Publications by authors named "Sarah Baatout"

106 Publications

X‑irradiation induces acute and early term inflammatory responses in atherosclerosis‑prone ApoE‑/‑ mice and in endothelial cells.

Mol Med Rep 2021 Jun 31;23(6). Epub 2021 Mar 31.

Department of Basic and Applied Medical Sciences, Physiology Group, Ghent University, 9000 Ghent, Belgium.

Thoracic radiotherapy is an effective treatment for many types of cancer; however it is also associated with an increased risk of developing cardiovascular disease (CVD), appearing mainly ≥10 years after radiation exposure. The present study investigated acute and early term physiological and molecular changes in the cardiovascular system after ionizing radiation exposure. Female and male ApoE mice received a single exposure of low or high dose X‑ray thoracic irradiation (0.1 and 10 Gy). The level of cholesterol and triglycerides, as well as a large panel of inflammatory markers, were analyzed in serum samples obtained at 24 h and 1 month after irradiation. The secretion of inflammatory markers was further verified in coronary artery and microvascular endothelial cell lines after exposure to low and high dose of ionizing radiation (0.1 and 5 Gy). Local thoracic irradiation of ApoE mice increased serum growth differentiation factor‑15 (GDF‑15) and C‑X‑C motif chemokine ligand 10 (CXCL10) levels in both female and male mice 24 h after high dose irradiation, which were also secreted from coronary artery and microvascular endothelial cells . Sex‑specific responses were observed for triglyceride and cholesterol levels, and some of the assessed inflammatory markers as detailed below. Male ApoE mice demonstrated elevated intercellular adhesion molecule‑1 and P‑selectin at 24 h, and adiponectin and plasminogen activator inhibitor‑1 at 1 month after irradiation, while female ApoE mice exhibited decreased monocyte chemoattractant protein‑1 and urokinase‑type plasminogen activator receptor at 24 h, and basic fibroblast growth factor 1 month after irradiation. The inflammatory responses were mainly significant following high dose irradiation, but certain markers showed significant changes after low dose exposure. The present study revealed that acute/early inflammatory responses occurred after low and high dose thoracic irradiation. However, further research is required to elucidate early asymptomatic changes in the cardiovascular system post thoracic X‑irradiation and to investigate whether GDF‑15 and CXCL10 could be considered as potential biomarkers for the early detection of CVD risk in thoracic radiotherapy‑treated patients.
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http://dx.doi.org/10.3892/mmr.2021.12038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025474PMC
June 2021

Correction to: The role of connexin proteins and their channels in radiation-induced atherosclerosis.

Cell Mol Life Sci 2021 Mar 29. Epub 2021 Mar 29.

Department of Basic and Applied Medical Sciences, Physiology group, Ghent University, Ghent, Belgium.

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http://dx.doi.org/10.1007/s00018-021-03811-zDOI Listing
March 2021

Assessment of the DNA Damage Response in Dental Mesenchymal Stromal Cells Following Low Dose X-ray Exposure.

Front Public Health 2021 15;9:584484. Epub 2021 Feb 15.

Belgian Nuclear Research Centre, Institute for Environment, Health and Safety, Radiobiology Unit, Mol, Belgium.

Stem cells contained within the dental mesenchymal stromal cell (MSC) population are crucial for tissue homeostasis. Assuring their genomic stability is therefore essential. Exposure of stem cells to ionizing radiation (IR) is potentially detrimental for normal tissue homeostasis. Although it has been established that exposure to high doses of ionizing radiation (IR) has severe adverse effects on MSCs, knowledge about the impact of low doses of IR is lacking. Here we investigated the effect of low doses of X-irradiation with medical imaging beam settings (<0.1 Gray; 900 mGray per hour), , on pediatric dental mesenchymal stromal cells containing dental pulp stem cells from deciduous teeth, dental follicle progenitor cells and stem cells from the apical papilla. DNA double strand break (DSB) formation and repair kinetics were monitored by immunocytochemistry of γH2AX and 53BP1 as well as cell cycle progression by flow cytometry and cellular senescence by senescence-associated β-galactosidase assay and ELISA. Increased DNA DSB repair foci, after exposure to low doses of X-rays, were measured as early as 30 min post-irradiation. The number of DSBs returned to baseline levels 24 h after irradiation. Cell cycle analysis revealed marginal effects of IR on cell cycle progression, although a slight G/M phase arrest was seen in dental pulp stromal cells from deciduous teeth 72 h after irradiation. Despite this cell cycle arrest, no radiation-induced senescence was observed. In conclusion, low X-ray IR doses (< 0.1 Gray; 900 mGray per hour), were able to induce significant increases in the number of DNA DSBs repair foci, but cell cycle progression seems to be minimally affected. This highlights the need for more detailed and extensive studies on the effects of exposure to low IR doses on different mesenchymal stromal cells.
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http://dx.doi.org/10.3389/fpubh.2021.584484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939020PMC
February 2021

Radiation-induced cardiovascular disease: an overlooked role for DNA methylation?

Epigenetics 2021 Jan 31:1-22. Epub 2021 Jan 31.

Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN) , Mol, Belgium.

Radiotherapy in cancer treatment involves the use of ionizing radiation for cancer cell killing. Although radiotherapy has shown significant improvements on cancer recurrence and mortality, several radiation-induced adverse effects have been documented. Of these adverse effects, radiation-induced cardiovascular disease (CVD) is particularly prominent among patients receiving mediastinal radiotherapy, such as breast cancer and Hodgkin's lymphoma patients. A number of mechanisms of radiation-induced CVD pathogenesis have been proposed such as endothelial inflammatory activation, premature endothelial senescence, increased ROS and mitochondrial dysfunction. However, current research seems to point to a so-far unexamined and potentially novel involvement of epigenetics in radiation-induced CVD pathogenesis. Firstly, epigenetic mechanisms have been implicated in CVD pathophysiology. In addition, several studies have shown that ionizing radiation can cause epigenetic modifications, especially DNA methylation alterations. As a result, this review aims to provide a summary of the current literature linking DNA methylation to radiation-induced CVD and thereby explore DNA methylation as a possible contributor to radiation-induced CVD pathogenesis.
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http://dx.doi.org/10.1080/15592294.2021.1873628DOI Listing
January 2021

Folic Acid Fortification Prevents Morphological and Behavioral Consequences of X-Ray Exposure During Neurulation.

