The individual response to ionizing radiation (IR) raises a number of medical, scientific, and societal issues. While the term “radiosensitivity” was used by the pioneers at the beginning of the 20st century to describe only the radiation-induced adverse tissue reactions related to cell death, a confusion emerged in the literature from the 1930s, as “radiosensitivity” was indifferently used to describe the toxic, cancerous, or aging effect of IR. In parallel, the predisposition to radiation-induced adverse tissue reactions (radiosensitivity), notably observed after radiotherapy appears to be caused by different mechanisms than those linked to predisposition to radiation-induced cancer (radiosusceptibility). This review aims to document these differences in order to better estimate the different radiation-induced risks. It reveals that there are very few syndromes associated with the loss of biological functions involved directly in DNA damage recognition and repair as their role is absolutely necessary for cell viability. By contrast, some cytoplasmic proteins whose functions are independent of genome surveillance may also act as phosphorylation substrates of the ATM protein to regulate the molecular response to IR. The role of the ATM protein may help classify the genetic syndromes associated with radiosensitivity and/or radiosusceptibility.

Tissue overreactions (OR), whether called adverse effects, radiotoxicity, or radiosensitivity reactions, may occur during or after anti-cancer radiotherapy (RT). They represent a medical, economic, and societal issue and raise the question of individual response to radiation. To predict and prevent them are among the major tasks of radiobiologists. To this aim, radiobiologists have developed a number of predictive assays involving different cellular models and endpoints. To date, while no consensus has been reached to consider one assay as the best predictor of the OR occurrence and severity, radiation oncologists have proposed consensual scales to quantify OR in six different grades of severity, whatever the organ/tissue concerned and their early/late features. This is notably the case with the Common Terminology Criteria for Adverse Events (CTCAE). Few radiobiological studies have used the CTCAE scale as a clinical endpoint to evaluate the statistical robustness of the molecular and cellular predictive assays in the largest range of human radiosensitivity. Here, by using 200 untransformed skin fibroblast cell lines derived from RT-treated cancer patients eliciting OR in the six CTCAE grades range, correlations between CTCAE grades and the major molecular and cellular endpoints proposed to predict OR (namely, cell survival at 2 Gy (SF2), yields of micronuclei, recognized and unrepaired DSBs assessed by immunofluorescence with γH2AX and pATM markers) were examined. To our knowledge, this was the first time that the major radiosensitivity endpoints were compared together with the same cohort and irradiation conditions. Both SF2 and the maximal number of pATM foci reached after 2 Gy appear to be the best predictors of the OR, whatever the CTCAE grades range. All these major radiosensitivity endpoints are mathematically linked in a single mechanistic model of individual response to radiation in which the ATM kinase plays a major role.

Radiation-induced bystander effects (RIBE) describe the biological events occurring in non-targeted cells in the vicinity of irradiated ones. Various experimental procedures have been used to investigate RIBE. Interestingly, most micro-irradiation experiments have been performed with alpha particles, whereas most medium transfers have been done with X-rays. With their high fluence, synchrotron X-rays represent a real opportunity to study RIBE by applying these two approaches with the same radiation type. The RIBE induced in human fibroblasts by the medium transfer approach resulted in a generation of DNA double-strand breaks (DSB) occurring from 10 min to 4 h post-irradiation. Such RIBE was found to be dependent on dose and on the number of donor cells. The RIBE induced with the micro-irradiation approach produced DSB with the same temporal occurrence. Culture media containing high concentrations of phosphates were found to inhibit RIBE, while media rich in calcium increased it. The contribution of the RIBE to the biological dose was evaluated after synchrotron X-rays, media transfer, micro-irradiation, and 6 MeV photon irradiation mimicking a standard radiotherapy session: the RIBE may represent less than 1%, about 5%, and about 20% of the initial dose, respectively. However, RIBE may result in beneficial or otherwise deleterious effects in surrounding tissues according to their radiosensitivity status and their capacity to release Ca²⁺ ions in response to radiation.

