scholarly journals Out-of-Field Hippocampus from Partial-Body Irradiated Mice Displays Changes in Multi-Omics Profile and Defects in Neurogenesis

2021 ◽  
Vol 22 (8) ◽  
pp. 4290
Author(s):  
Simonetta Pazzaglia ◽  
Barbara Tanno ◽  
Francesca Antonelli ◽  
Paola Giardullo ◽  
Gabriele Babini ◽  
...  
Keyword(s):  
Radiation Effects ◽  
Critical Role ◽  
Hippocampal Neurogenesis ◽  
Whole Body ◽  
Potential Contribution ◽  
X Rays ◽  
Neurocognitive Dysfunction ◽  
Post Irradiation ◽  
Radiation Induced ◽  
Partial Body

The brain undergoes ionizing radiation exposure in many clinical situations, particularly during radiotherapy for brain tumors. The critical role of the hippocampus in the pathogenesis of radiation-induced neurocognitive dysfunction is well recognized. The goal of this study is to test the potential contribution of non-targeted effects in the detrimental response of the hippocampus to irradiation and to elucidate the mechanisms involved. C57Bl/6 mice were whole body (WBI) or partial body (PBI) irradiated with 0.1 or 2.0 Gy of X-rays or sham irradiated. PBI consisted of the exposure of the lower third of the mouse body, whilst the upper two thirds were shielded. Hippocampi were collected 15 days or 6 months post-irradiation and a multi-omics approach was adopted to assess the molecular changes in non-coding RNAs, proteins and metabolic levels, as well as histological changes in the rate of hippocampal neurogenesis. Notably, at 2.0 Gy the pattern of early molecular and histopathological changes induced in the hippocampus at 15 days following PBI were similar in quality and quantity to the effects induced by WBI, thus providing a proof of principle of the existence of out-of-target radiation response in the hippocampus of conventional mice. We detected major alterations in DAG/IP3 and TGF-β signaling pathways as well as in the expression of proteins involved in the regulation of long-term neuronal synaptic plasticity and synapse organization, coupled with defects in neural stem cells self-renewal in the hippocampal dentate gyrus. However, compared to the persistence of the WBI effects, most of the PBI effects were only transient and tended to decrease at 6 months post-irradiation, indicating important mechanistic difference. On the contrary, at low dose we identified a progressive accumulation of molecular defects that tended to manifest at later post-irradiation times. These data, indicating that both targeted and non-targeted radiation effects might contribute to the pathogenesis of hippocampal radiation-damage, have general implications for human health.

Effect of Two Graded Doses of Whole-Body X-Irradiation and Radioprotection by the Use of S-Phenethyl Formamidino 4 (N-Ethyl Isothioamide) Morpholine Dihydrochloride

1983 ◽  
Vol 22 (05) ◽  
pp. 237-245 ◽  
Author(s):  
P. K. Chaturvedi ◽  
S. N. Pandeya ◽  
S. S. Hasan
Keyword(s):  
Radiation Effects ◽  
Whole Body ◽  
X Irradiation ◽  
Radiation Induced ◽  
Induced Changes ◽  
The Brain

The protection offered by a newly synthesized compound (S-phenethyl-formamidino-4(N-ethyl isothioamide) morpholine dihydrochloride) against radiation effects on DNA, RNA and protein biosynthetic processes in the brain, and on metabolites of 5-HT and nor-adrenalin, i.e., 5-HIAA and VMA, in the urine, including the radiobiological damage to thyroid and testes, was evaluated. The use of the compound prior to irradiation prevented radiation-induced changes in the thyroid and testes. The radiation-induced alterations in the pattern of DNA, RNA, protein in the brain, and in 5-HIAA and VMA in urine could be averted by treatment with this compound prior to each dose of X-irradiation.

scholarly journals Metabolomic Studies of Tissue Injury in Nonhuman Primates Exposed to Gamma-Radiation

2019 ◽  
Vol 20 (13) ◽  
pp. 3360 ◽  
Author(s):  
Amrita K. Cheema ◽  
Khyati Y. Mehta ◽  
Meena U. Rajagopal ◽  
Stephen Y. Wise ◽  
Oluseyi O. Fatanmi ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Radiation Effects ◽  
Nonhuman Primates ◽  
Clinical Symptoms ◽  
Tissue Injury ◽  
Predictive Biomarkers ◽  
Whole Body ◽  
Biomarkers Of Exposure ◽  
Radiation Induced ◽  
Over Time