Front Behav Neurosci 2020 8;14:609660. Epub 2021 Jan 8.

Radiobiology Unit, Interdisciplinary Biosciences, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (Studiecentrum voor Kernenergie; Centre d'étude de l'énergie nucléaire), Mol, Belgium.

Previous studies suggested a causal link between pre-natal exposure to ionizing radiation and birth defects such as microphthalmos and exencephaly. In mice, these defects arise primarily after high-dose X-irradiation during early neurulation. However, the impact of sublethal (low) X-ray doses during this early developmental time window on adult behavior and morphology of central nervous system structures is not known. In addition, the efficacy of folic acid (FA) in preventing radiation-induced birth defects and persistent radiation-induced anomalies has remained unexplored. To assess the efficacy of FA in preventing radiation-induced defects, pregnant C57BL6/J mice were X-irradiated at embryonic day (E)7.5 and were fed FA-fortified food. FA partially prevented radiation-induced (1.0 Gy) anophthalmos, exencephaly and gastroschisis at E18, and reduced the number of pre-natal deaths, fetal weight loss and defects in the cervical vertebrae resulting from irradiation. Furthermore, FA food fortification counteracted radiation-induced impairments in vision and olfaction, which were evidenced after exposure to doses ≥0.1 Gy. These findings coincided with the observation of a reduction in thickness of the retinal ganglion cell and nerve fiber layer, and a decreased axial length of the eye following exposure to 0.5 Gy. Finally, MRI studies revealed a volumetric decrease of the hippocampus, striatum, thalamus, midbrain and pons following 0.5 Gy irradiation, which could be partially ameliorated after FA food fortification. Altogether, our study is the first to offer detailed insights into the long-term consequences of X-ray exposure during neurulation, and supports the use of FA as a radioprotectant and antiteratogen to counter the detrimental effects of X-ray exposure during this crucial period of gestation.
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http://dx.doi.org/10.3389/fnbeh.2020.609660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820780PMC
January 2021

The role of connexin proteins and their channels in radiation-induced atherosclerosis.

Cell Mol Life Sci 2021 Apr 3;78(7):3087-3103. Epub 2021 Jan 3.

Department of Basic and Applied Medical Sciences, Physiology group, Ghent University, Ghent, Belgium.

Radiotherapy is an effective treatment for breast cancer and other thoracic tumors. However, while high-energy radiotherapy treatment successfully kills cancer cells, radiation exposure of the heart and large arteries cannot always be avoided, resulting in secondary cardiovascular disease in cancer survivors. Radiation-induced changes in the cardiac vasculature may thereby lead to coronary artery atherosclerosis, which is a major cardiovascular complication nowadays in thoracic radiotherapy-treated patients. The underlying biological and molecular mechanisms of radiation-induced atherosclerosis are complex and still not fully understood, resulting in potentially improper radiation protection. Ionizing radiation (IR) exposure may damage the vascular endothelium by inducing DNA damage, oxidative stress, premature cellular senescence, cell death and inflammation, which act to promote the atherosclerotic process. Intercellular communication mediated by connexin (Cx)-based gap junctions and hemichannels may modulate IR-induced responses and thereby the atherosclerotic process. However, the role of endothelial Cxs and their channels in atherosclerotic development after IR exposure is still poorly defined. A better understanding of the underlying biological pathways involved in secondary cardiovascular toxicity after radiotherapy would facilitate the development of effective strategies that prevent or mitigate these adverse effects. Here, we review the possible roles of intercellular Cx driven signaling and communication in radiation-induced atherosclerosis.
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http://dx.doi.org/10.1007/s00018-020-03716-3DOI Listing
April 2021

Pharmacokinetics, Biodistribution and Toxicity of Antibody-Conjugated Gold Nanoparticles in Healthy Mice.

J Biomed Nanotechnol 2020 Jun;16(6):985-996

Cetuximab-conjugated gold nanoparticles are known to target cancer cells, but display toxicity towards normal kidney, liver and endothelial cells . In this study, we investigated their pharmacokinetics, biodistribution and toxicity after intravenous administration in healthy mice. Our data showed that these nanoparticles were rapidly cleared from the blood and accumulated mainly in the liver and spleen with long-term retention. Acute liver injury, inflammatory activity and vascular damage were transient and negligible, as confirmed by the liver functionality tests and serum marker analysis. There was no sign of altered liver, kidney, lung and spleen morphology up to 4 weeks post-injection. After 6 months, kidney casts and splenic apoptosis appeared to be more prevalent than in the controls. Furthermore, occasional immune cell infiltration was observed in the lungs. Therefore, we recommend additional studies, in order to investigate the long-term toxicity and elimination of gold nanoparticles after multiple dosing in their preclinical validation as new targeted anti-cancer therapies.
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http://dx.doi.org/10.1166/jbn.2020.2928DOI Listing
June 2020

Hippocampal and cortical tissue-specific epigenetic clocks indicate an increased epigenetic age in a mouse model for Alzheimer's disease.

Aging (Albany NY) 2020 10 20;12(20):20817-20834. Epub 2020 Oct 20.

Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN), Mol 2400, Belgium.

