Assessment of Radio-Induced Damage in Endothelial Cells Irradiated with 40 kVp, 220 kVp, and 4 MV X-rays by Means of Micro and Nanodosimetric Calculations

Abstract

The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (109) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (γ-H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de sûreté nucléaire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV.

Assessment of DNA damage with an adapted independent reaction time approach implemented in Geant4‐DNA for the simulation of diffusion‐controlled reactions between radio‐induced reactive species and a chromatin fiber

“…2,33 In the latter case, it was suggested that a time of 10 ns would be more appropriate. 35 Under these conditions, it must therefore be considered that the IRT method presented in this study gives results that are reasonably close to those of the method we have considered as a reference for Geant4-DNA calculations about 10% at 10 ns (SBS-dynamic time step using 0.1 ps minimum user time step).…”

“…For example, the simulation time of the chemical step with the SBS method of Geant4‐DNA was limited to 1 ns for the calculation of damage to a chromatin fiber 33 or 2.5 ns for damage to a complete cell nucleus 2,33 . In the latter case, it was suggested that a time of 10 ns would be more appropriate 35 . Under these conditions, it must therefore be considered that the IRT method presented in this study gives results that are reasonably close to those of the method we have considered as a reference for Geant4‐DNA calculations about 10% at 10 ns (SBS‐dynamic time step using 0.1 ps minimum user time step).…”

Fully integrated Monte Carlo simulation for evaluating radiation induced DNA damage and subsequent repair using Geant4-DNA

“…In accordance with our previous works 45,46 , to perform more realistic simulations, the chemical stage is modelled for an extended period of time up to 5 ns, limiting the simulation time to reasonable value (see "Simulation configuration" section), which is two times longer than the chemical stage duration considered in Geant4-DNA_2019.…”

Ionizing Radiation and Complex DNA Damage: Quantifying the Radiobiological Damage Using Monte Carlo Simulations

“…Tang et al [149] simulated by the full Geant4-DNA chain (that includes the physical, physico-chemical, and chemical stages) the IR action to endothelial cells by different photon energy sources. The IR-induced damage was quantified in terms of early DNA damage, specifically DSB induction, and the theoretical analysis included both microdosimetric and nanodosimetric methods.…”