A Review of Radiation-Induced Alterations of Multi-Omic Profiles, Radiation Injury Biomarkers, and Countermeasures.

Increasing utilization of nuclear power enhances the risks associated with industrial accidents, occupational hazards, and the threat of nuclear terrorism. Exposure to ionizing radiation interferes with genomic stability and gene expression resulting in the disruption of normal metabolic processes in cells and organs by inducing complex biological responses. Exposure to high-dose radiation causes acute radiation syndrome, which leads to hematopoietic, gastrointestinal, cerebrovascular, and many other organ-specific injuries. Altered genomic variations, gene expression, metabolite concentrations, and microbiota profiles in blood plasma or tissue samples reflect the whole-body radiation injuries. Hence, multi-omic profiles obtained from high-resolution omics platforms offer a holistic approach for identifying reliable biomarkers to predict the radiation injury of organs and tissues resulting from radiation exposures. In this review, we performed a literature search to systematically catalog the radiation-induced alterations from multi-omic studies and radiation countermeasures. We covered radiation-induced changes in the genomic, transcriptomic, proteomic, metabolomic, lipidomic, and microbiome profiles. Furthermore, we have covered promising multi-omic biomarkers, FDA-approved countermeasure drugs, and other radiation countermeasures that include radioprotectors and radiomitigators. This review presents an overview of radiation-induced alterations of multi-omics profiles and biomarkers, and associated radiation countermeasures.

Proteomic Evaluation of the Natural History of the Acute Radiation Syndrome of the Gastrointestinal Tract in a Non-human Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing Includes Dysregulation of the Retinoid Pathway.

Exposure to ionizing radiation results in injuries of the hematopoietic, gastrointestinal, and respiratory systems, which are the leading causes responsible for morbidity and mortality. Gastrointestinal injury occurs as an acute radiation syndrome. To help inform on the natural history of the radiation-induced injury of the partial body irradiation model, we quantitatively profiled the proteome of jejunum from non-human primates following 12 Gy partial body irradiation with 2.5% bone marrow sparing over a time period of 3 wk. Jejunum was analyzed by liquid chromatography-tandem mass spectrometry, and pathway and gene ontology analysis were performed. A total of 3,245 unique proteins were quantified out of more than 3,700 proteins identified in this study. Also a total of 289 proteins of the quantified proteins showed significant and consistent responses across at least three time points post-irradiation, of which 263 proteins showed strong upregulations while 26 proteins showed downregulations. Bioinformatic analysis suggests significant pathway and upstream regulator perturbations post-high dose irradiation and shed light on underlying mechanisms of radiation damage. Canonical pathways altered by radiation included GP6 signaling pathway, acute phase response signaling, LXR/RXR activation, and intrinsic prothrombin activation pathway. Additionally, we observed dysregulation of proteins of the retinoid pathway and retinoic acid, an active metabolite of vitamin A, as quantified by liquid chromatography-tandem mass spectrometry. Correlation of changes in protein abundance with a well-characterized histological endpoint, corrected crypt number, was used to evaluate biomarker potential. These data further define the natural history of the gastrointestinal acute radiation syndrome in a non-human primate model of partial body irradiation with minimal bone marrow sparing.

Diagnosis and treatment of polonium poisoning.

OBJECTIVES: Interest in the clinical toxicology of (210)polonium ((210)Po) has been stimulated by the poisoning of Alexander Litvinenko in 2006. This article reviews the clinical features, diagnosis, and treatment of acute radiation syndrome (ARS) resulting from the ingestion of (210)Po. PHYSICAL CHARACTERISTICS: (210)Po is a high-energy alpha-emitter (radioactive half-life 138 days) that presents a radiation hazard only if taken into the body, for example, by ingestion, because of the low range of alpha particles in biological tissues. As a result, external contamination does not cause radiation sickness. TOXICOKINETICS: Ingested (210)Po is concentrated initially in red blood cells and then the liver, kidneys, spleen, bone marrow, gastrointestinal (GI) tract, and gonads. (210)Po is excreted in urine, bile, sweat, and (possibly) breath and is also deposited in hair. After ingestion, unabsorbed (210)Po is present in the faeces. The elimination half-life in man is approximately 30-50 days. In the absence of medical treatment, the fatal oral amount is probably in the order of 10-30 microg. CLINICAL PRESENTATION: If the absorbed dose is sufficiently large (e.g., >0.7 Gy), (210)Po can cause ARS. This is characterized by a prodromal phase, in which nausea, vomiting, anorexia, lymphopenia, and sometimes diarrhea develop after exposure. Higher radiation doses cause a more rapid onset of symptoms and a more rapid reduction in lymphocyte count. The prodromal phase may be followed by a latent phase during which there is some clinical improvement. Subsequently, the characteristic bone marrow (0.7-10 Gy), GI (8-10 Gy), or cardiovascular/central nervous system syndromes (>20 Gy) develop, with the timing and pattern of features dependent on the systemic dose. The triad of early emesis followed by hair loss and bone marrow failure is typical of ARS. Those patients who do not recover die within weeks to months, whereas in those who survive, full recovery can take many months. INVESTIGATION AND DIAGNOSIS: Serial blood counts are important for assessing the rate of reduction in lymphocyte counts. Chromosome analysis, especially the dicentric count, may establish radiation effects and provides an estimation of dose. The diagnosis of (210)Po poisoning is established by the presence of (210)Po in urine and faeces and the exclusion of other possible causes. In the absence of a history of exposure, diagnosis is very difficult as clinical features are similar to those of much more common conditions, such as GI infections and bone marrow failure caused, for example, by drugs, other toxins, or infections. MANAGEMENT: Good supportive care is essential and should be directed at controlling symptoms, preventing infections but treating those that do arise, and transfusion of blood and platelets as appropriate. Gastric aspiration or lavage may be useful if performed soon after ingestion. Chelation therapy is also likely to be beneficial, with research in animals suggesting reduced retention in the body and improvements in survival, although increased activity in some radiosensitive organs has also been reported with some chelating agents. Dimercaprol (British Anti-Lewisite) (with penicillamine as an alternative) is currently recommended for (210)Po poisoning, but animal models also indicate efficacy for 2,3,-dimercapto-1-propanesulfonic acid, meso-dimercaptosuccinic acid, or N,N -dihydroxyethylethelene-diamine-N,N -bis-dithiocarbamate. CONCLUSIONS: Internal contamination with (210)Po can cause ARS, which should be considered in patients presenting initially with unexplained emesis, followed later by bone marrow failure and hair loss.