Epigenetic clocks are based on age-associated changes in DNA methylation of CpG-sites, which can accurately measure chronological age in different species. Recently, several studies have indicated that the difference between chronological and epigenetic age, defined as the age acceleration, could reflect biological age indicating functional decline and age-associated diseases. In humans, an epigenetic clock associated Alzheimer's disease (AD) pathology with an acceleration of the epigenetic age. In this study, we developed and validated two mouse brain region-specific epigenetic clocks from the C57BL/6J hippocampus and cerebral cortex. Both clocks, which could successfully estimate chronological age, were further validated in a widely used mouse model for AD, the triple transgenic AD (3xTg-AD) mouse. We observed an epigenetic age acceleration indicating an increased biological age for the 3xTg-AD mice compared to non-pathological C57BL/6J mice, which was more pronounced in the cortex as compared to the hippocampus. Genomic region enrichment analysis revealed that age-dependent CpGs were enriched in genes related to developmental, aging-related, neuronal and neurodegenerative functions. Due to the limited access of human brain tissues, these epigenetic clocks specific for mouse cortex and hippocampus might be important in further unravelling the role of epigenetic mechanisms underlying AD pathology or brain aging in general.
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http://dx.doi.org/10.18632/aging.104056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655172PMC
October 2020

Unloading-Induced Cortical Bone Loss is Exacerbated by Low-Dose Irradiation During a Simulated Deep Space Exploration Mission.

Calcif Tissue Int 2020 08 25;107(2):170-179. Epub 2020 May 25.

INSERM U1059-SAINBIOSE, Université de Lyon, 10 rue de la Marandière, 42270, Saint-Priest-en-Jarez, France.

Spaceflight-induced bone losses have been reliably reproduced in Hind-Limb-Unloading (HLU) rodent models. However, a considerable knowledge gap exists regarding the effects of low-dose radiation and microgravity together. Ten-week-old male C57BL/6J mice, randomly allocated to Control (CONT), Hind-Limb Unloading (HLU), and Hind-Limb Unloading plus Irradiation (HLUIR), were acclimatized at 28 °C, close to thermoneutral temperature, for 28 days prior to the 14-day HLU protocol. HLUIR mice received a 25 mGy dose of X-ray irradiation, simulating 14 days of exposure to the deep space radiation environment, on day 7 of the HLU protocol. Trabecular bone mass was similarly reduced in HLU and HLUIR mice when compared to CONT, with losses driven by osteoclastic bone resorption rather than changes to osteoblastic bone formation. Femoral cortical thickness was reduced only in the HLUIR mice (102 μm, 97.5-107) as compared to CONT (108.5 μm, 102.5-120.5). Bone surface area was also reduced only in the HLUIR group, with no difference between HLU and CONT. Cortical losses were driven by osteoclastic resorption on the posterior endosteal surface of the distal femoral diaphysis, with no increase in the numbers of dead osteocytes. In conclusion, we show that low-dose radiation exposure negatively influences bone physiology beyond that induced by microgravity alone.
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http://dx.doi.org/10.1007/s00223-020-00708-0DOI Listing
August 2020

Rosiglitazone Protects Endothelial Cells From Irradiation-Induced Mitochondrial Dysfunction.

Front Pharmacol 2020 13;11:268. Epub 2020 Mar 13.

Institute for Environment, Health and Safety, Radiobiology Unit, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium.

Background And Purpose: Up to 50-60% of all cancer patients receive radiotherapy as part of their treatment strategy. However, the mechanisms accounting for increased vascular risks after irradiation are not completely understood. Mitochondrial dysfunction has been identified as a potential cause of radiation-induced atherosclerosis.

Materials And Methods: Assays for apoptosis, cellular metabolism, mitochondrial DNA content, functionality and morphology were used to compare the response of endothelial cells to a single 2 Gy dose of X-rays under basal conditions or after pharmacological treatments that either reduced (EtBr) or increased (rosiglitazone) mitochondrial content.

Results: Exposure to ionizing radiation caused a persistent reduction in mitochondrial content of endothelial cells. Pharmacological reduction of mitochondrial DNA content rendered endothelial cells more vulnerable to radiation-induced apoptosis, whereas rosiglitazone treatment increased oxidative metabolism and redox state and decreased the levels of apoptosis after irradiation.

Conclusion: Pre-existing mitochondrial damage sensitizes endothelial cells to ionizing radiation-induced mitochondrial dysfunction. Rosiglitazone protects endothelial cells from the detrimental effects of radiation exposure on mitochondrial metabolism and oxidative stress. Thus, our findings indicate that rosiglitazone may have potential value as prophylactic for radiation-induced atherosclerosis.
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http://dx.doi.org/10.3389/fphar.2020.00268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082323PMC
March 2020

Connexin43 Hemichannel Targeting With TAT-Gap19 Alleviates Radiation-Induced Endothelial Cell Damage.

Front Pharmacol 2020 5;11:212. Epub 2020 Mar 5.

Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), Mol, Belgium.

Background: Emerging evidence indicates an excess risk of late occurring cardiovascular diseases, especially atherosclerosis, after thoracic cancer radiotherapy. Ionizing radiation (IR) induces cellular effects which may induce endothelial cell dysfunction, an early marker for atherosclerosis. In addition, intercellular communication through channels composed of transmembrane connexin proteins (Cxs), i.e. Gap junctions (direct cell-cell coupling) and hemichannels (paracrine release/uptake pathway) can modulate radiation-induced responses and therefore the atherosclerotic process. However, the role of endothelial hemichannel in IR-induced atherosclerosis has never been described before.

Materials And Methods: Telomerase-immortalized human Coronary Artery/Microvascular Endothelial cells (TICAE/TIME) were exposed to X-rays (0.1 and 5 Gy). Production of reactive oxygen species (ROS), DNA damage, cell death, inflammatory responses, and senescence were assessed with or without applying a Cx43 hemichannel blocker (TAT-Gap19).