Exposure to ionizing radiation induces a complex cascade of systemic and tissue-specific responses that lead to functional impairment over time in the surviving population. However, due to the lack of predictive biomarkers of tissue injury, current methods for the management of survivors of radiation exposure episodes involve monitoring of individuals over time for the development of adverse clinical symptoms and death. Herein, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that were exposed to a single dose of 7.2 Gy whole-body 60Co γ-radiation that either survived or succumbed to radiation toxicities over a 60-day period. This study involved the delineation of the radiation effects in the liver, kidney, jejunum, heart, lung, and spleen. We found robust metabolic changes in the kidney and liver and modest changes in other tissue types at the 60-day time point in a cohort of NHPs. Remarkably, we found significant elevation of long-chain acylcarnitines in animals that were exposed to radiation across multiple tissue types underscoring the role of this class of metabolites as a generic indicator of radiation-induced normal tissue injury. These studies underscore the utility of a metabolomics approach for delineating anticipatory biomarkers of exposure to ionizing radiation.

scholarly journals Accelerated senescence in skin in a murine model of radiation-induced multi-organ injury

2017 ◽  
Vol 58 (5) ◽  
pp. 636-646 ◽  
Author(s):  
Elizabeth A McCart ◽  
Rajesh L Thangapazham ◽  
Eric D Lombardini ◽  
Steven R Mog ◽  
Ronald Allan M Panganiban ◽  
...  
Keyword(s):  
Stem Cells ◽  
Histological Evaluation ◽  
Radiation Dermatitis ◽  
Stem Cell Population ◽  
X Rays ◽  
Epithelial Stem Cells ◽  
Post Irradiation ◽  
Radiation Induced ◽  
Accelerated Senescence ◽  
P21 Waf1

Abstract Accidental high-dose radiation exposures can lead to multi-organ injuries, including radiation dermatitis. The types of cellular damage leading to radiation dermatitis are not completely understood. To identify the cellular mechanisms that underlie radiation-induced skin injury in vivo, we evaluated the time-course of cellular effects of radiation (14, 16 or 17 Gy X-rays; 0.5 Gy/min) in the skin of C57BL/6 mice. Irradiation of 14 Gy induced mild inflammation, observed histologically, but no visible hair loss or erythema. However, 16 or 17 Gy radiation induced dry desquamation, erythema and mild ulceration, detectable within 14 days post-irradiation. Histological evaluation revealed inflammation with mast cell infiltration within 14 days. Fibrosis occurred 80 days following 17 Gy irradiation, with collagen deposition, admixed with neutrophilic dermatitis, and necrotic debris. We found that in cultures of normal human keratinocytes, exposure to 17.9 Gy irradiation caused the upregulation of p21/waf1, a marker of senescence. Using western blot analysis of 17.9 Gy–irradiated mice skin samples, we also detected a marker of accelerated senescence (p21/waf1) 7 days post-irradiation, and a marker of cellular apoptosis (activated caspase-3) at 30 days, both preceding histological evidence of inflammatory infiltrates. Immunohistochemistry revealed reduced epithelial stem cells from hair follicles 14–30 days post-irradiation. Furthermore, p21/waf1 expression was increased in the region of the hair follicle stem cells at 14 days post 17 Gy irradiation. These data indicate that radiation induces accelerated cellular senescence in the region of the stem cell population of the skin.

scholarly journals Radiation-Induced Alterations in Proliferation, Migration, and Adhesion in Lens Epithelial Cells and Implications for Cataract Development

2022 ◽  
Vol 9 (1) ◽  
pp. 29
Author(s):  
Graysen Vigneux ◽  
Jake Pirkkanen ◽  
Taylor Laframboise ◽  
Hallie Prescott ◽  
Sujeenthar Tharmalingam ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Radiation Effects ◽  
Lens Epithelial Cells ◽  
Boyden Chamber ◽  
X Rays ◽  
Functional Changes ◽  
Transcriptional Alterations ◽  
Transcriptional Changes ◽  
Radiation Induced ◽  
Cataract Development

