RESUMEN
Chronic exposure to low-dose ionizing radiation is associated with an increased risk of cardiovascular disease. Alteration in energy metabolism has been suggested to contribute to radiation-induced heart pathology, mitochondrial dysfunction being a hallmark of this disease. The goal of this study was to investigate the regulatory role of acetylation in heart mitochondria in the long-term response to chronic radiation. ApoE-deficient C57Bl/6J mice were exposed to low-dose-rate (20 mGy/day) gamma radiation for 300 days, resulting in a cumulative total body dose of 6.0 Gy. Heart mitochondria were isolated and analyzed using quantitative proteomics. Radiation-induced proteome and acetylome alterations were further validated using immunoblotting, enzyme activity assays, and ELISA. In total, 71 proteins showed peptides with a changed acetylation status following irradiation. The great majority (94%) of the hyperacetylated proteins were involved in the TCA cycle, fatty acid oxidation, oxidative stress response and sirtuin pathway. The elevated acetylation patterns coincided with reduced activity of mitochondrial sirtuins, increased the level of Acetyl-CoA, and were accompanied by inactivation of major cardiac metabolic regulators PGC-1 alpha and PPAR alpha. These observations suggest that the changes in mitochondrial acetylation after irradiation is associated with impairment of heart metabolism. We propose a novel mechanism involved in the development of late cardiac damage following chronic irradiation.
Asunto(s)
Proteínas Mitocondriales/metabolismo , Miocitos Cardíacos/metabolismo , Procesamiento Proteico-Postraduccional , Sirtuinas/genética , Irradiación Corporal Total/efectos adversos , Acetilación , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Regulación hacia Abajo , Femenino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/efectos de la radiación , Proteínas Mitocondriales/efectos de la radiación , Miocitos Cardíacos/efectos de la radiación , PPAR alfa/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismoRESUMEN
PURPOSE: The radiation protection community has been particularly attentive to the risks of delayed effects on offspring from low dose or low dose-rate exposures to ionizing radiation. Despite this, the current epidemiologic studies and scientific data are still insufficient to provide the necessary evidence for improving risk assessment guidelines. This literature review aims to inform future studies on multigenerational and transgenerational effects. It primarily focuses on animal studies involving in utero exposure and discusses crucial elements for interpreting the results. These elements include in utero exposure scenarios relative to the developmental stages of the embryo/fetus, and the primary biological mechanisms responsible for transmitting heritable or hereditary effects to future generations. The review addresses several issues within the contexts of both multigenerational and transgenerational effects, with a focus on hereditary perspectives. CONCLUSIONS: Knowledge consolidation in the field of Developmental Origins of Health and Disease (DOHaD) has led us to propose a new study strategy. This strategy aims to address the transgenerational effects of in utero exposure to low dose and low dose-rate radiation. Within this concept, there is a possibility that disruption of epigenetic programming in embryonic and fetal cells may occur. This disruption could lead to metabolic dysfunction, which in turn may cause abnormal responses to future environmental challenges, consequently increasing disease risk. Lastly, we discuss methodological limitations in our studies. These limitations are related to cohort size, follow-up time, model radiosensitivity, and analytical techniques. We propose scientific and analytical strategies for future research in this field.
Asunto(s)
Efectos Tardíos de la Exposición Prenatal , Humanos , Femenino , Animales , Embarazo , Radiación Ionizante , Medición de Riesgo , Epigénesis Genética/efectos de la radiación , Exposición a la Radiación/efectos adversosRESUMEN
Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE-/-) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE-/- females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE-/- also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury.
