Jean-Paul Jay-Gerin

Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

Cellular exposure to ionizing radiation leads to oxidizing events that alter atomic structure through direct interactions of radiation with target macromolecules or via products of water radiolysis. Further, the oxidative damage may spread from the targeted to neighboring, non-targeted bystander cells through redox-modulated intercellular communication mechanisms. To cope with the induced stress and the changes in the redox environment, organisms elicit transient responses at the molecular, cellular and tissue levels to counteract toxic effects of radiation. Metabolic pathways are induced during and shortly after the exposure. Depending on radiation dose, dose-rate and quality, these protective mechanisms may or may not be sufficient to cope with the stress. When the harmful effects exceed those of homeostatic biochemical processes, induced biological changes persist and may be propagated to progeny cells. Physiological levels of reactive oxygen and nitrogen species play critical roles in many cellular functions. In irradiated cells, levels of these reactive species may be increased due to perturbations in oxidative metabolism and chronic inflammatory responses, thereby contributing to the long-term effects of exposure to ionizing radiation on genomic stability. Here, in addition to immediate biological effects of water radiolysis on DNA damage, we also discuss the role of mitochondria in the delayed outcomes of ionization radiation. Defects in mitochondrial functions lead to accelerated aging and numerous pathological conditions. Different types of radiation vary in their linear energy transfer (LET) properties, and we discuss their effects on various aspects of mitochondrial physiology. These include short and long-term in vitro and in vivo effects on mitochondrial DNA, mitochondrial protein import and metabolic and antioxidant enzymes.

Low-Energy Electron Penetration Range in Liquid Water

Abstract Meesungnoen, J., Jay-Gerin, J-P., Filali-Mouhim, A. and Mankhetkorn, S. Low-Energy Electron Penetration Range in Liquid Water. Radiat. Res. 158, 657–660 (2002). Monte Carlo simulations of electron tracks in liquid water are performed to calculate the energy dependence of the electron penetration range at initial electron energies between 0.2 eV and 150 keV, including the subexcitation electron region (<7.3 eV). Our calculated electron penetration distances are compared with available experimental data and earlier calculations as well as with the results of simulations using newly reported amorphous ice electron scattering cross sections in the range ∼1–100 eV.

On the reactions of hydrated electrons with OH⋅ and H3O+. Analysis of photoionization experiments

With the help of Monte Carlo simulation techniques, we study the recombination kinetics of hydrated electrons (e−aq) with H3O+ and OH⋅ which results from the photoionization of pure water with femtosecond pulsed lasers. A full description of the simulation procedure is given and various comparisons are made with analytical formulations of the reaction kinetics. Particular attention is given to the reaction of e−aq with H3O+, which is only partially diffusion controlled and which involves a Coulombic interaction with dielectric saturation effects. We find that the probability of reaction per e−aq –H3O+ encounter is small (∼6%) and that the encounter duration can be of the order of a few picoseconds. The competition between the reaction of e−aq with H3O+ and with OH⋅ is analyzed with the simulations and with the independent reaction times method. Both approaches indicate that the e−aq decay is largely dominated by the reaction of e−aq with OH⋅. The effect of neighboring ionization sites on the e−aq decay ki...

The role of gap junction communication and oxidative stress in the propagation of toxic effects among high-dose α-particle-irradiated human cells.

Abstract We investigated the roles of gap junction communication and oxidative stress in modulating potentially lethal damage repair in human fibroblast cultures exposed to doses of α particles or γ rays that targeted all cells in the cultures. As expected, α particles were more effective than γ rays at inducing cell killing; further, holding γ-irradiated cells in the confluent state for several hours after irradiation promoted increased survival and decreased chromosomal damage. However, maintaining α-particle-irradiated cells in the confluent state for various times prior to subculture resulted in increased rather than decreased lethality and was associated with persistent DNA damage and increased protein oxidation and lipid peroxidation. Inhibiting gap junction communication with 18-α-glycyrrhetinic acid or by knockdown of connexin43, a constitutive protein of junctional channels in these cells, protected against the toxic effects in α-particle-irradiated cell cultures during confluent holding. Upregulation of antioxidant defense by ectopic overexpression of glutathione peroxidase protected against cell killing by α particles when cells were analyzed shortly after exposure. However, it did not attenuate the decrease in survival during confluent holding. Together, these findings indicate that the damaging effect of α particles results in oxidative stress, and the toxic effects in the hours after irradiation are amplified by intercellular communication, but the communicated molecule(s) is unlikely to be a substrate of glutathione peroxidase.