The lens of the eye is one of the most radiosensitive tissues. Although the exact mechanism of radiation-induced cataract development remains unknown, altered proliferation, migration, and adhesion have been proposed as factors. Lens epithelial cells were exposed to X-rays (0.1–2 Gy) and radiation effects were examined after 12 h and 7 day. Proliferation was quantified using an MTT assay, migration was measured using a Boyden chamber and wound-healing assay, and adhesion was assessed on three extracellular matrices. Transcriptional changes were also examined using RT-qPCR for a panel of genes related to these processes. In general, a nonlinear radiation response was observed, with the greatest effects occurring at a dose of 0.25 Gy. At this dose, a reduction in proliferation occurred 12 h post irradiation (82.06 ± 2.66%), followed by an increase at 7 day (116.16 ± 3.64%). Cell migration was increased at 0.25 Gy, with rates 121.66 ± 6.49% and 232.78 ± 22.22% greater than controls at 12 h and 7 day respectively. Cell adhesion was consistently reduced above doses of 0.25 Gy. Transcriptional alterations were identified at these same doses in multiple genes related to proliferation, migration, and adhesion. Overall, this research began to elucidate the functional changes that occur in lens cells following radiation exposure, thereby providing a better mechanistic understanding of radiation-induced cataract development.

ATM and RAD51 Repair Pathways in Human Lymphocytes Irradiated with 70 MeV Therapeutic Proton Beam

2021 ◽  
Author(s):  
Agnieszka Panek ◽  
Justyna Miszczyk
Keyword(s):  
Proton Beam ◽  
Human Lymphocytes ◽  
Strand Break ◽  
Double Strand Break ◽  
Double Strand Break Repair ◽  
X Rays ◽  
X Ray ◽  
Post Irradiation ◽  
Repair Protein ◽  
Radiation Induced

The repair of radiation-induced DNA damage is a key factor differentiating patients in terms of the therapeutic efficacy and toxicity to surrounding normal tissue. Proton energy substantially determines the types of cancers that can be treated. The present work investigated the DNA double-strand break repair systems, represented by phosphorylated ATM and Rad51. The status of proton therapy energy used to treat major types of cancer is summarized. Here, human lymphocytes from eight healthy donors (male and female) were irradiated with a spread-out Bragg peak using a therapeutic 70 MeV proton beam or with reference X rays. For both types of radiation, the kinetics of pATM and Rad51 repair protein activation (0–24 h) were estimated as determinants of homologous and non-homologous double-strand break repair. Additionally, γ-H2AX was used as the gold standard marker of double-strand breaks. Our results showed that at 30 min postirradiation there was significantly greater accumulation of γ-H2AX (0.6-fold), pATM (2.0-fold), and Rad51 (0.6-fold) in the proton-irradiated cells compared with the X-ray-treated cells. At 24 h post irradiation, for both types of radiation and all investigated proteins, the foci number was still significantly higher when compared with control. Furthermore, the mean value of pATM and Rad51 repair effectiveness was higher in cells exposed to protons than in cells exposed to X rays; however, the difference was significant only for pATM. The largest inter-individual differences in the repair capabilities were noted for Rad51. The association between the frequency of repair protein foci and the frequency of lymphocyte viability at 1 h post irradiation showed a positive correlation for protons but a negative correlation for X rays. These findings indicate that the accumulation of radiation-induced repair protein foci after proton versus X-ray irradiation differs between patients, consequently affecting the cellular responses to particle therapy and conventional radiation therapy.

scholarly journals Phenotypic and Functional Characteristics of Exosomes Derived from Irradiated Mouse Organs and Their Role in the Mechanisms Driving Non-Targeted Effects

2020 ◽  
Vol 21 (21) ◽  
pp. 8389
Author(s):  
Seda Tuncay Cagatay ◽  
Ammar Mayah ◽  
Mariateresa Mancuso ◽  
Paola Giardullo ◽  
Simonetta Pazzaglia ◽  
...  
Keyword(s):  
Membrane Vesicles ◽  
Mouse Embryonic Fibroblast ◽  
Whole Body ◽  
Recipient Mouse ◽  
Oxygen Species ◽  
Cellular Viability ◽  
Radiation Induced ◽  
Partial Body ◽  
Embryonic Fibroblast