Results: We report here that IR induces an increase in oxidative stress, cell death, inflammatory responses (IL-8, IL-1β, VCAM-1, MCP-1, and Endothelin-1) and premature cellular senescence in TICAE and TIME cells. These effects are significantly reduced in the presence of the Cx43 hemichannel-targeting peptide TAT-Gap19.

Conclusion: Our findings suggest that endothelial Cx43 hemichannels contribute to various IR-induced processes, such as ROS, cell death, inflammation, and senescence, resulting in an increase in endothelial cell damage, which could be protected by blocking these hemichannels. Thus, targeting Cx43 hemichannels may potentially exert radioprotective effects.
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http://dx.doi.org/10.3389/fphar.2020.00212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066501PMC
March 2020

Combination Therapy With Charged Particles and Molecular Targeting: A Promising Avenue to Overcome Radioresistance.

Front Oncol 2020 14;10:128. Epub 2020 Feb 14.

Radiobiology Unit, Belgian Nuclear Research Center (SCK•CEN), Mol, Belgium.

Radiotherapy plays a central role in the treatment of cancer patients. Over the past decades, remarkable technological progress has been made in the field of conventional radiotherapy. In addition, the use of charged particles (e.g., protons and carbon ions) makes it possible to further improve dose deposition to the tumor, while sparing the surrounding healthy tissues. Despite these improvements, radioresistance and tumor recurrence are still observed. Although the mechanisms underlying resistance to conventional radiotherapy are well-studied, scientific evidence on the impact of charged particle therapy on cancer cell radioresistance is restricted. The purpose of this review is to discuss the potential role that charged particles could play to overcome radioresistance. This review will focus on hypoxia, cancer stem cells, and specific signaling pathways of EGFR, NFκB, and Hedgehog as well as DNA damage signaling involving PARP, as mechanisms of radioresistance for which pharmacological targets have been identified. Finally, new lines of future research will be proposed, with a focus on novel molecular inhibitors that could be used in combination with charged particle therapy as a novel treatment option for radioresistant tumors.
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http://dx.doi.org/10.3389/fonc.2020.00128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033551PMC
February 2020

Quantification of DNA Double Strand Breaks and Oxidation Response in Children and Adults Undergoing Dental CBCT Scan.

Sci Rep 2020 02 7;10(1):2113. Epub 2020 Feb 7.

Belgian Nuclear Research Centre, Radiobiology Unit, SCK•CEN, Mol, Belgium.

Assessing the possible biological effects of exposure to low doses of ionizing radiation (IR) is one of the prime challenges in radiation protection, especially in medical imaging. Today, radiobiological data on cone beam CT (CBCT) related biological effects are scarce. In children and adults, the induction of DNA double strand breaks (DSBs) in buccal mucosa cells and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and antioxidant capacity in saliva samples after CBCT examination were examined. No DNA DSBs induction was observed in children nor adults. In children only, an increase in 8-oxo-dG levels was observed 30 minutes after CBCT. At the same time an increase in antioxidant capacity was observed in children, whereas a decrease was observed in adults. Our data indicate that children and adults react differently to IR doses associated with CBCT. Fully understanding these differences could lead to an optimal use of CBCT in different age categories as well as improved radiation protection guidelines.
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http://dx.doi.org/10.1038/s41598-020-58746-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005754PMC
February 2020

Abnormal retinal pigment epithelium melanogenesis as a major determinant for radiation-induced congenital eye defects.

Reprod Toxicol 2020 01 6;91:59-73. Epub 2019 Nov 6.

Radiobiology Unit, Interdisciplinary Biosciences, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre SCK-CEN, Boeretang 200, Mol 2400, Belgium. Electronic address:

Recent studies highlighted a link between ionizing radiation exposure during neurulation and birth defects such as microphthalmos and anophthalmos. Because the mechanisms underlying these defects remain largely unexplored, we irradiated pregnant C57BL/6J mice (1.0 Gy, X-rays) at embryonic day (E)7.5, followed by histological and gene/protein expression analyses at defined days. Irradiation impaired embryonic development at E9 and we observed a delayed pigmentation of the retinal pigment epithelium (RPE) at E11. In addition, a reduced RNA expression and protein abundance of critical eye-development genes (e.g. Pax6 and Lhx2) was observed. Furthermore, a decreased expression of Mitf, Tyr and Tyrp1 supported the radiation-induced perturbation in RPE pigmentation. Finally, via immunostainings for proliferation (Ki67) and mitosis (phosphorylated histone 3), a decreased mitotic index was observed in the E18 retina after exposure at E7.5. Overall, we propose a plausible etiological model for radiation-induced eye-size defects, with RPE melanogenesis as a major determining factor.
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http://dx.doi.org/10.1016/j.reprotox.2019.10.002DOI Listing
January 2020

Targeting the Hedgehog pathway in combination with X‑ray or carbon ion radiation decreases migration of MCF‑7 breast cancer cells.

Int J Oncol 2019 Dec 18;55(6):1339-1348. Epub 2019 Oct 18.

Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK•CEN), Antwerp, 2400 Mol, Belgium.

The use of carbon ion therapy for cancer treatment is becoming more widespread due to the advantages of carbon ions compared with X‑rays. Breast cancer patients may benefit from these advantages, as the surrounding healthy tissues receive a lower dose, and the increased biological effectiveness of carbon ions can better control radioresistant cancer cells. Accumulating evidence indicates that the Hedgehog (Hh) pathway is linked to the development and progression of breast cancer, as well as to resistance to X‑irradiation and the migratory capacity of cancer cells. Hence, there is an increasing interest in targeting the Hh pathway in combination with radiotherapy. Several studies have already investigated this treatment strategy with conventional radiotherapy. However, to the best of our knowledge, the combination of Hh inhibitors with particle therapy has not yet been explored. The aim of the present study was to investigate the potential of the Hh inhibitor GANT61 as an effective modulator of radiosensitivity and migration potential in MCF‑7 breast cancer cells, and compare potential differences between carbon ion irradiation and X‑ray exposure. Although Hh targeting was not able to radiosensitise cells to any radiation type used, the combination of GANT61 with X‑rays or carbon ions (energy: 95 MeV/n; linear energy transfer: 73 keV/µm) was more effective in decreasing MCF‑7 cell migration compared with either radiation type alone. Gene expression of the Hh pathway was affected to different degrees in response to X‑ray and carbon ion irradiation, as well as in response to the combination of GANT61 with irradiation. In conclusion, combining Hh inhibition with radiation (X‑rays or carbon ions) more effectively decreased breast cancer cell migration compared with radiation treatment alone.
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http://dx.doi.org/10.3892/ijo.2019.4901DOI Listing
December 2019

Gold nanoparticles affect the antioxidant status in selected normal human cells.

