Chronic Irradiation Research Articles

Decrease in Langerhans Cells and Increase in Lymph Node Dendritic Cells Following Chronic Exposure of Mice to Suberythemal Doses of Solar Simulated Radiation

Exposure of certain strains of mice to ultraviolet radiation (UVR) causes suppression of some innate and adaptive immune responses. One such consequence of acute UVB exposure is a reduction in the number of Langerhans cells (LC) in the epidermis and an increase in dendritic cells (DC) in lymph nodes draining the irradiated skin sites. Exposure to chronic UVB irradiation also has effects on the immune system, but it is unknown what effects are caused by repeated doses of solar simulated radiation (SSR). Consequently, the main aims of the present study were to determine whether repeated exposure to low doses of SSR would lead to similar changes in these cell populations and whether chronic doses of SSR activate a protective photoadaptation mechanism. Groups of C3H/HeN mice were irradiated daily with 3.7 J/cm(2) SSR from Cleo Natural lamps for 2, 10, 20, 30 or 60 days. Further groups of mice received an additional dose of 7.4 J/cm(2) SSR on days 2, 10, 30 or 60 to test for photoadaptation. The numbers of LC in the epidermis and DC in the lymph nodes draining irradiated skin sites were counted 24 h after the final irradiation. With the exception of mice irradiated for only 2 days, LC were significantly reduced throughout the chronic irradiation protocol, and no recovery occurred. DC numbers were significantly increased in the draining lymph nodes of mice irradiated for 20 days and 60 days.

8-Oxoguanine Formation Induced by Chronic UVB Exposure Makes Ogg1 Knockout Mice Susceptible to Skin Carcinogenesis

8-Oxoguanine is one of the oxidative DNA damages that can result in stable mutations. The Ogg1 gene encodes the repair enzyme 8-oxoguanine-DNA glycosylase, which removes the oxidized base from DNA. In this study, we investigated the role of 8-oxoguanine in skin carcinogenesis induced by UVB irradiation using Ogg1 knockout mice (C57Bl/6J background). We examined the effect of UVB irradiation on the formation of 8-oxoguanine in epidermal cells using immunostaining and found that the level of 8-oxoguanine in Ogg1 knockout mice 24 hours after UVB irradiation remained high compared with that in wild-type and heterozygous mice. To verify the effect of chronic UVB irradiation on 8-oxoguanine formations in epidermal cells, we irradiated wild-type, heterozygous, and Ogg1 knockout mice with UVB at a dose of 2.5 kJ/m2 thrice a week for 40 weeks. We found that the mean number of tumors in Ogg1 knockout mice was 3.71, which was significantly more than in wild-type and heterozygous mice, being 1.71 and 2.28, respectively. The rate of developing malignant tumors in Ogg1 knockout mice was also significantly higher (88.5%; squamous cell carcinomas, 73.1%; sarcomas, 15.4%) than in wild-type mice (50.0%; squamous cell carcinomas, 41.7%; sarcomas, 8.3%). Moreover, the age of onset of developing skin tumors in Ogg1 knockout mice was earlier than in the other types of mice. These results clearly indicate that oxidative DNA damage induced by sunlight plays an important role in the development of skin cancers.

Effect of administration of caffeine or green tea on the mutation profile in the p53 gene in early mutant p53-positive patches of epidermal cells induced by chronic UVB-irradiation of hairless SKH-1 mice

