functions for the virtual dissociation of alpha particles are considered

Transport model of nucleon-nucleus reaction

A simplified model of nucleon-nucleus reaction is developed and some of its properties are examined. Comparisons with proton production measured for targets of Al-27, Ni-58, Zr-90, and Bi-209 show some hope for developing an accurate model for these complex reactions. It is suggested that binding effects are the next step required for further development

Multiple nucleon knockout by Coulomb dissociation in relativistic heavy-ion collisions

The Coulomb dissociation contributions to fragmentation cross sections in relativistic heavy ion collisions, where more than one nucleon is removed, are estimated using the Weizsacker-Williams method of virtual quanta. Photonuclear cross sections taken from experimental results were used to fold into target photon number spectra calculated with the Weizsacker-Williams method. Calculations for several projectile target combinations over a wide range of charge numbers, and a wide range of incident projectile energies, are reported. These results suggest that multiple nucleon knockout by the Coulomb field may be of negligible importance in galactic heavy ion studies for projectiles lighter than Fe-56

Special Issue: 4th International Workshop on Space Radiation (IWSRR)

This special issue of the journal "Radiation and Environmental Biophysics" contains 20 peer-reviewed papers contributed by leading space radiation researcher's world-wide attending the 4th IWSRR. Manuscripts cover a broad range of topics ranging from radiation environments and transport in shielding and planetary surfaces to new results in understanding the biological effects of protons and high-charge and energy (HZE) nuclei on the risk of cancer, and degenerative diseases such as central nervous system effects, heart disease, and cataracts. The issue provides a snapshot of the state-of-the-art of the research in this field, demonstrating both the important results gathered in the past few years with experiments at accelerators, and the need for more research to quantify the risk and develop countermeasures

Quasi-elastic nuclear scattering at high energies

The quasi-elastic scattering of two nuclei is considered in the high-energy optical model. Energy loss and momentum transfer spectra for projectile ions are evaluated in terms of an inelastic multiple-scattering series corresponding to multiple knockout of target nucleons. The leading-order correction to the coherent projectile approximation is evaluated. Calculations are compared with experiments