Asunto(s)
Apolipoproteínas E , Hipocampo , MicroARNs , Radiación Ionizante , Animales , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Hipocampo/metabolismo , Hipocampo/efectos de la radiación , Ratones , Femenino , MicroARNs/metabolismo , MicroARNs/genética , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/efectos de la radiación , Neurogénesis/efectos de la radiación , Irradiación Corporal Total , Exposición a la Radiación/efectos adversos , Giro Dentado/metabolismo , Giro Dentado/efectos de la radiación , Giro Dentado/patologíaRESUMEN
The effects of radiation exposure on germ cells and the gonads have been well studied at acute high-dose exposures, but the effects of chronic low-dose-rate (LDR) irradiation, particularly relevant for radiation protection, on germ cells and the gonads are largely unknown. Our previous study revealed that chronic exposure of mice to medium-dose-rate (MDR, 200 or 400 mGy/day) gamma-rays in utero for the entire gestation period (18 days) induced only a mild degree of general growth retardation, but with very drastic effects on the gonads and germ cells. In the current study, we further investigated the histomorphological changes in the gonads and the number of germ cells from gestation day (GD) 18 fetuses irradiated with MDR throughout the entire gestation period. The germ cells in the testes and ovaries of the MDR-irradiated fetuses were almost obliterated. Gestation day 18 fetuses exposed to LDR (20 mGy/day) radiation for the entire gestation period showed decreases in the number of the germ cells, which were not statistically significant or only marginally significant at most. Further investigations on the effects of LDR irradiation in utero using more sensitive methods are necessary.
Asunto(s)
Aberraciones Cromosómicas/efectos de la radiación , Feto/efectos de la radiación , Rayos gamma/efectos adversos , Células Germinativas/efectos de la radiación , Animales , Supervivencia Celular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Femenino , Feto/fisiopatología , Células Germinativas/patología , Masculino , Ratones , Ovario/fisiopatología , Ovario/efectos de la radiación , Dosis de Radiación , Protección Radiológica , Testículo/fisiopatología , Testículo/efectos de la radiaciónRESUMEN
In this work, we utilized spontaneously hypertensive rats (SHR) and Wister Kyoto rats (WKY), from which the SHR was established, to evaluate the effects of whole-body acute radiation on the cardiovascular system at doses from 0 to 4 Gy. In the irradiated SHR, the systolic blood pressure (SBP) increased with increasing dose, while body weight gain decreased with increasing radiation dose. Furthermore, pathological observations of SHR demonstrated that the number of rats with cystic degeneration in the liver increased with increasing dose. The effects observed among SHR, such as increased SBP and retardation of body weight gain, appear very similar to those observed in Japanese atomic bomb survivors. In contrast, the SBP among WKY did not change relative to dose; the body weight, however, did change, as in the SHR. Therefore, the association between radiation exposure and SBP, but not between radiation exposure and retardation of body weight gain, may be affected by genetic background, as evident from strain difference. These results suggest that the SHR and WKY animal models may be useful for studying radiation effects on non-cancer diseases including circulatory diseases, chronic liver disease and developmental retardation.
Asunto(s)
Presión Sanguínea/genética , Presión Sanguínea/efectos de la radiación , Peso Corporal/genética , Peso Corporal/efectos de la radiación , Antecedentes Genéticos , Animales , Hígado/patología , Hígado/efectos de la radiación , Masculino , Ratas , Ratas Endogámicas SHRRESUMEN
This review summarizes the results of experiments conducted in the Institute for Environmental Sciences for the past 21 years, focusing on the biological effects of long-term low dose-rate radiation exposure on mice. Mice were chronically exposed to gamma rays at dose-rates of 0.05, 1 or 20 mGy/day for 400 days to total doses of 20, 400 or 8000 mGy, respectively. The dose rate 0.05 mGy/day is comparable to the dose limit for radiation workers. The parameters examined were lifespan, neoplasm incidence, antineoplasm immunity, body weight, chromosome aberration(s), gene mutation(s), alterations in mRNA and protein levels and trans-generational effects. At 20 mGy/day, all biological endpoints were significantly altered except neoplasm incidence in the offspring of exposed males. Slight but statistically significant changes in lifespan, neoplasm incidences, chromosome abnormalities and gene expressions were observed at 1 mGy/day. Except for transient alterations in the mRNA levels of some genes and increased liver neoplasm incidence attributed to radiation exposure, the remaining biological endpoints were not influenced after exposure to 0.05 mGy/day. Results suggest that chronic low dose-rate exposure may induce small biological effects.