Water Chemistry in a Supercritical Water-Cooled Pressure Tube Reactor

The long-term viability of a supercritical water-cooled reactor (SCWR) will depend on the ability of designers and operators to control and maintain water chemistry conditions that will minimize corrosion and the transport of both corrosion products and radionuclides, at a pressure of 25 MPa and temperatures from 300°C to 625°C. To achieve this goal, the behavior of low concentrations of impurities such as transition metal corrosion products, chemistry control agents, impurities in the feedwater, and radionuclides (fission and activation products) in subcritical and supercritical water must be understood. A second key aspect of SCWR water chemistry control will be mitigation of the effects of water radiolysis. Preliminary studies suggest markedly different behavior than that predicted by extrapolating conventional water-cooled reactor behavior. The principal challenge in predicting corrosion and fission product transport is the lack of thermochemical and kinetic data above 300°C. Calculations with extrapolated data show that the formation of neutral complexes increases with temperature and can become important under near-critical and supercritical conditions. The most important region is from 300°C to 450°C, where the properties of water change dramatically and solvent compressibility effects exert a huge influence on solvation. The potential for increased transport and deposition of corrosion products (radioactive and inactive), leading to increased deposition on fuel cladding surfaces and increased out-of-core radiation fields and worker dose, must be assessed. The commonly used strategy of adding excess hydrogen at concentrations sufficient to suppress the net radiolytic production of primary oxidizing species may not be effective in an SCWR. Because direct measurement of the chemistry under such extreme conditions of temperature, pressure, and radiation fields is difficult, the most promising approach involves a combination of theoretical calculations, chemical models, and experimental work.

High-LET Ion Radiolysis of Water: Visualization of the Formation and Evolution of Ion Tracks and Relevance to the Radiation-Induced Bystander Effect

Abstract Muroya, Y., Plante, I., Azzam, E. I., Meesungnoen, J., Katsumura, Y. and Jay-Gerin, J-P. High-LET Ion Radiolysis of Water: Visualization of the Formation and Evolution of Ion Tracks and Relevance to the Radiation-Induced Bystander Effect. Radiat. Res. 165, 485–491 (2006). Ionizing radiation-induced bystander effects, commonly observed in cell populations exposed to high-linear energy transfer (LET) radiations, are initiated by damage to a cellular molecule which then gives rise to a toxic signal exported to neighboring cells not directly hit by radiation. A major goal in studies of this phenomenon is the identification of this initial radiation-induced lesion. Liquid water being the main constituent of biological matter, reactive species produced by water radiolysis in the cellular environment are likely to be major contributors to the induction of this lesion. In this context, the radiation track structure is of crucial importance in specifying the precise location and identity of all the radiolytic species and their subsequent signaling or damaging effects. We report here Monte Carlo track structure simulations of the radiolysis of liquid water by four different impacting ions 1H+, 4He2+, 12C6+ and 20Ne10+, with the same LET (∼70 keV/ μm). The initial radial distribution profiles of the various water decomposition products (eaq−, ·OH, H·, H2 and H2O2) for the different ions considered are presented and discussed briefly in the context of track structure theory. As an example, the formation and temporal evolution of simulated 24 MeV 4He2+ ion tracks (LET ∼26 keV/μm) are reported for each radiolytic species from 1 ps to 10 μs. The calculations reveal that the ion track structure is completely lost by ∼1 μs.

Monte Carlo Calculation of the Primary Radical and Molecular Yields of Liquid Water Radiolysis in the Linear Energy Transfer Range 0.3–6.5 keV/μm: Application to 137Cs Gamma Rays1

Abstract Meesungnoen, J., Benrahmoune, M., Filali-Mouhim, A., Mankhetkorn, S. and Jay-Gerin, J-P. Monte Carlo Calculation of the Primary Radical and Molecular Yields of Liquid Water Radiolysis in the Linear Energy Transfer Range 0.3–6.5 keV/μm: Application to 137Cs Gamma Rays. Monte Carlo simulations of the radiolysis of neutral liquid water and 0.4 M H2SO4 aqueous solutions at ambient temperature are used to calculate the variations of the primary radical and molecular yields (at 10–6 s) as a function of linear energy transfer (LET) in the range ∼0.3 to 6.5 keV/μm. The early energy deposition is approximated by considering short (∼20–100 μm) high-energy (∼300–6.6 MeV) proton track segments, over which the LET remains essentially constant. The subsequent nonhomogeneous chemical evolution of the reactive species formed in these tracks is simulated by using the independent reaction times approximation, which has previously been used successfully to model the radiolysis of water under various conditions. The results obtained are in good general agreement with available experimental data over the whole LET range studied. After normalization of our computed yields relative to the standard radical and molecular yields for 60Co γ radiation (average LET ∼0.3 keV/μm), we obtain empirical relationships of the primary radiolytic yields as a function of LET over the LET range studied. Such relationships are of practical interest since they allow us to predict a priori values of the radical and molecular yields for any radiation from the knowledge of the average LET of this radiation only. As an application, we determine the corresponding yields for the case of 137Cs γ radiation. For this purpose, we use the value of ∼0.91 keV/μm for the average LET of 137Cs γ rays, chosen so that our calculated yield G(Fe3+) for ferrous-ion oxidation in air-saturated 0.4 M sulfuric acid reproduces the value of 15.3 molecules/100 eV for this radiation recommended by the International Commission on Radiation Units and Measurements. The uncertainty range on those primary radical and molecular yields are also determined knowing the experimental error (∼2%) for the measured G(Fe3+) value. The following values (expressed in molecules/100 eV) are obtained: (1) for neutral water: Ge–aq = 2.50 ± 0.16, GH· = 0.621 ± 0.019, GH2 = 0.474 ± 0.025, G·OH = 2.67 ± 0.14, GH2O2 = 0.713 ± 0.031, and G–H2O = 4.08 ± 0.22; and (2) for 0.4 M H2SO4 aqueous solutions: GH· = 3.61 ± 0.09, GH2 = 0.420 ± 0.019, G·OH = 2.78 ± 0.12, GH2O2 = 0.839 ± 0.037, and G–H2O = 4.46 ± 0.16. These computed values are found to differ from the standard yields for 60Co γ rays by up to ∼6%.

