Recent epidemiology studies highlighted the detrimental health effects of exposure to low dose and low dose rate ionizing radiation (IR): nuclear industry workers studies have shown increased ...leukaemia and solid tumour risks following cumulative doses of <100mSv and dose rates of <10mGy per year; paediatric patients studies have reported increased leukaemia and brain tumours risks after doses of 30–60mGy from computed tomography scans. Questions arise, however, about the impact of even lower doses and dose rates where classical epidemiological studies have limited power but where subsets within the large cohorts are expected to have an increased risk. Further progress requires integration of biomarkers or bioassays of individual exposure, effects and susceptibility to IR. The European DoReMi (Low Dose Research towards Multidisciplinary Integration) consortium previously reviewed biomarkers for potential use in IR epidemiological studies. Given the increased mechanistic understanding of responses to low dose radiation the current review provides an update covering technical advances and recent studies. A key issue identified is deciding which biomarkers to progress. A roadmap is provided for biomarker development from discovery to implementation and used to summarise the current status of proposed biomarkers for epidemiological studies. Most potential biomarkers remain at the discovery stage and for some there is sufficient evidence that further development is not warranted. One biomarker identified in the final stages of development and as a priority for further research is radiation specific mRNA transcript profiles.
Ionizing radiation is a known human carcinogen that can induce a variety of biological effects depending on the physical nature, duration, doses and dose-rates of exposure. However, the magnitude of ...health risks at low doses and dose-rates (below 100mSv and/or 0.1mSvmin−1) remains controversial due to a lack of direct human evidence. It is anticipated that significant insights will emerge from the integration of epidemiological and biological research, made possible by molecular epidemiology studies incorporating biomarkers and bioassays. A number of these have been used to investigate exposure, effects and susceptibility to ionizing radiation, albeit often at higher doses and dose rates, with each reflecting time-limited cellular or physiological alterations. This review summarises the multidisciplinary work undertaken in the framework of the European project DoReMi (Low Dose Research towards Multidisciplinary Integration) to identify the most appropriate biomarkers for use in population studies. In addition to logistical and ethical considerations for conducting large-scale epidemiological studies, we discuss the relevance of their use for assessing the effects of low dose ionizing radiation exposure at the cellular and physiological level. We also propose a temporal classification of biomarkers that may be relevant for molecular epidemiology studies which need to take into account the time elapsed since exposure. Finally, the integration of biology with epidemiology requires careful planning and enhanced discussions between the epidemiology, biology and dosimetry communities in order to determine the most important questions to be addressed in light of pragmatic considerations including the appropriate population to be investigated (occupationally, environmentally or medically exposed), and study design. The consideration of the logistics of biological sample collection, processing and storing and the choice of biomarker or bioassay, as well as awareness of potential confounding factors, are also essential.
