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IntroductionRadiobiological studies at low dose rates allow us to improve our knowledge of the mechanisms by which radiation exerts its effects on biological systems following chronic exposures. Moreover, these studies can complement available epidemiological data on the biological effects of low doses and dose rates of ionizing radiation. Very few studies have simultaneously compared the biological effects of low- and high-LET radiations at the same dose rate for chronic irradiation.MethodsWe compared, for the first time in the same experiment, the effects of chronic (dose rates as low as ~18 and 5 mGy/h) and acute irradiations on clonogenicity and micronucleus formation in AG1522 normal human skin fibroblasts in the confluent state exposed to doses of low- and high-LET radiation (gamma rays and alpha particles) to investigate any differences due to the different radiation quality and different dose rate (in the dose range 0.006–0.9 Gy for alpha particles and 0.4–2.3 Gy for gamma rays).ResultsAs expected, alpha particles were more effective than gamma rays at inducing cytogenetic damage and reduced clonogenic cell survival. For gamma rays, the cytogenetic damage and the reduction of clonogenic cell survival were greater when the dose was delivered acutely instead of chronically. Instead, for the alpha particles, at the same dose, we found equal cytogenetic damage and reduction of clonogenic cell survival for both chronic and acute exposure (except for the highest doses of 0.4 and 0.9 Gy, where cytogenetic damage is greater at a low dose rate).ConclusionThe results of this study may have an impact on space and terrestrial radioprotection of humans at low doses and low dose rates, on biodosimetry, and on the use of ionizing radiation in medicine. These results also provide insights into understanding damage induction and cell reaction mechanisms following chronic exposure (at dose rates as low as 18 and 5 mGy/h) to low- and high-LET radiation.

One of the most intriguing and still pending questions in radiobiology is to understand whether and how natural environmental background radiation has shaped Life over millions of years of evolution on Earth. Deep Underground Laboratories (DULs) represent the ideal below-background exposure facilities where to address such a question. Among the few worldwide DULs, INFN-Laboratorio Nazionale del Gran Sasso (LNGS) is one of the largest in terms of size and infrastructure. Designed and built to host neutrino and dark matter experiments, since the 1990 s the LNGS has been one of the first DULs to systematically host radiobiology experiments. Here we present the DISCOVER22 (DNA Damage and Immune System Cooperation in VEry low Radiation environment 2022) experiment recently started at LNGS. DISCOVER22 aims at investigating how the low radiation background modulates the Immune System (IS) response in in vitro and in vivo models. Underground radiobiology experiments are particularly complex and tricky to design and perform. In these studies, the accurate characterization of exposure scenarios is mandatory, but a challenging aspect is to understand how the very few ionizing tracks in the ultra-Low Radiation Environment (LRE) interact with the living matter in space and time in order to trigger different biological responses. In this Perspective, we describe these challenges and how we address them through a microdosimetric and a radiobiological approaches. We aim at linking physical microdosimetric measurements and the corresponding biological radiation responses by using radiation biophysical models that could shed light on many as yet unresolved questions.

Radiobiological studies conducted in Deep Underground Laboratories allow to improve the knowledge of the biological effects induced by ionizing radiation at low doses/dose rates. At the Gran Sasso National Laboratory of the Italian Institute of Nuclear Physics we can study the possible differences in behavior between parallel biological systems, one maintained in a Reference-Radiation Environment (RRE, external) and the other maintained in an extremely Low-Radiation Environment (LRE, underground), in the absence of pressure changes, the RRE and LRE laboratories being at the same altitude. For these investigations, it is mandatory to evaluate the dose rate values at RRE and LRE. The aim of our work is to provide a comprehensive dosimetric analysis for external and underground laboratories. Measurements of the different low Linear Energy Transfer (LET) components at RRE and LRE were performed using different detectors. Gamma dose rates were 31 nSv/h at RRE and 27 nSv/h at LRE respectively. The muon dose rate was 47 nSv/h at RRE and negligible at LRE (less than pGy/h). Dosimetric measurements were also carried out to characterize the devices used to modulate the gamma dose rate, namely, a gamma source irradiator (to increase the dose rate by about 90 nSv/h) and shields (of iron at LRE and lead at RRE). Using the iron shield at LRE a dose reduction factor of about 20, compared to the RRE, was obtained for the low LET components; inside the lead shield at RRE the gamma component was negligible compared to the muonic component. Radon activity concentrations were approximately of 20 Bq/m3 at both LRE and RRE. The intrinsic contribution of radioactivity in the experimental set up was of 0.25 nGy/h, as evaluated with a GEANT4-simulation, using as input the measured activity concentrations. GEANT4 simulations were also performed to calculate the neutron dose rate at RRE, yielding a value of 1.4 nGy/h, much larger than that at LRE (which is less than pGy/h). In conclusion, RRE and LRE are currently characterized and equipped to perform radiobiological studies aimed at understanding the involvement of the different low LET components in determining the response of biological systems.

Glioblastoma is the most common and lethal primary malignant brain tumor in adults. Glioblastoma stem cells (GSCs) promote and are responsible for glioblastoma intratumoral heterogeneity and therapy resistance, due to their two main features: self-renewal and differentiation. Lipids have important biological and physiological functions that are critical for understanding the regulation and control of stem cell fate; lipid metabolism and related unsaturation levels play a possible role as the target of therapeutics to overcome glioblastoma radioresistance. This paper aimed at an in-depth analysis of 13 GSC mesenchymal (MES) lines, two subclones, and a stabilized glioblastoma line (T98G) by magnetic resonance spectroscopy (MRS). Particularly, 2D MRS was used to investigate lipid unsaturation behavior during growth in culture and after treatment with etomoxir and photon beams. MES lines, although belonging to the same genetic and metabolic cluster, showed metabolic heterogeneity when observed by MRS, focusing on lipid signals. Nonetheless, the observed unsaturation level stability for two representative lines after stressful treatments suggests unusual robustness of the unsaturation levels for each line, as a peculiar and intrinsic characteristic of GSCs.