Int J Nanomedicine 2019 8;14:4991-5015. Epub 2019 Jul 8.

Radiobiology Research Unit, Interdisciplinary Biosciences, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK.CEN), Mol, Belgium.

This study evaluates the cytotoxicity of AuNPs coated with polyallylamine (AuNPs-PAA) and conjugated or not to the epidermal growth factor receptor (EGFR)-targeting antibody Cetuximab (AuNPs-PAA-Ctxb) in normal human kidney (HK-2), liver (THLE-2) and microvascular endothelial (TIME) cells, and compares it with two cancer cell lines that are EGFR-overexpressing (A431) or EGFR-negative (MDA-MB-453). Conjugation of Cetuximab to AuNPs-PAA increased the AuNPs-PAA-Ctxb interactions with cells, but reduced their cytotoxicity. TIME cells exhibited the strongest reduction in viability after exposure to AuNPs-PAA(±Ctxb), followed by THLE-2, MDA-MB-453, HK-2 and A431 cells. This cell type-dependent sensitivity was strongly correlated to the inhibition of thioredoxin reductase (TrxR) and glutathione reductase (GR), and to the depolarization of the mitochondrial membrane potential. Both are suggested to initiate apoptosis, which was indeed detected in a concentration- and time-dependent manner. The role of oxidative stress in AuNPs-PAA(±Ctxb)-induced cytotoxicity was demonstrated by co-incubation of the cells with N-acetyl L-cysteine (NAC), which significantly decreased apoptosis and mitochondrial membrane depolarization. This study helps to identify the cells and tissues that could be sensitive to AuNPs and deepens the understanding of the risks associated with the use of AuNPs in vivo.
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http://dx.doi.org/10.2147/IJN.S203546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635753PMC
September 2019

Exposure to Ionizing Radiation Triggers Prolonged Changes in Circular RNA Abundance in the Embryonic Mouse Brain and Primary Neurons.

Cells 2019 07 26;8(8). Epub 2019 Jul 26.

Radiobiology Unit, Belgian Nuclear Research Centre, SCK·CEN, 2400 Mol, Belgium.

The exposure of mouse embryos in utero and primary cortical neurons to ionizing radiation results in the P53-dependent activation of a subset of genes that is highly induced during brain development and neuronal maturation, a feature that these genes reportedly share with circular RNAs (circRNAs). Interestingly, some of these genes are predicted to express circular transcripts. In this study, we validated the abundance of the circular transcript variants of four P53 target genes (, , and ). These circular variants were overall more stable than their linear counterparts. They were furthermore highly enriched in the brain and their transcript levels continuously increase during subsequent developmental stages (from embryonic day 12 until adulthood), while no further increase could be observed for linear mRNAs beyond post-natal day 30. Finally, whereas radiation-induced expression of P53 target mRNAs peaks early after exposure, several of the circRNAs showed prolonged induction in irradiated embryonic mouse brain, primary mouse cortical neurons, and mouse blood. Together, our results indicate that the circRNAs from these P53 target genes are induced in response to radiation and they corroborate the findings that circRNAs may represent biomarkers of brain age. We also propose that they may be superior to mRNA as long-term biomarkers for radiation exposure.
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http://dx.doi.org/10.3390/cells8080778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721538PMC
July 2019

Single and fractionated ionizing radiation induce alterations in endothelial connexin expression and channel function.

Sci Rep 2019 06 20;9(1):4643. Epub 2019 Jun 20.

Radiobiology Unit, Belgian Nuclear Research Centre (SCK·CEN), Mol, Belgium.

Radiotherapy is an effective treatment for most tumor types. However, emerging evidence indicates an increased risk for atherosclerosis after ionizing radiation exposure, initiated by endothelial cell dysfunction. Interestingly, endothelial cells express connexin (Cx) proteins that are reported to exert proatherogenic as well as atheroprotective effects. Furthermore, Cxs form channels, gap junctions and hemichannels, that are involved in bystander signaling that leads to indirect radiation effects in non-exposed cells. We here aimed to investigate the consequences of endothelial cell irradiation on Cx expression and channel function. Telomerase immortalized human Coronary Artery/Microvascular Endothelial cells were exposed to single and fractionated X-rays. Several biological endpoints were investigated at different time points after exposure: Cx gene and protein expression, gap junctional dye coupling and hemichannel function. We demonstrate that single and fractionated irradiation induce upregulation of proatherogenic Cx43 and downregulation of atheroprotective Cx40 gene and protein levels in a dose-dependent manner. Single and fractionated irradiation furthermore increased gap junctional communication and induced hemichannel opening. Our findings indicate alterations in Cx expression that are typically observed in endothelial cells covering atherosclerotic plaques. The observed radiation-induced increase in Cx channel function may promote bystander signaling thereby exacerbating endothelial cell damage and atherogenesis.
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http://dx.doi.org/10.1038/s41598-019-39317-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584668PMC
June 2019

The Combination of Particle Irradiation With the Hedgehog Inhibitor GANT61 Differently Modulates the Radiosensitivity and Migration of Cancer Cells Compared to X-Ray Irradiation.