Irradiation of SKH-1 mice with UVB light for 20 weeks resulted in a large number of patches of epidermal cells, which was visualized with an antibody that recognizes mutated p53 protein. Oral treatment of mice with caffeine (0.4 mg/ml) or green tea (6 mg tea solids/ml) as the drinking fluid during UVB irradiation decreased the number of patches by approximately 40%. Sequencing analysis of the p53 gene (exons 3 to 9) detected 88, 82 or 39 point mutations in 67, 70 or 29 patches from water, caffeine or tea treated mice, respectively. A major hotspot at codon 270 (Arg-->Cys) accounted for 47.7% (water), 70.7% (caffeine) or 46.2% (tea) of all mutations. Patches from caffeine treated mice had fewer types of mutations than patches from mice treated with water or tea. Administration of caffeine or tea during 20 weeks of UVB irradiation eliminated mutations at codons 149 (Pro-->Ser) and 210 (Arg-->Cys) but increased the frequency of mutations at codon 238 (Ser-->Phe). Topical applications of caffeine (1.2 mg in 100 microl acetone) once a day, five times a week for 6 weeks after stopping UVB decreased the number of patches by 63% when compared with mice treated with acetone. DNA sequencing analysis detected 63 and 68 mutations in 48 and 57 patches from acetone or caffeine treated mice, respectively. Although no differences in the frequency, position or types of mutations were observed, the caffeine group harbored less homozygous mutations (12.3% of the total) than the acetone group (31.3% of the total, P = 0.029). In summary, oral treatment of mice with caffeine or green tea during chronic UVB irradiation changed the mutation profile of the p53 gene in early mutant p53 positive epidermal patches, and topical applications of caffeine after discontinuation of chronic UVB irradiation specifically eliminated patches harboring homozygous p53 mutations.

Production of the long and short forms of MFG-E8 by epidermal keratinocytes

Mouse milk fat globule-EGF factor 8, MFG-E8, is the ortholog to the human mammary tumor marker, lactadherin, and comprises two spliced variants, the L and S forms. Recent studies have suggested that MFG-E8-L produced by macrophages and Langerhans cells in the skin serves as a linker between phagocytic cells and apoptotic cells, and that MFG-E8-S, also termed SED1, facilitates sperm-egg interaction for fertilization. However, Mfge8 gene expression occurs in various tissues apparently unrelated to these critical events. Our in situ hybridization study has revealed that Mfge8 is expressed in the periderm (the premature epidermis) on embryonic day-14, well before Langerhans cells begin to grow in the prenatal phase. Mfge8 transcript is detectable in the basal and spinous layers throughout skin development, whereas immunostaining has revealed MFG-E8 protein accumulation in the spinous layer. Cultured keratinocyte stem cells consistently express Mfge8-L and -S mRNAs and produce the L protein, which is primarily detectable in the culture supernatant, and the S protein, which is mostly associated with the cells. Upon Ca(2+)-stimulated differentiation, which is detected by a decrease in keratinocyte stem cell marker p63(p51) and the induction of keratin1, we have observed suppression of Mfge8, and the protein becomes localized to the cell-cell borders. Papillomas and carcinomas caused by chronic UV-B irradiation produce MFG-E8 as determined by immunostaining. Thus, undifferentiated and poorly differentiated keratinocytes produce the L and S forms of MFG-E8 during normal and pathological tissue development, probably to support an as yet unidentified membrane function.

Patches of Mutant p53-Immunoreactive Epidermal Cells Induced by Chronic UVB Irradiation Harbor the Same p53 Mutations as Squamous Cell Carcinomas in the Skin of Hairless SKH-1 Mice

