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Abstract A radiological accident may result in the development of a local skin radiation injury (LRI) which may evolve, depending on the dose, from dry desquamation to deep ulceration and necrosis through unpredictable inflammatory waves. Therefore, early diagnosis of victims of LRI is crucial for improving medical care efficiency. This preclinical study aims to identify circulating metabolites as biomarkers associated with LRI using a C57BL/6J mouse model of hind limb irradiation. More precisely, two independent mice cohorts were used to conduct a broad-spectrum profiling study followed by a suspect screening analysis performed on plasma metabolites by mass spectrometry. An integrative analysis was conducted through a multi-block sparse partial least square discriminant analysis (sPLS-DA) to establish multi-scale correlations between specific metabolites levels and biological, physiological (injury severity), and functional parameters (skin perfusion). The identified biomarker signature consists in a 6-metabolite panel including putrescine, uracil, 2,3-dihydroxybenzoate, 3-hydroxybenzoate, L-alanine and pyroglutamate, that can discriminate mice according to radiation dose and injury severity. Our results demonstrate relevant molecular signature associated with LRI in mice and support the use of plasma metabolites as suitable molecular biomarkers for LRI prognosis and diagnosis.

Abstract A radiological accident, whether from industrial, medical, or malicious origin, may result in localized exposure to high doses of ionizing radiations, leading to the development of local radiation injury (LRI), that may evolve toward deep ulceration and necrosis of the skin and underlying tissues. Early diagnosis is therefore crucial to facilitate identification and management of LRI victims. Circulating microRNAs (miRNA) have been studied as potential diagnostic biomarkers of several diseases including hematological defects following whole-body irradiation (WBI). This study aims to identify a blood miRNA signature associated with LRI in a preclinical C57BL/6J mouse model of hindlimb irradiation using different 10-MV X-ray doses that lead to injuries of different severities. To this end, we first performed broad-spectrum plasma miRNA profiling, followed by a targeted validation step, on two independent animal cohorts. Using a multivariate sparse partial least square discriminant analysis, we identified a panel of eight circulating miRNAs able to segregate mice according to LRI severity. Interestingly, these miRNAs were previously associated with WBI (miR-150-5p, miR-342-3p, miR-146a-5p), inflammation (miR-18a-5p, miR-148b-3p, miR-532-5p) and skin diseases (miR-139-5p, miR-195-5p). Our results suggest the use of circulating miRNAs as suitable molecular biomarkers for LRI prognosis and diagnosis.

Prophylaxis by “KI 65 mg, breakable tablet” is a pharmacological countermeasure of radiological protection adapted for the prevention of thyroid cancer after exposure to radioactive iodine. A first modification of the marketing authorization of “KI 65 mg, breakable tablet” for repeated prophylaxis for adults and children above 12 years old was obtained in France in 2020. At this point in time it is recommended to exclude the repeated intake of “KI- 65 mg, breakable tablet” by pregnant and breastfeeding women and children below 12 years old, who should consequently be subjected to a priority evacuation from the contaminated zone. Regulatory toxicology studies are underway in order to support an upcoming proposal of modification of the marketing authorization of “KI- 65 mg, breakable tablet” for repeated prophylaxis for pregnant women and children below 12 years old.

Summary: The vascular endothelium is a hot spot in the response to radiation therapy for both tumors and normal tissues. To improve patient outcomes, interpretable systemic hypotheses are needed to help radiobiologists and radiation oncologists propose endothelial targets that could protect normal tissues from the adverse effects of radiation therapy and/or enhance its antitumor potential. To this end, we captured the kinetics of multi-omics layers—i.e. miRNome, targeted transcriptome, proteome, and metabolome—in irradiated primary human endothelial cells cultured in vitro. We then designed a strategy of deep learning as in convolutional graph networks that facilitates unsupervised high-level feature extraction of important omics data to learn how ionizing radiation-induced endothelial dysfunction may evolve over time. Last, we present experimental data showing that some of the features identified using our approach are involved in the alteration of angiogenesis by ionizing radiation.

Changes in metabolomics over time were studied in rats to identify early biomarkers and highlight the main metabolic pathways that are significantly altered in the period immediately following acute low-dose uranium exposure. A dose response relationship study was established from urine and plasma samples collected periodically over 9 months after the exposure of young adult male rats to uranyl nitrate. LC-MS and biostatistical analysis were used to identify early discriminant metabolites. As expected, low doses of uranium lead to time-based non-toxic biological effects, which can be used to identify early and delayed markers of exposure in both urine and plasma samples. A combination of surrogate markers for uranium exposure was validated from the most discriminant early markers for making effective predictions. N-methyl-nicotinamide, kynurenic acid, serotonin, tryptophan, tryptamine, and indole acetic acid associated with the nicotinate–nicotinamide and tryptophan pathway seem to be one of the main biological targets, as shown previously for chronic contaminations and completed, among others, by betaine metabolism. This study can be considered as a proof of concept for the relevance of metabolomics in the field of low-dose internal contamination by uranium, for the development of predictive diagnostic tests usable for radiotoxicological monitoring.

Background: Intake of potassium iodide (KI) reduces the accumulation of radioactive iodine in the thyroid gland in the event of possible contamination by radioactive iodine released from a nuclear facility. The World Health Organization (WHO) has stated the need for research for optimal timing, appropriate dosing regimen, and safety for repetitive iodine thyroid blocking (ITB). The French PRIODAC project, addressed all these issues, involving prolonged or repeated releases of radioactive iodine. Preclinical studies established an effective dose through pharmacokinetic modeling, demonstrating the safety of repetitive KI treatment without toxicity. Summary: Recent preclinical studies have determined an optimal effective dose for repetitive administration, associated with pharmacokinetic modeling. The results show the safety and absence of toxicity of repetitive treatment with KI. Good laboratory practice level preclinical studies corresponding to individuals >12 years have shown a safety margin established between animal doses without toxic effect. After approval from the French health authorities, the market authorization of the two tablets of KI, 65 mg/day, was defined with a new dosing scheme of a daily repetitive intake of the treatment up to 7 days unless otherwise instructed by the competent authorities for all categories of population except pregnant women and children under the age of 12 years. Conclusion: This new marketed authorization resulting from scientific-based evidence obtained as part of the PRIODAC project may serve as an example to further harmonize the application of KI for repetitive ITB in situations of prolonged radioactive release at the European and international levels, under the umbrella of the WHO.