The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of ...received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood in vivo. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.e. after 1, 2, and 25 fractionated RT procedures. We collected circulating peripheral blood from ten patients with tumor of endometrium (1.8 Gy per fraction) and eight patients with tumor of head and neck (2.0-2.121 Gy per fraction). Incidence of dicentrics and micronuclei was monitored as well as determination of apoptosis and the transcription level of selected radiation-responsive genes. Since mitochondrial DNA (mtDNA) has been reported to be a potential indicator of radiation damage in vitro, we also assessed mtDNA content and deletions by novel multiplex quantitative PCR. Cytogenetic data confirmed linear dose-dependent increase in dicentrics (p < 0.01) and micronuclei (p < 0.001) in peripheral blood mononuclear cells after PBI. Significant up-regulations of five previously identified transcriptional biomarkers of radiation exposure (PHPT1, CCNG1, CDKN1A, GADD45, and SESN1) were also found (p < 0.01). No statistical change in mtDNA deletion levels was detected; however, our data indicate that the total mtDNA content decreased with increasing number of RT fractions. Interestingly, the number of micronuclei appears to correlate with late radiation toxicity (r2 = 0.9025) in endometrial patients suggesting the possibility of predicting the severity of RT-related toxicity by monitoring this parameter. Overall, these data represent, to our best knowledge, the first study providing a multiparametric comparison of radiation biomarkers in human blood in vivo, which have potential for improving biological dosimetry.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Salivary biomarkers have important potential to facilitate breakthroughs in epidemiologic studies, management of emergency situations, and detection and surveillance of diseases by medical staff. ...During the last decade, an increasing number of studies on salivary biomarkers have been published as a consequence of the impressive development of new high-throughput technologies. Here, we present a review of salivary biomarkers potentially useful in ionizing radiation (IR) research, particularly in molecular epidemiologic studies. Although several salivary biomarkers of cancer and other IR-associated diseases have been identified, few salivary biomarkers of exposure and no biomarker of susceptibility or effects specific to IR have been reported so far. Further studies are therefore needed to fully assess the potential of saliva as a source of biomarkers in the radiation research field. Although the use of saliva samples is not without drawbacks, it could represent an ideal noninvasive alternative to blood, particularly in children and in the context of large molecular epidemiology studies on the effects of low doses of IR, where, given the expected limited magnitude of effects, an extensive number of samples is required to reach statistical significance. See all the articles in this CEBP Focus section, "Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology."
The primary cilium is an antenna-like structure that protrudes from the cell surface of quiescent/differentiated cells and participates in extracellular signal processing. Here, we report that mice ...deficient for the lipid 5-phosphatase Inpp5e develop a multiorgan disorder associated with structural defects of the primary cilium. In ciliated mouse embryonic fibroblasts, Inpp5e is concentrated in the axoneme of the primary cilium. Inpp5e inactivation did not impair ciliary assembly but altered the stability of pre-established cilia after serum addition. Blocking phosphoinositide 3-kinase (PI3K) activity or ciliary platelet-derived growth factor receptor α (PDGFRα) restored ciliary stability. In human INPP5E, we identified a mutation affecting INPP5E ciliary localization and cilium stability in a family with MORM syndrome, a condition related to Bardet-Biedl syndrome. Together, our results show that INPP5E plays an essential role in the primary cilium by controlling ciliary growth factor and PI3K signaling and stability, and highlight the consequences of INPP5E dysfunction.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Despite substantial experimental and epidemiological research, there is limited knowledge of the uranium-induce health effects after chronic low-dose exposures in humans. Biological markers can ...objectively characterize pathological processes or environmental responses to uranium and confounding agents. The integration of such biological markers into a molecular epidemiological study would be a useful approach to improve and refine estimations of uranium-induced health risks. To initiate such a study, Concerted Uranium Research in Europe (CURE) was established, and involves biologists, epidemiologists and dosimetrists. The aims of the biological work package of CURE were: 1. To identify biomarkers and biological specimens relevant to uranium exposure; 2. To define standard operating procedures (SOPs); and 3. To set up a common protocol (logistic, questionnaire, ethical aspects) to perform a large-scale molecular epidemiologic study in uranium-exposed cohorts. An intensive literature review was performed and led to the identification of biomarkers related to: 1. retention organs (lungs, kidneys and bone); 2. other systems/organs with suspected effects (cardiovascular system, central nervous system and lympho-hematopoietic system); 3. target molecules (DNA damage, genomic instability); and 4. high-throughput methods for the identification of new biomarkers. To obtain high-quality biological materials, SOPs were established for the sampling and storage of different biospecimens. A questionnaire was developed to assess potential confounding factors. The proposed strategy can be adapted to other internal exposures and should improve the characterization of the biological and health effects that are relevant for risk assessment.