Molecular communication between irradiated and unirradiated neighbouring cells initiates radiation-induced bystander effects (RIBE) and out-of-field (abscopal) effects which are both an example of the non-targeted effects (NTE) of ionising radiation (IR). Exosomes are small membrane vesicles of endosomal origin and newly identified mediators of NTE. Although exosome-mediated changes are well documented in radiation therapy and oncology, there is a lack of knowledge regarding the role of exosomes derived from inside and outside the radiation field in the early and delayed induction of NTE following IR. Therefore, here we investigated the changes in exosome profile and the role of exosomes as possible molecular signalling mediators of radiation damage. Exosomes derived from organs of whole body irradiated (WBI) or partial body irradiated (PBI) mice after 24 h and 15 days post-irradiation were transferred to recipient mouse embryonic fibroblast (MEF) cells and changes in cellular viability, DNA damage and calcium, reactive oxygen species and nitric oxide signalling were evaluated compared to that of MEF cells treated with exosomes derived from unirradiated mice. Taken together, our results show that whole and partial-body irradiation increases the number of exosomes, instigating changes in exosome-treated MEF cells, depending on the source organ and time after exposure.

scholarly journals IKKβ Inhibitor IMD-0354 Attenuates Radiation Damage in Whole-body X-Irradiated Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Kengo Waga ◽  
Masaru Yamaguchi ◽  
Shuta Miura ◽  
Teruki Nishida ◽  
Akiko Itai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Survival Rate ◽  
Critical Role ◽  
Reactive Oxygen Species Generation ◽  
Whole Body ◽  
Spleen Cells ◽  
Antitumor Effects ◽  
X Irradiation ◽  
Radiation Induced ◽  
Complex Signaling

Nuclear factor-kappa B (NF-κB) transcription factor plays a critical role in regulating radiation-induced inflammatory and immune responses. Intracellular reactive oxygen species generation induces the activation of NF-κB via the inhibitor of κB (IκB) kinase (IKK) complex signaling. Previous studies have reported that the inhibition of IKK-driven NF-κB activation offers a therapeutic strategy for managing inflammatory disorders and various cancers, but it has additionally been reported that treatment targeting NF-κB also shows a radioprotective effect. IMD-0354 is an IKKβ inhibitor that blocks IκBα phosphorylation in the NF-κB pathway. This compound is known to exert anti-inflammatory and antitumor effects, but its radioprotective effects are unclear. Therefore, in the present study, we examined whether or not IMD-0354 has a mitigative effect on radiation-induced damages in mice. IMD-0354 was dissolved in soybean oil and subcutaneously administered to C57BL/6J Jcl mice for 3 consecutive days after 7 Gy of whole-body X-irradiation. The survival rate on day 30 and the NF-κB p65 and IκBα in bone marrow and spleen cells based on flow cytometry were assessed. IMD-0354 administration significantly suppressed the lethality induced by whole-body X-irradiation, and the survival rate increased by 83%. The NF-κB p65 and IκBα in bone marrow and spleen cells were significantly lower in IMD-0354-treated mice than in irradiated mice, suggesting that the IKKβ inhibitor IMD-0354 exerts a radiomitigative effect by suppressing the NF-κB.

scholarly journals The elevation of blood levels of zinc protoporphyrin in mice following whole body irradiation

Blood ◽  
1984 ◽  
Vol 63 (5) ◽  
pp. 1159-1167 ◽  
Author(s):  
TL Walden ◽  
PS Draganac ◽  
WR Farkas
Keyword(s):  
Iron Deficiency ◽  
Radiation Injury ◽  
Whole Body ◽  
Deficiency Anemia ◽  
Blood Levels ◽  
Zinc Protoporphyrin ◽  
X Rays ◽  
Radiation Induced ◽  
Sublethal Doses ◽  
Lethal Doses

Abstract Elevation of zinc protoporphyrin (ZPP) levels in the blood has served as an indicator of lead poisoning and iron deficiency anemia for many years. We have discovered that sublethal doses of whole body irradiation with x-rays also elevates ZPP 2–3-fold over normal levels. The ZPP level does not begin to increase until days 12–14 postirradiation and peaks between days 18 and 20 before returning to normal levels between days 28 and 35. Increasing the radiation dose delays the onset of the rise in ZPP, but does not affect the magnitude of the elevation. At lethal doses, ZPP elevation is not observed. Neither of the two previously described mechanisms that cause elevations of ZPP, namely iron deficiency and inhibition of ferrochelatase, are responsible for the radiation-induced elevation of ZPP. The elevation of ZPP appears to be correlated with the recovery of the hematopoietic system from radiation injury.