Asunto(s)
Aberraciones Cromosómicas , Relación Dosis-Respuesta en la Radiación , Mutación , Neoplasias Inducidas por Radiación , Dosis de Radiación , Exposición a la Radiación , Animales , Femenino , Rayos gamma , Humanos , Japón , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias/etiología , Neoplasias/genética , ARN Mensajero/metabolismoRESUMEN
PURPOSE: Chronic low-dose-rate (20 mGy/day) γ-irradiation increases the incidence of hepatocellular adenomas (HCA) in female B6C3F1 mice. The purpose of this study is to identify potential serum biomarkers for these HCAs by a new approach. MATERIAL AND METHODS: Microarray analysis were performed to compare the gene expression profiles of HCAs from mice exposed to low-dose-rate γ-rays with those of normal livers from non-irradiated mice. From the differentially expressed genes, those for possibly secretory proteins were selected. Then, the levels of the proteins in sera were analysed by ELISA. RESULTS: Microarray analysis identified 4181 genes differentially expressed in HCAs (>2.0-fold). From these genes, those for α-fetoprotein (Afp), α-1B-glycoprotein (A1bg) and serine peptidase inhibitor Kazal type-3 (Spink3) were selected as the genes for candidate proteins. ELISA revealed that the levels of Afp and A1bg proteins in sera significantly increased and decreased, respectively, in low-dose-rate irradiated mice with HCAs and also same tendency was observed in human patients with hepatocellular carcinomas. CONCLUSION: These results indicate that A1bg could be a new serum biomarker for liver tumor. This new approach of using microarray to select genes for secretory proteins is useful for prediction of novel tumor markers in sera.
Asunto(s)
Adenoma/diagnóstico , Biomarcadores de Tumor/sangre , Glicoproteínas/sangre , Inmunoglobulinas/sangre , Neoplasias Hepáticas/diagnóstico , Neoplasias Inducidas por Radiación/diagnóstico , Adenoma/sangre , Adenoma/etiología , Animales , Femenino , Rayos gamma , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/etiología , Ratones , Neoplasias Inducidas por Radiación/sangre , Proteínas de Secreción Prostática/sangre , Dosis de Radiación , Transcriptoma , Inhibidor de Tripsina Pancreática de Kazal/sangre , alfa-Fetoproteínas/análisisRESUMEN
Molecular mechanisms of radiation dose-rate effects are not well understood. Among many possibilities, long-lasting sustained alterations in protein levels would provide critical information. To evaluate sustained effects after acute and chronic radiation exposure, we analyzed alterations in protein expression in the livers of mice. Acute exposure consisted of a lethal dose of 8 Gy and a sublethal dose of 4 Gy, with analysis conducted 6 days and 3 months after irradiation, respectively. Chronic irradiation consisted of a total dose of 8 Gy delivered over 400 days (20 mGy/day). Analyses following chronic irradiation were done immediately and at 3 months after the end of the exposure. Based on antibody arrays of protein expression following both acute lethal and sublethal dose exposures, common alterations in the expression of two proteins were detected. In the sublethal dose exposure, the expression of additional proteins was altered 3 months after irradiation. Immunohistochemical analysis showed that the increase in one of the two commonly altered proteins, MyD88, was observed around blood vessels in the liver. The alterations in protein expression after chronic radiation exposure were different from those caused by acute radiation exposures. Alterations in the expression of proteins related to inflammation and apoptosis, such as caspase 12, were observed even at 3 months after the end of the chronic radiation exposure. The alterations in protein expression depended on the dose, the dose rate, and the passage of time after irradiation. These changes could be involved in long-term effects of radiation in the liver.