Treatment of SKH-1 hairless mice with UVB (30 mJ/cm(2)) twice a week for 20 weeks results in the formation of cellular patches, long before the appearance of tumors, that are visualized in epidermal sheets with an antibody (PAb240) recognizing mutated p53 protein. Direct sequencing analysis of the whole coding region of the p53 gene (exons 2-11) detected one or two mutations in 64.4% of 104 analyzed patches and no mutations in nonstained adjacent normal controls. Homozygous mutation was detected in 22.4% of the mutant patches. Except for two nonsense mutations, all others were missense (exons 4-9) and mostly (95.5%) at the DNA-binding domain. Primer extension analysis of cloned PCR fragments found three of four double-mutated patches harboring different mutations in separate alleles. All mutation hotspots reported earlier in UVB-induced mouse squamous cell carcinomas (SCC) at codons 270 (Arg --> Cys), 149 (Pro --> Ser), 275 (Pro --> Leu and Pro --> Ser), and 176 (His --> Tyr) with a frequency of 32.1%, 7.1%, 14.7%, and 3.2% were detected in epidermal patches at a frequency 47.7%, 9.1%, 4.5%, and 2.3%, respectively. Mutations at codons 210 and 191 found in patches at respective frequencies of 8.0% and 4.5% were not previously detected in UVB-induced mouse SCC. In summary, (a) the p53 mutation profile of UVB-induced skin patches and SCC was very similar suggesting that patches are precursor lesions for SCC, (b) a small number of patches harbored mutations that were not before observed in SCC from UVB-treated mice, and (c) about 36% of the patches did not harbor a p53 mutation.

Developing experimental protocols for chronic irradiation studies: The application of a good practice guide framework

A recent review of radiation effects data highlighted that information on the effects of low-dose, chronic exposure was, at best, fragmentary. These data are required to define the dose effect relationships, which must underpin assessments of the impact of ionising radiation on biota. In response, four Good Practice Guides (GPGs) have been produced as part of a protocol development framework that aims to harmonise experimental approaches, with a view to ensuring that appropriate endpoint data are collected and reliable dose effect relationships determined. The GPGs cover test species selection, endpoint selection, radiation exposure and experimental design considerations. A key guides researchers through the GPGs and the decisions made are recorded on a pro-forma, which is the basis of the experimental protocol. This paper describes the first application of the framework to a radiation effects study. The framework has been adopted by the UK Environment Agency as a document upon which future Agency-funded experimental work in this field will be based. It is hoped that the framework will gain acceptance in the wider scientific community and enable knowledge gaps to be addressed, in order that successful protection of non-human biota can be demonstrated.

A system of dose-effects relationships for the northern wildlife: Radiation protection criteria

The key issue in the assessment system for radiation protection of wildlife is the establishment of dose-effects relationships for reference representatives of natural biota. Within the frame of the EC Project EPIC Environmental Protection from Ionizing Contaminants (2000-2003), a database has been created, which includes about 1600 records from 440 publications in Russian on the dose-effects relationships in wildlife from northern-temperate climatic zones. The EPIC database Radiation effects on biota is based on Russian/FSU experimental and field studies; chronic/lifetime exposures are the focus of the data collection. The database information covers a very wide range of radiation dose rates to biota: from below 1E(-5) Gy d -1 up to more than 1 Gy d -1 . A great variety of radiation effects are registered in the EPIC database, from stimulation at low doses up to death from acute radiation syndrome at high doses. The paper presents the dose-effects relationships for northern wildlife in the conditions of low-LET chronic irradiation. The system of dose-effects relationships forms the scale of severity of radiation effects at increasing levels of chronic radiation exposure. The system can be used as a basis for establishing criteria for radiation protection of the Northern wildlife.

A case study in the Chernobyl zone Part 2: Predicting radiation induced effects in biota

In this paper we use the FASSET framework to estimate absorbed dose rates for biota within the Chernobyl exclusion zone. The estimated doses are compared to observed biological effects within the Chernobyl exclusion zone and effects expected from summaries of existing knowledge and the extent of contamination. Although paucity of observations under conditions of chronic irradiation makes direct comparison difficult, the biological effects observed in the Chernobyl exclusion zone over the period considered here (1988-2003) are broadly in agreement with those which may have been expected.

