Double-strand breaks (DSBs) in nuclear DNA represents radiation-induced damage that has been identified as particularly deleterious. Calculating this damage using Monte Carlo track structure modeling could be a suitable indicator to better assess and anticipate the side-effects of radiation therapy. However, as already demonstrated in previous work, the geometrical description of the nucleus and the DNA content used in the simulation significantly influence damage calculations. Therefore, in order to obtain accurate results, this geometry must be as realistic as possible. In this study, a new geometrical model of an endothelial cell nucleus and DNA distribution according to the isochore theory are presented and used in a Monte Carlo simulation chain based on the Geant4-DNA toolkit. In this theory, heterochromatin and euchromatin compaction are distributed along the genome according to five different families (L1, L2, H1, H2, and H3). Each of these families is associated with a different hetero/euchromatin rate related to its compaction level. In order to compare the results with those obtained using a previous nuclear geometry, simulations were performed for protons with linear energy transfers (LETs) of 4.29 keV/µm, 19.51 keV/µm, and 43.25 keV/µm. The organization of the chromatin fibers at different compaction levels linked to isochore families increased the DSB yield by 6–10%, and it allowed the most affected part of the genome to be identified. These new results indicate that the genome core is more radiosensitive than the genome desert, with a 3–8% increase in damage depending on the LET. This work highlights the importance of using realistic distributions of chromatin compaction levels to calculate radio-induced damage using Monte Carlo simulation methods.

Objective . The mechanisms of radiation-induced DNA damage can be understood via the fundamental acquisition of knowledge through a combination of experiments and modeling. Currently, most biological experiments are performed by irradiating an entire cell population, whereas modeling of radiation-induced effects is usually performed via Monte Carlo simulations with track structure codes coupled to realistic DNA geometries of a single-cell nucleus. However, the difference in scale between the two methods hinders a direct comparison because the dose distribution in the cell population is not necessarily uniform owing to the stochastic nature of the energy deposition. Thus, this study proposed the MINAS TIRITH tool to model the distribution of radiation-induced DNA damage in a cell population. Approach . The proposed method is based on precomputed databases of microdosimetric parameters and DNA damage distributions generated using the Geant4-DNA Monte Carlo Toolkit. First, a specific energy z was assigned to each cell of an irradiated population for a particular absorbed dose D abs , following microdosimetric formalism. Then, each cell was assigned a realistic number of DNA damage events according to the specific energy z , respecting the stochastic character of its occurrence. Main results . This study validated the MINAS TIRITH tool by comparing its results with those obtained using the Geant4-DNA track structure code and a Geant4-DNA based simulation chain for DNA damage calculation. The different elements of comparison indicated consistency between MINAS TIRITH and the Monte Carlo simulation in case of the dose distribution in the population and the calculation of the amount of DNA damage. Significance . MINAS TIRITH is a new approach for the calculation of radiation-induced DNA damage at the cell population level that facilitates reasonable simulation times compared to those obtained with track structure codes. Moreover, this tool enables a more direct comparison between modeling and biological experimentation.

In the domains of medicine and space exploration, refining risk assessment models for protecting healthy tissue from ionizing radiation is crucial. Understanding radiation-induced effects requires biological experimentations at the cellular population level and the cellular scale modeling using Monte Carlo track structure codes. We present MINAS TIRITH, a tool using Geant4-DNA Monte Carlo-generated databases to study DNA damage distribution at the cell population scale. It introduces a DNA damage location module and proposes a method to convert double-strand breaks (DSB) into DNA Damage Response foci. We evaluate damage location precision and DSB-foci conversion parameters. MINAS TIRITH’s accuracy is validated against γ -H2AX foci distribution from cell population exposed to monoenergetic neutron beams (2.5 or 15.1 MeV) under different configurations, yielding mixed radiation fields. Strong agreement between simulation and experimental results was found demonstrating MINAS TIRITH’s predictive precision in radiation-induced DNA damage topology. Additionally, modeling intercellular damage variability within a population subjected to a specific macroscopic dose identifies subpopulations, enhancing realistic fate models. This approach advances our understanding of radiation-induced effects on cellular systems for risk assessment improvement.

A travers le programme de recherche ROSIRIS, l’IRSN souhaite proposer des outils pour améliorerla prédiction du risque associé à l’exposition des tissus sains dans les traitements de radiothérapie. Aucours de ce projet, il est recherché la mise en corrélation des caractéristiques physiques desrayonnements ionisants à l’échelle moléculaire aux effets biologiques mis en valeur par l’acquisitionde données fondamentales qui ne sont actuellement pas considérés dans les modèles de risquecliniques. Dans le même temps, une chaine de simulation du dommage radio-induit à l’ADN basée surle code Monte Carlo de structure de trace Geant4-DNA a été développée. Les résultats produits parcette chaine pourraient servir de données d’entrée pour développer des modèles de risques plusperformants. Néanmoins, ces résultats demeurent à l’échelle de la cellule unique à cause des tempsde calculs prohibitifs, ce qui induit également des biais dans la validation expérimentale des codes.Dans ce travail un nouvel outil de simulation (MINAS TIRITH) a été développé et validé pour permettrele calcul de la distribution des dommages à l’ADN à l’échelle d’une population cellulaire. Cette nouvelleméthode de calcul a permis d’adapter un modèle de réparation pour prédire de la fraction de survieclonogénique d’une population à partir des chances de survie individuelles de chaque cellule qui lacompose. Également, une nouvelle géométrie nucléaire pour le calcul du dommage à l’ADN a étéproposée afin d’identifier quels dommages ont lieu dans les parties les plus codantes du génome. Cettenouvelle géométrie a permis de mettre en évidence des corrélations entre le dommage précoce radioinduitcalculé avec MINAS TIRITH et des données expérimentales de viabilité cellulaire et desénescence produites dans le cadre du programme ROSIRIS pour des rayons X sur une gamme de doseabsorbée comprise entre 2 Gy et 20 Gy.

We are constantly exposed to various ionizing radiations, whether from natural sources such as cosmic rays or from human-made sources like medical procedures or nuclear activities (Goodhead 2019). ...