Front Oncol 2019 14;9:391. Epub 2019 May 14.

Radiobiology Unit, Belgian Nuclear Research Center (SCK•CEN), Institute for Environment, Health and Safety, Mol, Belgium.

Due to the advantages of charged particles compared to conventional radiotherapy, a vast increase is noted in the use of particle therapy in the clinic. These advantages include an improved dose deposition and increased biological effectiveness. Metastasis is still an important cause of mortality in cancer patients and evidence has shown that conventional radiotherapy can increase the formation of metastasizing cells. An important pathway involved in the process of metastasis is the Hedgehog (Hh) signaling pathway. Recent studies have demonstrated that activation of the Hh pathway, in response to X-rays, can lead to radioresistance and increased migratory, and invasive capabilities of cancer cells. Here, we investigated the effect of X-rays, protons, and carbon ions on cell survival, migration, and Hh pathway gene expression in prostate cancer (PC3) and medulloblastoma (DAOY) cell lines. In addition, the potential modulation of cell survival and migration by the Hh pathway inhibitor GANT61 was investigated. We found that in both cell lines, carbon ions were more effective in decreasing cell survival and migration as well as inducing more significant alterations in the Hh pathway genes compared to X-rays or protons. In addition, we show here for the first time that the Hh inhibitor GANT61 is able to sensitize DAOY medulloblastoma cells to particle radiation (proton and carbon ion) but not to conventional X-rays. This important finding demonstrates that the results of combination treatment strategies with X-ray radiotherapy cannot be automatically extrapolated to particle therapy and should be investigated separately. In conclusion, combining GANT61 with particle radiation could offer a benefit for specific cancer types with regard to cancer cell survival.
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http://dx.doi.org/10.3389/fonc.2019.00391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527843PMC
May 2019

Call to arms: need for radiobiology in molecular radionuclide therapy.

Eur J Nucl Med Mol Imaging 2019 Jul 8;46(8):1588-1590. Epub 2019 May 8.

IRCM, Institut de Recherche en Cancérologie de Montpellier, F-34298, Montpellier, France.

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http://dx.doi.org/10.1007/s00259-019-04334-3DOI Listing
July 2019

Food Supplements to Mitigate Detrimental Effects of Pelvic Radiotherapy.

Microorganisms 2019 Apr 3;7(4). Epub 2019 Apr 3.

Interdisciplinary Biosciences Group, Belgian Nuclear Research Centre (SCK•CEN), Boeretang 200, 2400 Mol, Belgium.

Pelvic radiotherapy has been frequently reported to cause acute and late onset gastrointestinal (GI) toxicities associated with significant morbidity and mortality. Although the underlying mechanisms of pelvic radiation-induced GI toxicity are poorly understood, they are known to involve a complex interplay between all cell types comprising the intestinal wall. Furthermore, increasing evidence states that the human gut microbiome plays a role in the development of radiation-induced health damaging effects. Gut microbial dysbiosis leads to diarrhea and fatigue in half of the patients. As a result, reinforcement of the microbiome has become a hot topic in various medical disciplines. To counteract GI radiotoxicities, apart from traditional pharmacological compounds, adjuvant therapies are being developed including food supplements like vitamins, prebiotics, and probiotics. Despite the easy, cheap, safe, and feasible approach to protect patients against acute radiation-induced toxicity, clinical trials have yielded contradictory results. In this review, a detailed overview is given of the various clinical, intestinal manifestations after pelvic irradiation as well as the role of the gut microbiome herein. Furthermore, whilst discussing possible strategies to prevent these symptoms, food supplements are presented as auspicious, prophylactic, and therapeutic options to mitigate acute pelvic radiation-induced GI injury by exploring their molecular mechanisms of action.
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http://dx.doi.org/10.3390/microorganisms7040097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518429PMC
April 2019

Growth of Endothelial Cells in Space and in Simulated Microgravity - a Comparison on the Secretory Level.

Cell Physiol Biochem 2019 ;52(5):1039-1060

Clinic for Plastic, Aesthetic and Hand Surgery, Otto von Guericke University Magdeburg, Magdeburg, Germany.

Background/aims: Endothelial cells exposed to the Random Positioning Machine (RPM) reveal three different phenotypes. They grow as a two-dimensional monolayer and form three-dimensional (3D) structures such as spheroids and tubular constructs. As part of the ESA-SPHEROIDS project we want to understand how endothelial cells (ECs) react and adapt to long-term microgravity.

Methods: During a spaceflight to the International Space Station (ISS) and a subsequent stay onboard, human ECs (EA.hy926 cell line) were cultured for 12 days in real microgravity inside an automatic flight hardware, specially designed for use in space. ECs were cultivated in the absence or presence of vascular endothelial growth factor, which had demonstrated a cell-protective effect on ECs exposed to an RPM simulating microgravity. After cell fixation in space and return of the samples, we examined cell morphology and analyzed supernatants by Multianalyte Profiling technology.

Results: The fixed samples comprised 3D multicellular spheroids and tube-like structures in addition to monolayer cells, which are exclusively observed during growth under Earth gravity (1g). Within the 3D aggregates we detected enhanced collagen and laminin. The supernatant analysis unveiled alterations in secretion of several growth factors, cytokines, and extracellular matrix components as compared to cells cultivated at 1g or on the RPM. This confirmed an influence of gravity on interacting key proteins and genes and demonstrated a flight hardware impact on the endothelial secretome.

Conclusion: Since formation of tube-like aggregates was observed only on the RPM and during spaceflight, we conclude that microgravity may be the major cause for ECs' 3D aggregation.
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http://dx.doi.org/10.33594/000000071DOI Listing
May 2019

Modulation of Iberian Ribbed Newt Complement Component C3 by Stressors Similar to those Encountered during a Stay Onboard the International Space Station.