Successful treatment of photo-damaged skin of nano-scale atRA particles using a novel transdermal delivery

We show a novel drug delivery system (DDS) for improved all- trans retinoic acid (atRA) therapy for external treatments of photo-damaged skin. We prepared inorganic-coated atRA nanoparticles, in turn an egg-like structure in nano-scale (Nano-atRA), using boundary-organized reaction droplets. The interfacial properties of organic architectures, in atRA micelles, were used to template the nucleation of inorganic minerals. As a result, irritation and inflammation associated with atRA therapy were substantially reduced due to the complete encapsulation of the carboxylic function. Both irritative symptoms and physicochemical instability of the atRA micelle were improved. Since Nano-atRA which is prepared following to this new DDS system developmentally improved the permeability to the stratum corneum, the remarkable pharmacological effects were resulted in comparison with atRA as such as follows: (1) thicker epidermis than classical atRA treatment and (2) the overexpression of mRNA for heparin-binding epidermal growth factor (HB-EGF) as the provocation epidermal hyperplasia. Furthermore, we found a surprising boost in production of hyaluronan (HA) among the intercellular spaces of the basal and spinous cell layers in epidermis. Nano-atRA technology for atRA therapy could not only efficiently regulate keratinocyte cell proliferation and differentiation, but also markedly produce the additional benefit. Severely injured human skin by chronic ultraviolet irradiation will completely repair due to the accelerated turnover of skin tissue, which is induced by Nano-atRA.

Measurement of the whole-body 137Cs in residents around the Chernobyl nuclear power plant

To understand the current situation of internal radiation exposure in the population around the Chernobyl Nuclear Power Plant (CNPP), we examined the 137Cs body burden in six residents of Belarus, Ukraine and Russia in 2002 and 2004 using the whole-body counter (WBC) at Nagasaki University (Japan). The data were compared with those of our previous study performed in 1993-1994 using the same method. In 2002 and 2004, peaks of 137Cs were detected in two residents from Gomel, which was heavily contaminated by the CNPP accident, one from Minsk (Belarus) and one from Kiev (Ukraine), but another resident from Minsk showed no 137Cs peaks. The results of the present study suggests that residents around the CNPP are still exposed to chronic 137Cs internal irradiation, probably due to the daily consumption of contaminated domestic foods, but the risk of any disease by the irradiation is quite low. Long-term follow-up of WBC around the CNPP is useful and may contribute to radiation safety regulation together with a reduction of unnecessary radiophobia for the residents.

Inverse Relationship Between Increased Apoptosis and Decreased Skin Cancer in UV-irradiated CD1d−/− Mice¶

We previously demonstrated that CD1d knockout mice were resistant to ultraviolet (UV)-induced immunosuppression. Because immune suppression is a critical factor in the development of UV-induced skin cancers, we investigated the response of wild type (WT) and CD1d-/- mice to UV carcinogenesis. We found that although 100% of WT mice developed skin tumors after 45 weeks of UV irradiation, only 60% of CD1d-/- mice developed skin tumors. To investigate the mechanisms involved in the resistance of CD1d-/- mice to UV-induced carcinogenesis, we determined the time course and kinetics of keratinocyte cell death after UV irradiation. After acute UV exposure, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL)-positive keratinocytes were eliminated from the skin of WT mice by 72 h post-UV, but they still persisted until 96 h in CD1d-/- mice. The kinetics of p53 protein expression closely followed the kinetics of apoptotic cell death. Chronic UV irradiation resulted in induction of a significantly higher number of apoptotic keratinocytes in CD1d-/- than WT mice. In addition, epidermis and dermis from chronically UV-irradiated CD1d-/- mice harbored significantly fewer p53 mutations than WT mice. These results indicate that the resistance of CD1d-/- mice to UV carcinogenesis may be due to increased cell death and elimination of keratinocytes and fibroblasts containing DNA damage and p53 mutations.