Volitional Activity Response of Rats to Partial-Body X-Irradiation

1957 ◽  
Vol 189 (1) ◽  
pp. 15-20 ◽  
Author(s):  
D. C. Jones ◽  
D. J. Kimeldorf ◽  
G. K. Osborn ◽  
T. J. Castanera ◽  
D. O. Rubadeau
Keyword(s):  
The Body ◽  
Transient Increase ◽  
Whole Body ◽  
X Rays ◽  
Control Activity ◽  
Initial Decrease ◽  
Significant Depression ◽  
X Irradiation ◽  
Partial Body ◽  
High Doses

Shielding of the abdomen during x-irradiation was used to test the hypothesis that the initial decrease in the volitional activity of rats observed after whole-body x-irradiation is related primarily to irradiation of the abdomen. Exposure of the abdomen to 200 r, or of the remaining half of the body to 200 or 600 r did not result in a significant depression in activity. When the abdomen was exposed to 600 or 750 r, however, a depression in activity was observed, with a minimum on the 3rd day postirradiation, followed by increasing activity. When animals were exposed to relatively high doses (1500 or 2000 r) with the abdomen shielded, or with only the head exposed (1500 r), there was an immediate depression in activity on the 1st day postirradiation, then a transient increase in activity to values equal to or well above control levels, followed by a rapid decrease below control activity, and then by increasing activity. The transient increase above control activity was duplicated by pair-feeding nonirradiated animals to the head-exposed group. It appears that the initial decrease in volitional activity may be mediated by altered gastrointestinal function, particularly with respect to the 3rd day postirradiation. In abdomen-shielded or head-exposed animals subjected to higher doses of x-rays, the transient rise in activity appears to be related to restricted food intake, probably as a result of radiation damage of the oral mucosa. The subsequent depression in volitional activity in these animals may be related to central nervous system injury.

scholarly journals Age-dependent effects on radiation-induced carcinogenesis in the rat thyroid

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mutsumi Matsuu-Matsuyama ◽  
Kazuko Shichijo ◽  
Katsuya Matsuda ◽  
Nariaki Fujimoto ◽  
Hisayoshi Kondo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Damage Response ◽  
X Rays ◽  
Thyroid Tumors ◽  
Ki 67 ◽  
Post Irradiation ◽  
Damage Response ◽  
Radiation Induced ◽  
Rat Thyroid

AbstractChildhood radiation exposure is a known thyroid cancer risk factor. This study evaluated the effects of age on radiation-induced thyroid carcinogenesis in rats irradiated with 8 Gy X-rays. We analyzed cell proliferation, cell death, DNA damage response, and autophagy-related markers in 4-week-old (4W) and 7-month-old (7M) rats and the incidence of thyroid tumors in 4W, 4-month-old (4M), and 7M rats 18 months after irradiation. Cell death and DNA damage response were increased in 4W rats compared to those in controls at 1 month post-irradiation. More Ki-67-positive cells were observed in 4W rats at 12 months post-irradiation. Thyroid tumors were confirmed in 61.9% (13/21), 63.6% (7/11), and 33.3% (2/6) of irradiated 4W, 4M, and 7M rats, respectively, compared to 0%, 14.3% (1/7), and 16.7% (1/6) in the respective nonirradiated controls. There were 29, 9, and 2 tumors in irradiated 4W, 4M, and 7M rats, respectively. The expression of several autophagy components was downregulated in the area surrounding radiation-induced thyroid carcinomas in 4W and 7M rats. LC3 and p62 expression levels decreased in radiation-induced follicular carcinoma in 4W rats. Radiosensitive cells causing thyroid tumors may be more prevalent in young rats, and abrogation of autophagy may be associated with radiation-induced thyroid carcinogenesis.

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