Those working in interventional cardiology and related medical procedures are potentially subject to considerable exposure to x-rays. Two types of tissue of particular concern that may receive ...considerable doses during such procedures are the lens of the eye and the brain. Ocular radiation exposure results in lens changes that, with time, may progress to partial or total lens opacification (cataracts). In the early stages, such opacities do not result in visual disability; the severity of such changes tends to increase progressively with dose and time until vision is impaired and cataract surgery is required. Scattered radiation doses to the eye lens of an interventional cardiologist in typical working conditions can exceed 34 μGy min−1 in high-dose fluoroscopy modes and 3 μGy per image during image acquisition (instantaneous rate values) when radiation protection tools are not used. A causal relation between exposure to ionising radiation and increased risk of brain and central nervous system tumours has been shown in a number of studies. Although absorbed doses to the brain in interventional cardiology procedures are lower than those to the eye lens by a factor between 3.40 and 8.08 according to our simulations, doses to both tissues are among the highest occupational radiation doses documented for medical staff whose work involves exposures to x-rays. We present InterCardioRisk, a tool featuring an easy-to-use web interface that provides a general estimation of both cumulated absorbed doses experienced by medical staff exposed in the interventional cardiology setting and their estimated associated health risks. The tool is available at http://intercardiorisk.creal.cat.
The function of the phosphoinositide 5-phosphatase Ship2 was investigated in a new mouse model expressing a germline catalytically-inactive Ship2∆/∆ mutant protein. Ship2∆/∆ mice were viable with ...defects in somatic growth and in development of muscle, adipose tissue and female genital tract. Lipid metabolism and insulin secretion were also affected in these mice, but glucose tolerance, insulin sensitivity and insulin-induced PKB phosphorylation were not. We expected that the expression of the catalytically inactive Ship2 protein in PI 3′-kinase-defective p110αD933A/+ mice would counterbalance the phenotypes of parental mice by restoring normal PKB signaling but, for most of the parameters tested, this was not the case. Indeed, often, the Ship2∆/∆ phenotype had a dominant effect over the p110αD933A/+ phenotype and, sometimes, there was a surprising additive effect of both mutations. p110αD933A/+Ship2∆/∆ mice still displayed a reduced PKB phosphorylation in response to insulin, compared to wild type mice yet had a normal glucose tolerance and insulin sensitivity, like the Ship2∆/∆ mice. Together, our results suggest that the Ship2∆/∆ phenotype is not dependent on an overstimulated class I PI 3-kinase–PKB signaling pathway and thus, indirectly, that it may be more dependent on the lack of Ship2-produced phosphatidylinositol 3,4-bisphosphate and derived phosphoinositides.
► A mouse model expressing a catalytically-inactive Ship2∆/∆ protein was generated. ► Ship2∆/∆ mice presented developmental and metabolic alterations. ► The Ship2∆/∆ phenotype had a dominant effect in p110αD933A/+ Ship2∆/∆ mice. ► The Ship2∆/∆ phenotype is not dependent on an overstimulated PKB signaling pathway. ► The Ship2∆/∆ phenotype may be more dependent on the lack of Ship2-produced PI(3,4)P2.
The potential health impacts of chronic exposures to uranium, as they occur in occupational settings, are not well characterized. Most epidemiological studies have been limited by small sample sizes, ...and a lack of harmonization of methods used to quantify radiation doses resulting from uranium exposure. Experimental studies have shown that uranium has biological effects, but their implications for human health are not clear. New studies that would combine the strengths of large, well-designed epidemiological datasets with those of state-of-the-art biological methods would help improve the characterization of the biological and health effects of occupational uranium exposure. The aim of the European Commission concerted action CURE (Concerted Uranium Research in Europe) was to develop protocols for such a future collaborative research project, in which dosimetry, epidemiology and biology would be integrated to better characterize the effects of occupational uranium exposure. These protocols were developed from existing European cohorts of workers exposed to uranium together with expertise in epidemiology, biology and dosimetry of CURE partner institutions. The preparatory work of CURE should allow a large scale collaborative project to be launched, in order to better characterize the effects of uranium exposure and more generally of alpha particles and low doses of ionizing radiation.
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