Protective Effects of an Antioxidant Derived from Serine and Vitamin B6 on Skin Photoaging in Hairless Mice

The generation of reactive oxygen species (ROS) by ultraviolet radiation (UVR) accelerates skin aging, which is known as photoaging. Because cutaneous iron catalyzes ROS generation, sequestering iron by chelating agents is thought to be an effective approach toward preventing photoaging. Previously, N-(4-pyridoxylmethylene)-l-serine (PYSer) was designed as an antioxidant to suppress iron-catalyzed ROS generation by its iron-sequestering activity. In this study, PYSer showed protective effects against skin damage in hairless mice irradiated with ultraviolet B (UV-B). Topical application of PYSer to the skin significantly delayed and/or decreased the visible wrinkle formation induced by chronic UV-B irradiation. A histological study indicated that UV-B-induced epidermal hypertrophy and lymphocytic infiltration were suppressed by PYSer. Moreover, PYSer showed suppressive activity against the UV-B-induced increase in glycosaminoglycans (GAG). These results indicate that PYSer is a promising antioxidant for the prevention of chronic skin photoaging by its iron-sequestering activity.

Adaptation of the Human Skin by Chronic Solar-simulating UV Irradiation Prevents Ultraviolet-B Irradiation-induced Rise in Serum C–Reactive Protein Levels¶

Adaptation of the Human Skin by Chronic Solar-simulating UV Irradiation Prevents Ultraviolet-B Irradiation-induced Rise in Serum C–Reactive Protein Levels¶

Adaptation of the Human Skin by Chronic Solar-simulating Ultraviolet Irradiation Prevents Ultraviolet-B Irradiation-induced Rise in Serum C-Reactive Protein Levels

Exposure of the skin to UV radiation induces local inflammation. We hypothesized that inflammation induced by erythemal UV-B irradiation could elevate levels of serum C-reactive protein (CRP) and that suberythemal repeating doses of solar-simulating UV radiation (SSR) would produce photoadaptation to such inflammation. Separation-free high-sensitivity assays of CRP show an increase by 42% (P = 0.046) in CRP concentrations in healthy human subjects 24 h after a 3 minimal erythemal dose (MED) dose of UV-B delivered onto a 100 cm2 skin area. Preceding daily suberythemal doses of whole-body SSR for 10 or 30 consecutive days completely prevented the CRP increase. UV-B-induced skin erythema was partially attenuated by 30 preceding days of SSR only (P = 0.00066). After 10 daily SSR doses, the mean baseline CRP concentrations (0.24 +/- 0.21 mg/L) declined by 35% (P = 0.018). Using high-sensitivity analysis of serum CRP as the endpoint marker for cutaneous inflammation, we show that acute exposure of even a relatively small skin area to erythemal UV-B induces skin inflammation detectable also at the systemic level and that photoadaptation by preceding repeating suberythemal doses of SSR reduces signs of inflammation. Our data complement the view given by previous studies in that local photoadaptation also has systemic manifestations.

Protective Effects of an Antioxidant Derived from Serine and Vitamin B6 on Skin Photoaging in Hairless Mice¶

The generation of reactive oxygen species (ROS) by ultraviolet radiation (UVR) accelerates skin aging, which is known as photoaging. Because cutaneous iron catalyzes ROS generation, sequestering iron by chelating agents is thought to be an effective approach toward preventing photoaging. Previously, N-(4-pyridoxylmethylene)-l-serine (PYSer) was designed as an antioxidant to suppress iron-catalyzed ROS generation by its iron-sequestering activity. In this study, PYSer showed protective effects against skin damage in hairless mice irradiated with ultraviolet B (UV-B). Topical application of PYSer to the skin significantly delayed and/or decreased the visible wrinkle formation induced by chronic UV-B irradiation. A histological study indicated that UV-B–induced epidermal hypertrophy and lymphocytic infiltration were suppressed by PYSer. Moreover, PYSer showed suppressive activity against the UV-B–induced increase in glycosaminoglycans (GAG). These results indicate that PYSer is a promising antioxidant for the prevention of chronic skin photoaging by its iron-sequestering activity.