Int J Mol Sci 2019 Mar 29;20(7). Epub 2019 Mar 29.

Stress Immunity Pathogens Laboratory, EA 7300, Faculty of Medicine, Université de Lorraine, 9 avenue de la Foret de Haye, F-54500 Vandœuvre-lès-Nancy, France.

The complement system plays an important role in inflammation, innate and acquired immunity, as well as homeostasis. Despite these functions, the effects of spaceflight conditions on the complement system have not yet been intensively studied. Consequently, we investigated the effects of five types of chronic stressors, similar to those encountered during a stay onboard the International Space Station, on C3 expression in larvae of the urodele amphibian . We focused on C3 because it is a critical component of this system. These studies were completed by the analysis of adult mice exposed to two models of inflight stressors. Our data show that simulating space radiation, or combining a modification of the circadian rhythm with simulated microgravity, affects the amount of C3 proteins. These results suggest that C3 expression could be modified under real spaceflight conditions, potentially increasing the risk of inflammation and associated tissue damage.
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http://dx.doi.org/10.3390/ijms20071579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6479312PMC
March 2019

Method validation to assess in vivo cellular and subcellular changes in buccal mucosa cells and saliva following CBCT examinations.

Dentomaxillofac Radiol 2019 Sep 5;48(6):20180428. Epub 2019 Apr 5.

Belgian Nuclear Research Centre, Radiobiology Unit, SCK•CEN, Mol, Belgium.

Objectives: Cone-beam CT (CBCT) is a medical imaging technique used in dental medicine. However, there are no conclusive data available indicating that exposure to X-ray doses used by CBCT are harmless. We aim, for the first time, to characterize the potential age-dependent cellular and subcellular effects related to exposure to CBCT imaging. Current objective is to describe and validate the protocol for characterization of cellular and subcellular changes after diagnostic CBCT.

Methods: Development and validation of a dedicated two-part protocol: 1) assessing DNA double strand breaks (DSBs) in buccal mucosal (BM) cells and 2) oxidative stress measurements in saliva samples. BM cells and saliva samples are collected prior to and 0.5 h after CBCT examination. BM cells are also collected 24 h after CBCT examination. DNA DSBs are monitored in BM cells via immunocytochemical staining for γH2AX and 53BP1. 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and total antioxidant capacity are measured in saliva to assess oxidative damage.

Results: Validation experiments show that sufficient BM cells are collected (97.1 ± 1.4 %) and that γH2AX/53BP1 foci can be detected before and after CBCT examination. Collection and analysis of saliva samples, either sham exposed or exposed to IR, show that changes in 8-oxo-dG and total antioxidant capacity can be detected in saliva samples after CBCT examination.

Conclusion: The DIMITRA Research Group presents a two-part protocol to analyze potential age-related biological differences following CBCT examinations. This protocol was validated for collecting BM cells and saliva and for analyzing these samples for DNA DSBs and oxidative stress markers, respectively.
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http://dx.doi.org/10.1259/dmfr.20180428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747439PMC
September 2019

Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain.

Neurobiol Dis 2019 07 14;127:398-409. Epub 2019 Mar 14.

Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; Department of Molecular Biotechnology, Ghent University, Coupure Links 653, 9000 Ghent, Belgium.

We have exploited whole brain microscopy to map the progressive deposition of hyperphosphorylated tau in intact, cleared mouse brain. We found that the three-dimensional spreading pattern of hyperphosphorylated tau in the brain of an aging Tau.P301L mouse model did not resemble that observed in AD patients. Injection of synthetic or patient-derived tau fibrils in the CA1 region resulted in a more faithful spreading pattern. Atlas-guided volumetric analysis showed a connectome-dependent spreading from the injection site and also revealed hyperphosphorylated tau deposits beyond the direct anatomical connections. In fibril-injected brains, we also detected a persistent subpopulation of rod-like and swollen microglia. Furthermore, we showed that the hyperphosphorylated tau load could be reduced by intracranial co-administration of, and to a lesser extent, by repeated systemic dosing with an antibody targeting the microtubule-binding domain of tau. Thus, the combination of targeted seeding and in toto staging of tau pathology allowed assessing regional vulnerability in a comprehensive manner, and holds potential as a preclinical drug validation tool.
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http://dx.doi.org/10.1016/j.nbd.2019.03.010DOI Listing
July 2019

An appraisal of folates as key factors in cognition and ageing-related diseases.

Crit Rev Food Sci Nutr 2020 7;60(5):722-739. Epub 2019 Feb 7.

Radiobiology Unit, Belgian Nuclear Research Centre SCK•CEN, Mol, Belgium.

Folic acid (FA) is often consumed as a food supplement and can be found in fortified staple foods in various western countries. Even though FA supplementation during pregnancy is known to prevent severe congenital anomalies in the developing child (e.g., neural tube defects), much less is known about its influence on cognition and neurological functioning. In this review, we address the advances in this field and situate how folate intake during pregnancy, postnatal life, adulthood and in the elderly affects cognition. In addition, an association between folate status and ageing, dementia and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis is discussed. While its role in the incidence and severity of these diseases is becoming apparent, the underlying action of folates and related metabolites remains elusive. Finally, the potential of FA as a nutraceutical has been proposed, although the efficacy will highly depend on the interplay with other micronutrients, the disease stage and the duration of supplementation. Hence, the lack of consistent data urges for more animal studies and (pre)clinical trials in humans to ascertain a potential beneficial role for folates in the treatment or amelioration of cognitive decline and ageing-related disorders.
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http://dx.doi.org/10.1080/10408398.2018.1549017DOI Listing
March 2020

Modulations of Neuroendocrine Stress Responses During Confinement in Antarctica and the Role of Hypobaric Hypoxia.

Front Physiol 2018 26;9:1647. Epub 2018 Nov 26.