Radiation impacting astronauts in their spacecraft come from a “bath” of high-energy rays (0.1–0.5 mGy per mission day) that reaches deep tissues like the heart and bones and a “stochastic rain” of low-energy particles from the shielding and impacting surface tissues like skin and lenses. However, these two components cannot be reproduced on Earth together. The MarsSimulator facility (Toulouse University, France) emits, thanks to a bag containing thorium salts, a continuous exposure of 120 mSv/y, corresponding to that prevailing in the International Space Station (ISS). By using immunofluorescence, we assessed DNA double-strand breaks (DSB) induced by 1–5 weeks exposure in ISS of human tissues evoked above, identified at risk for space exploration. All the tissues tested elicited DSBs that accumulated proportionally to the dose at a tissue-dependent rate (about 40 DSB/Gy for skin, 3 times more for lens). For the lens, bones, and radiosensitive skin cells tested, perinuclear localization of phosphorylated forms of ataxia telangiectasia mutated protein (pATM) was observed during the 1st to 3rd week of exposure. Since pATM crowns were shown to reflect accelerated aging, these findings suggest that a low dose rate of 120 mSv/y may accelerate the senescence process of the tested tissues. A mathematical model of pATM crown formation and disappearance has been proposed. Further investigations are needed to document these results in order to better evaluate the risks related to space exploration.

The radiation protection strategy with chemical agents has long been based on an antioxidative approach consisting in reducing the number of radical oxygen and nitrogen species responsible for the formation of the radiation-induced (RI) DNA damage, notably the DNA double-strand breaks (DSB), whose subset participates in the RI lethal effect as unrepairable damage. Conversely, a DSB repair-stimulating strategy that may be called the “pro-episkevic” approach (from the ancient Greek episkeve, meaning repair) can be proposed. The pro-episkevic approach directly derives from a mechanistic model based on the RI nucleoshuttling of the ATM protein (RIANS) and contributes to increase the number of DSB managed by NHEJ, the most predominant DSB repair and signaling pathway in mammalians. Here, three radioresistant and three radiosensitive human fibroblast cell lines were pretreated with antioxidative agents (N-acetylcysteine or amifostine) or to two pro-episkevic agents (zoledronate or pravastatin or both (ZOPRA)) before X-ray irradiation. The fate of the RI DSB was analyzed by using γH2AX and pATM immunofluorescence. While amifostine pretreatment appeared to be the most efficient antioxidative process, ZOPRA shows the most powerful radiation protection, suggesting that the pro-episkevic strategy may be an alternative to the antioxidative one. Additional investigations are needed to develop some new drugs that may elicit both antioxidative and pro-episkevic properties and to quantify the radiation protection action of both types of drugs applied concomitantly.

Context: Although carcinogenesis is a multi-factorial process, the mutability and the capacity of cells to proliferate are among the major features of the cells that contribute together to the initiation and promotion steps of cancer formation. Particularly, mutability can be quantified by hyper-recombination rate assessed with specific plasmid assay, hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations frequency rate, or MRE11 nuclease activities. Cell proliferation can be assessed by flow cytometry by quantifying G2/M, G1 arrests, or global cellular evasion. Methods: All these assays were applied to skin untransformed fibroblasts derived from eight major cancer syndromes characterized by their excess of relative cancer risk (ERR). Results: Significant correlations with ERR were found between hyper-recombination assessed by the plasmid assay and G2/M arrest and described a third-degree polynomial ERR function and a sigmoidal ERR function, respectively. The product of the hyper-recombination rate and capacity of proliferation described a linear ERR function that permits one to better discriminate each cancer syndrome. Conclusions: Hyper-recombination and cell proliferation were found to obey differential equations that better highlight the intrinsic bases of cancer formation. Further investigations to verify their relevance for cancer proneness induced by exogenous agents are in progress.