Inverse Relationship Between Increased Apoptosis and Decreased Skin Cancer in UV‐irradiated CD1d‐/‐ Mice¶

ABSTRACTWe previously demonstrated that CD1d knockout mice were resistant to ultraviolet (UV)‐induced immunosuppression. Because immune suppression is a critical factor in the development of UV‐induced skin cancers, we investigated the response of wild type (WT) and CD1d‐/‐ mice to UV carcinogenesis. We found that although 100% of WT mice developed skin tumors after 45 weeks of UV irradiation, only 60% of CD1d‐/‐ mice developed skin tumors. To investigate the mechanisms involved in the resistance of CD1d‐/‐ mice to UV‐induced carcinogenesis, we determined the time course and kinetics of keratinocyte cell death after UV irradiation. After acute UV exposure, the terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end‐labeling (TUNEL)‐positive keratinocytes were eliminated from the skin of WT mice by 72 h post‐UV, but they still persisted until 96 h in CD1d‐/‐ mice. The kinetics of p53 protein expression closely followed the kinetics of apoptotic cell death. Chronic UV irradiation resulted in induction of a significantly higher number of apoptotic keratinocytes in CD1d‐/‐ than WT mice. In addition, epidermis and dermis from chronically UV‐irradiated CD1d‐/‐ mice harbored significantly fewer p53 mutations than WT mice. These results indicate that the resistance of CD1d‐/‐ mice to UV carcinogenesis may be due to increased cell death and elimination of keratinocytes and fibroblasts containing DNA damage and p53 mutations.

Suppressive effect on carcinogenesis by chronic low dose-rate irradiation

Suppressive effect on carcinogenesis by chronic low dose-rate irradiation

Radioactive Contamination of Ukrainian Mushrooms

Even 18 years after the Chernobyl catastrophe, radioactive contamination of wild growing mushrooms, in some cases reaching very high levels, created human health problems resulting from their nutritional and medicinal use. According to radioecological evaluations, the internal dose of irradiation in this case may reach 40−60%. A combination of macro- and micromycetes mycelial biomass and its capacity to uptake and retain radionuclides play very important roles in their migration and distribution. Actually, knowledge about the mechanisms involved in the accumulation and retention is incomplete. There is a positive correlation among the levels of soil contamination, degree of humidity, pH, rainfall, and radionuclide accumulation in mushrooms, although the species and ecological specificities of uptake are also observed. To measure species specificity of uptake, species-hyperaccumulators—for instance, radiocaesium—were used as bioindicators of contaminated soils. Among them, the widely spread and common species, Lactarius rufus (Scop.:Fr.) Fr. and Paxillus involutus (Batsch:Fr.) Fr., not consumed by the population because of their inedibility and toxicity, are now the most convenient test objects for long-term monitoring.During the last few years in about 80% of mushroom samples traditionally included in the Ukrainian diet—species of Boletaceae (Xerocomus spp., Suillus spp., Leccinum scabrum (Bull.:Fr.) S.F.Gray, Boletus edulis Bull.:Fr.) and Cantharellus cibarius (Fr.:Fr.) Fr. taken from areas with an average soil contamination of 0.1−5 Ci/km2 (presently, the collecting and consuming of wild growing mushrooms are practically not controlled)—the 137Cs levels exceeded permissible limits adopted in the Ukraine (2500 Bq/kg d.w.). Mushrooms growing in the Exclusion Zone, in the vicinity of the Chernobyl Power Plant (with 137Cs contamination density of 837 Ci/km2) accumulated up to millions of Bq/kg d.w. In 2004 137Cs activity in samples from the location of Novo-Shepelychi was within (in Bk/kg d.w.) 340,000 (Armillariella mellea (Vahl.:Fr.) P.Kumm.) to 20,000,000 (Xerocomus subtomentosus (L.:Fr.) Quél.), and 90Sr within 2000 (X. subtomentosus) to 13,000 (Stropharia aeruginosa (W.Curt.:Fr.) Quél.). Transfer factors for 137Cs were in X. subtomentosus 645, P. involutus 548, Lactarius turpis (Weinm.)Fr.280, L. deliciosus (L.:Fr.) S.F.Gray 222; for 90Sr Tf were in S. aeruginosa 6.0, L. turpis 5.1,A. mellea 3.1. The ratio of 137Cs/90Sr was within the range of 7.5−10,000. Mushrooms growing on the highly contaminated territories are permanently subjected to chronic irradiation. Taking into account polymorphism peculiar to mushrooms, the direct finding of morphose for them is difficult. Microstructural morphology of three bioindicative species using light and electron scanning microscopy was studied. It was statistically established that the spore length in Xerocomus badius (Fr.:Fr.) Kuhn. ex Gilb., Paxillus involutus, and Lactarius turpis samples collected in the Exclusion Zone was bigger than in the controls. In some cases, in the hymenophore of studied samples, parts with abnormally large as well as with very small spores were found. The observed variability indicated that high dosages resulting from radionuclides incorporated by mycelium and fruiting bodies from contaminated soils affect the hereditary structures of mushrooms.In nature mushrooms accumulate less 90Sr than 137Cs. In cultivation conditions, increasing levels of radiostrontium accumulation for Lentinus edodes (Berk.) Singer and Pleurotus ostreatus (Jacq.:Fr.)P. Kumm. (Grodzinskaya and Kuchma, 2004) were observed. This phenomenon can be connected to the higher biological availability of 90Sr from mixed and watered substrates. An increase of 90Sr activity in wood (observed in the last few years in contaminated territories) inevitably will cause an increase in its content in lignotroph species. Therefore, the selective control of 90Sr accumulation in cultivated lignotrophs, even in territories with low surface soil contamination, is strongly recommended.