Asunto(s)
Hígado/metabolismo , Hígado/efectos de la radiación , Proteínas/metabolismo , Animales , Caspasa 12/metabolismo , Relación Dosis-Respuesta en la Radiación , Inmunohistoquímica , Laminina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 88 de Diferenciación Mieloide/metabolismoRESUMEN
We previously reported that mice chronically irradiated with low-dose-rate gamma rays had significantly shorter mean life spans than nonirradiated controls. This life shortening appeared to be due primarily to earlier death due to malignant lymphomas in the irradiated groups (Tanaka et al., Radiat. Res. 160, 376-379, 2003). To elucidate the molecular pathogenesis of murine lymphomas after low-dose-rate irradiation, chromosomal aberrations in 82 malignant lymphomas from mice irradiated at a dose rate of 21 mGy/day and from nonirradiated mice were compared precisely by microarray-based comparative genomic hybridization (array-CGH) analysis. The array carried 667 BAC clones densely selected for the genomic regions not only of lymphoma-related loci but also of surface antigen receptors, enabling immunogenotyping. Frequent detection of the apparent loss of the Igh region on chromosome 12 suggested that most lymphomas in both groups were of B-cell origin. Array-CGH profiles showed a frequent gain of whole chromosome 15 in lymphomas predominantly from the irradiated group. The profiles also demonstrated copy-number imbalances of partial chromosomal regions. Partial gains on chromosomes 12, 14 and X were found in tumors from nonirradiated mice, whereas losses on chromosomes 4 and 14 were significantly associated with the irradiated group. These findings suggest that lymphomagenesis under the effects of continuous low-dose-rate irradiation is accelerated by a mechanism different from spontaneous lymphomagenesis that is characterized by the unique spectrum of chromosomal aberrations.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas/genética , Cromosomas/efectos de la radiación , Predisposición Genética a la Enfermedad/genética , Linfoma/etiología , Linfoma/genética , Neoplasias Inducidas por Radiación/genética , Animales , Mapeo Cromosómico , Rayos gamma/efectos adversos , Hibridación in Situ , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia por Matrices de Oligonucleótidos , Dosis de RadiaciónRESUMEN
Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer´s. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer´s model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calcium-dependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFα expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer´s pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease.
Asunto(s)
Enfermedad de Alzheimer/etiología , Apolipoproteínas E/fisiología , Hipocampo/efectos de la radiación , Proteoma , Enfermedad de Alzheimer/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/fisiología , Modelos Animales de Enfermedad , Femenino , Hipocampo/metabolismo , Peroxidación de Lípido/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Neurogénesis/efectos de la radiación , Plasticidad Neuronal/efectos de la radiación , Fosforilación , Dosis de Radiación , Radiación Ionizante , Transducción de SeñalRESUMEN
There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE-/- mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE-/- females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response.
Asunto(s)
Aorta Torácica/efectos de la radiación , Enfermedades de la Aorta/etiología , Apolipoproteínas E/deficiencia , Aterosclerosis/etiología , Dosis de Radiación , Traumatismos Experimentales por Radiación/etiología , Animales , Aorta Torácica/metabolismo , Aorta Torácica/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Progresión de la Enfermedad , Relación Dosis-Respuesta en la Radiación , Femenino , Modelos Lineales , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica , Traumatismos Experimentales por Radiación/genética , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Medición de Riesgo , Factores de TiempoRESUMEN
Radiation exposure induces acute myeloid leukemia (AML) in humans and mice. Recent studies postulated that AML stem cells of spontaneous human AML arise from hematopoietic stem cells. However, other studies support the possibility that short-lived committed progenitors transform into AML stem cells, accompanied by a particular gene mutation. It remains unclear whether AML stem cells are present in radiation-induced AML, and information regarding AML-initiating cells is lacking. In this study, we identified and analyzed AML stem cells of mice with radiation-induced AML. The AML stem cells were identified by transplanting 100 bone marrow cells from mice with radiation-induced AML. We injected 100 cells of each of seven cell populations corresponding to different stages of hematopoietic cell differentiation and compared the latencies of AMLs induced in recipient mice. The identified radiation-induced AML stem cells frequently displayed similarities in both CD antigen and gene expression profiles with normal common myeloid progenitors. The number of common myeloid progenitor-like AML stem cells was significantly increased in mice with radiation-induced AML, but the progeny of common myeloid progenitors was decreased. In addition, analysis of radiation effects on the hematopoietic system showed that common myeloid progenitor cells were extremely radiosensitive and that their numbers remained at low levels for more than 2 months after radiation exposure. Our results suggest that murine radiation-induced AML stem cells arise from radiosensitive cells at a common myeloid progenitor stage.