Monocytes influence the fate of T cells challenged with oxidised low density lipoproteins towards apoptosis or MHC-restricted proliferation

Atherosclerosis has been implicated in myocardial infarction, stroke and a host of cardiovascular diseases. The presence of activated T lymphocytes and macrophages, and the increased expression of HLA-DR antigen are consistent with the notion of immune activity in the atherosclerotic plaque. The nature of the causative antigen has not been established although oxidised low density lipoproteins (oxLDL) that accumulate in atherosclerotic plaques could fulfil this role. Here, we report that monocytes play a key role in influencing the fate of purified peripheral human T lymphocytes from healthy donors when the cells are exposed to LDL oxidised under the controlled conditions of water radiolysis. Our data showed that oxLDL generated under these conditions were chemoattractants for T cells. However, they induced a state of apoptosis in T lymphocytes cultured in the absence of monocytes. The extent of apoptosis was related to the degree of oxidation of LDL and the time of T cell exposure to oxLDL. OxLDL-dependent apoptosis did not involve a scavenger-like receptor. CD4(+) cells were more sensitive to the apoptotic effect of oxLDL than CD8(+) cells. OxLDL-primed (12 h) autologous monocytes triggered a robust proliferation of T lymphocytes cultured in the absence of oxLDL. The strength of T cell stimulation was related to the degree of oxidation of the LDL used in priming. Heterologous monocytes exposed to oxLDL under similar conditions induced a response that was not different than monocytes exposed to untreated LDL (natLDL) which did not induce T cell proliferation. Fucoidan did not modify the oxLDL-, monocyte-dependent T cell response to proliferation, suggesting that a scavenger-like receptor was not involved. The expression of the HLA-DR marker and the B7.2 protein were up-regulated in monocytes exposed to oxLDL but not to natLDL. The levels of B7.1 were unchanged. Our data are consistent with the notion that monocytes are critical for T cell survival in the presence of oxLDL and MHC-restricted T cell proliferative response to oxLDL.

On apparent contradictions in some photophysical properties of liquid water

Apparent inconsistency has appeared between essentially two sets of data relative to the optical absorption limit of liquid water on the one hand and to its photoionization threshold and band-gap energy on the other. Recent data prompt a renewed examination.

High-LET Ion Radiolysis of Water: Oxygen Production in Tracks

Abstract Meesungnoen, J. and Jay-Gerin, J-P. High-LET Ion Radiolysis of Water: Oxygen Production in Tracks. Radiat. Res. 171, 379–386 (2009). It is known that molecular oxygen is a product of the radiolysis of water with high-linear energy transfer (LET) radiation, a result that is of particular significance in radiobiology and of practical relevance in radiotherapy. In fact, it has been suggested that the radiolytic formation of an oxygenated microenvironment around the tracks of high-LET heavy ions is an important factor in their enhanced biological efficiency in the sense that this may be due to an “oxygen effect” by O2 produced by these ions in situ. Using Monte Carlo track simulations of pure, deaerated water radiolysis by 4.8 MeV 4He2+ (LET ∼ 94 keV/μm) and 24 MeV 12C6+ (LET ∼ 490 keV/μm) ions, including the mechanism of multiple ionization of water, we have calculated the yields and concentrations of O2 in the tracks of these irradiating ions as a function of time between ∼10−12 and 10−5 s at 25 and 37°C. The track oxygen concentrations obtained compare very well with O2 concentrations estimated from the “effective” amounts of oxygen that are needed to produce the observed reduction in oxygen enhancement ratio (OER) with LET (assuming this decrease is attributable to the sole radiolytic formation of O2 in the tracks). For example, for 24 MeV 12C6+ ions, the initial track concentration of O2 is estimated to be more than three orders of magnitude higher than the oxygen levels present in normally oxygenated and hypoxic tumor regions as well as in normal human cells. Such results, which largely plead in favor of the “oxygen in the heavy-ion track” hypothesis, could explain at least in part the greater efficiency of high-LET radiation for cell inactivation (at equal radiation dose).