Response of the glutathione system to chronic irradiation of human population after the Chernobyl accident

A complex relationship between plasma glutathione level in human population (children living in radionuclide-contaminated regions and the Chernobyl liquidators) exposed to chronic low-level radiation after the Chernobyl accident was demonstrated. The obtained experimental data indicate different responses of the human glutathione system to low (from 0.1 to 20 cSv) and high (from 20 to 150 cSv) doses of ionizing radiation.

Selective brain responses to acute and chronic low-dose X-ray irradiation in males and females

Radiation exposure is known to have profound effects on the brain, leading to precursor cell dysfunction and debilitating cognitive declines [Nat. Med. 8 (2002) 955]. Although a plethora of data exist on the effects of high radiation doses, the effects of low-dose irradiation, such as ones received during repetitive diagnostic and therapeutic exposures, are still under-investigated [Am. J. Otolaryngol. 23 (2002) 215; Proc. Natl. Acad. Sci. USA 97 (2000) 889; Curr. Opin. Neurol. 16 (2003) 129]. Furthermore, most studies of the biological effects of ionizing radiation have been performed using a single acute dose, while clinically and environmentally relevant exposures occur predominantly under chronic/repetitive conditions. Here, we have used a mouse model to compare the effects of chronic/repetitive and acute low-dose radiation (LDR) exposure (0.5 Gy) to ionizing radiation on the brain in vivo. We examined the LDR effects on p42/44 MAPK (ERK1/ERK2), CaMKII, and AKT signaling—the interconnected pathways that have been previously shown to be crucial for neuronal survival upon irradiation. We report perturbations in ERK1/2, AKT, and CREB upon acute and chronic/repetitive low-dose exposure in the hippocampus and frontal cortex of mice. These studies were paralleled by the analysis of radiation effects on neurogenesis and cellular proliferation. Repetitive exposure had a much more pronounced effect on cellular signaling and neurogenesis than acute exposure. These results suggest that studies of single acute exposures might be limited in terms of their predictive value. We also present the first evidence of sex differences in radiation-induced signaling in the hippocampus and frontal cortex. We show the role of estrogens in brain radiation responses and discuss the implications of the observed changes.