Laboratory of Translational Research "Stress and Immunity", Department of Anaesthesiology, University Hospital, LMU Munich, Munich, Germany.

The Antarctic continent is an environment of extreme conditions. Only few research stations exist that are occupied throughout the year. The German station Neumayer III and the French-Italian Concordia station are such research platforms and human outposts. The seasonal shifts of complete daylight (summer) to complete darkness (winter) as well as massive changes in outside temperatures (down to -80°C at Concordia) during winter result in complete confinement of the crews from the outside world. In addition, the crew at Concordia is subjected to hypobaric hypoxia of ∼650 hPa as the station is situated at high altitude (3,233 m). We studied three expedition crews at Neumayer III (sea level) ( = 16) and two at Concordia (high altitude) ( = 15) to determine the effects of hypobaric hypoxia on hormonal/metabolic stress parameters [endocannabinoids (ECs), catecholamines, and glucocorticoids] and evaluated the psychological stress over a period of 11 months including winter confinement. In the (sea level) crew, EC and -acylethanolamide (NAE) concentrations increased significantly already at the beginning of the deployment ( < 0.001) whereas catecholamines and cortisol remained unaffected. Over the year, ECs and NAEs stayed elevated and fluctuated before slowly decreasing till the end of the deployment. The classical stress hormones showed small increases in the last third of deployment. By contrast, at (high altitude), norepinephrine concentrations increased significantly at the beginning ( < 0.001) which was paralleled by low EC levels. Prior to the second half of deployment, norepinephrine declined constantly to end on a low plateau level, whereas then the EC concentrations increased significantly in this second period during the overwintering ( < 0.001). Psychometric data showed no significant changes in the crews at either station. These findings demonstrate that exposition of healthy humans to the physically challenging extreme environment of Antarctica (i) has a distinct modulating effect on stress responses. Additionally, (ii) acute high altitude/hypobaric hypoxia at the beginning seem to trigger catecholamine release that downregulates the EC response. These results (iii) are not associated with psychological stress.
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http://dx.doi.org/10.3389/fphys.2018.01647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276713PMC
November 2018

Pathological effects of ionizing radiation: endothelial activation and dysfunction.

Cell Mol Life Sci 2019 Feb 30;76(4):699-728. Epub 2018 Oct 30.

Radiobiology Unit, Belgian Nuclear Research Centre (SCK•CEN), Mol, Belgium.

The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. Epidemiological data show that high doses of ionizing radiation lead to cardiovascular disease over time. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases.
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http://dx.doi.org/10.1007/s00018-018-2956-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514067PMC
February 2019

Gene expression-based biodosimetry for radiological incidents: assessment of dose and time after radiation exposure.

Int J Radiat Biol 2019 01 24;95(1):64-75. Epub 2018 Sep 24.

a Interdisciplinary Biosciences Group, Belgian Nuclear Research Centre, SCK•CEN, Mol , Belgium.

Purpose: In order to ensure efficient use of medical resources following a radiological incident, there is an urgent need for high-throughput time-efficient biodosimetry tools. In the present study, we tested the applicability of a gene expression signature for the prediction of exposure dose as well as the time elapsed since irradiation.

Materials And Methods: We used whole blood samples from seven healthy volunteers as reference samples (X-ray doses: 0, 25, 50, 100, 500, 1000, and 2000 mGy; time points: 8, 12, 24, 36 and 48 h) and samples from seven other individuals as 'blind samples' (20 samples in total).

Results: Gene expression values normalized to the reference gene without normalization to the unexposed controls were sufficient to predict doses with a correlation coefficient between the true and the predicted doses of 0.86. Importantly, we could also classify the samples according to the time since exposure with a correlation coefficient between the true and the predicted time point of 0.96. Because of the dynamic nature of radiation-induced gene expression, this feature will be of critical importance for adequate gene expression-based dose prediction in a real emergency situation. In addition, in this study we also compared different methodologies for RNA extraction available on the market and suggested the one most suitable for emergency situation which does not require on-spot availability of any specific reagents or equipment.

Conclusions: Our results represent an important advancement in the application of gene expression for biodosimetry purposes.
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http://dx.doi.org/10.1080/09553002.2018.1511926DOI Listing
January 2019

Immune sensitization during 1 year in the Antarctic high-altitude Concordia Environment.

Allergy 2019 01 20;74(1):64-77. Epub 2018 Nov 20.

Department of Anaesthesiology, Laboratory of Translational Research "Stress and Immunity" University Hospital, LMU Munich, Munich, Germany.

Background: Antarctica is a challenging environment for humans. It serves as a spaceflight ground analog, reflecting some conditions of long-duration exploration class space missions. The French-Italian Concordia station in interior Antarctica is a high-fidelity analog, located 1000 km from the coast, at an altitude of 3232 m. The aim of this field study was to characterize the extent, dynamics, and key mechanisms of the immune adaptation in humans overwintering at Concordia for 1 year.

Methods: This study assessed immune functions in fourteen crewmembers. Quantitative and phenotypic analyses from human blood were performed using onsite flow cytometry together with specific tests on receptor-dependent and receptor-independent functional innate and adaptive immune responses. Transcriptome analyses and quantitative identification of key response genes were assessed.

Results: Dynamic immune activation and a two-step escalation/activation pattern were observed. The early phase was characterized by moderately sensitized global immune responses, while after 3-4 months, immune responses were highly upregulated. The cytokine responses to an ex vivo stimulation were markedly raised above baseline levels. These functional observations were reflected at the gene transcriptional level in particular through the modulation of hypoxia-driven pathways.

Conclusions: This study revealed unique insights into the extent, dynamics, and genetics of immune dysfunctions in humans exposed for 1 year to the Antarctic environment at the Concordia station. The scale of immune function was imbalanced toward a sensitizing of inflammatory pathways.
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http://dx.doi.org/10.1111/all.13545DOI Listing
January 2019