| 1. |
- Bakshi, Mayur V., et al.
(författare)
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Long-term effects of acute low-dose ionizing radiation on the neonatal mouse heart : a proteomic study
- 2013
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Ingår i: Radiation and Environmental Biophysics. - : Springer Science and Business Media LLC. - 0301-634X .- 1432-2099. ; 52:4, s. 451-461
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies establish that children and young adults are especially susceptible to radiation-induced cardiovascular disease (CVD). The biological mechanisms behind the elevated CVD risk following exposure at young age remain unknown. The present study aims to elucidate the long-term effects of ionizing radiation by studying the murine cardiac proteome after exposure to low and moderate radiation doses. NMRI mice received single doses of total body Co-60 gamma-irradiation on postnatal day 10 and were sacrificed 7 months later. Changes in cardiac protein expression were quantified using isotope-coded protein label and tandem mass spectrometry. We identified 32, 31, 66, and 34 significantly deregulated proteins after doses of 0.02, 0.1, 0.5, and 1.0 Gy, respectively. The four doses shared 9 deregulated proteins. Bioinformatics analysis showed that most of the deregulated proteins belonged to a limited set of biological categories, including metabolic processes, inflammatory response, and cytoskeletal structure. The transcription factor peroxisome proliferator-activated receptor alpha was predicted as a common upstream regulator of several deregulated proteins. This study indicates that both adaptive and maladaptive responses to the initial radiation damage persist well into adulthood. It will contribute to the understanding of the long-term consequences of radiation-induced injury and developmental alterations in the neonatal heart.
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| 2. |
- Bakshi, Mayur V, et al.
(författare)
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Total body exposure to low-dose ionizing radiation induces long term alterations to the liver proteome of neonatally exposed mice
- 2015
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 14:1, s. 366-373
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Tidskriftsartikel (refereegranskat)abstract
- Tens of thousands of people are being exposed daily toenvironmental low-dose gamma radiation. Epidemiological data indicate thatsuch low radiation doses may negatively affect liver function and result in thedevelopment of liver disease. However, the biological mechanisms behindthese adverse effects are unknown. The aim of this study was to investigateradiation-induced damage in the liver after low radiation doses. Neonatal maleNMRI mice were exposed to total body irradiation on postnatal day 10 usingacute single doses ranging from 0.02 to 1.0 Gy. Early (1 day) and late (7months) changes in the liver proteome were tracked using isotope-codedprotein label technology and quantitative mass spectrometry. Our dataindicate that low and moderate radiation doses induce an immediateinhibition of the glycolysis pathway and pyruvate dehydrogenase availability inthe liver. Furthermore, they lead to significant long-term alterations in lipidmetabolism and increased liver inflammation accompanying inactivation of thetranscription factor peroxisome proliferator-activated receptor alpha. This study contributes to the understanding of the potentialrisk of liver damage in populations environmentally exposed to ionizing radiation.
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| 3. |
- Bivehed, Erik, et al.
(författare)
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DNA integrity under alkaline conditions : An investigation of factors affecting the comet assay
- 2023
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Ingår i: Mutation research. Genetic toxicology and environmental mutagenesis. - : Elsevier. - 1383-5718 .- 1879-3592. ; 891
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Tidskriftsartikel (refereegranskat)abstract
- The effect of pH on DNA integrity was assessed using a three-step approach. The comet assay was used on a whole genome level, with three different protocols: neutral (no alkaline unwinding), flash (pH 12.5 with 2.5 min unwinding), and the conventional alkaline protocol (pH>13 with 40 min unwinding). Real-time quantitative PCR (RT-qPCR) was then used to study the isolated DNA, revealing that gene amplification decreased with increasing pH, indicating DNA degradation. Specially designed molecular beacons were used to examine DNA at the molecular level, with or without alkali-labile site (ALS) insertions. At pH 12.5, fluorescence in the hairpins with ALS started to increase after 30 min, while at pH> 13, this increase was already observed after 5 min, indicating a significant increase in DNA strand breaks. Liquid chromatography analysis was also used, demonstrating that the hairpins remained intact up to pH 10, even after 1 h exposure, whereas, at pH 12.5, partial conversion into strand breaks occurred after 30 min. At pH> 13, the hairpins were almost completely degraded after 30 min. The flash protocol effectively detects DNA single- and double-strand breaks and identified these damages after 2.5 min of alkaline treatment at pH 12.5. When the hairpins were exposed to pH 12.5 for 60 min, ALS were converted to strand breaks, demonstrating the sensitivity of this approach to detect changes in DNA structure. These findings indicate that pH poses a substantial risk to DNA integrity, leading to significantly higher background levels of DNA damage compared to conditions closer to neutrality. Our study demonstrates the importance of understanding the influence of pH on DNA stability and provides insights into risks associated with alkaline environments, especially at pH> 13.
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| 4. |
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| 5. |
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| 6. |
- Buratovic, Sonja, et al.
(författare)
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Comparison of single and repeated exposure to low doses of pyrethroids, permethrin and bioallethrin, during neonatal brain development on adult spontaneous behaviour
- 2012
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Konferensbidrag (refereegranskat)abstract
- Permethrin and bioallethrin belong to the Type 1 class of pyrethroid pesticides. The primary mechanism of action is interference with nerve membrane sodium channels that results in increased neuronal activity. We have earlier reported on developmental neurotoxic effects after repeated, PND 10 to PND16, neonatal exposure to pyrethroids. The effects were manifested as altered spontaneous behavior, hyperactivity and reduced cognitive function and changes in cholinergic muscarinic/nicotinic receptors in the cerebral cortex of neonatal and adult mice. The present study was undertaken to compare repeated and single exposure to permethrin and bioallethrin during the neonatal brain growth spurt (BGS) on adult spontaneous behavior in a novel home environment. Neonatal NMRI male mice were given permethrin, orally (0.55; 3.3; 6.6 mg/kg bw/day) on PND 10-14, or just a single oral dose of 6.6 mg/kg bw on PND 10. Bioallethrin was given as a single oral dose of 0.7 mg/kg bw on PND 10, and compared to earlier published data on repeated exposure. Mice serving as controls received the 20 % fat emulsion vehicle. Spontaneous behavior test (locomotion, rearing, total activity) in 2-month-old mice revealed a significant higher activity in mice exposed to repeated doses of 6.6 mg permethrin, as well in mice just receiving a single 6.6 mg dose of permethrin. No significant difference was observed between repeated and single exposure. A single dose of 0.7 mg bioallethrin on PND 10 caused the same effects as a repeated dose of 0.7 mg between PND 10 to PND 16. This demonstrates that a single dose of these pyrethroids can cause the same developmental neurotoxic effects as that seen following repeated doses over one week during the neonatal BGS period in mouse. This research provides is consistent with previous findings that exposure during the BGS can result in persistent behavioral defects.
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| 7. |
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| 8. |
- Buratovic, Sonja, et al.
(författare)
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Developmental effects of fractionated low-dose exposure to gamma radiation on behaviour and susceptibility of the cholinergic system in mice
- 2016
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Ingår i: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 92:7, s. 371-379
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate whether neonatal exposure to fractionated external gamma radiation and co-exposure to radiation and nicotine can affect/exacerbate developmental neurotoxic effects, including altered behavior/cognitive function and the susceptibility of the cholinergic system in adult male mice. Materials and methods: Neonatal male Naval Medical Research Institute (NMRI) mice were irradiated with one 200 mGy fraction/day and/or exposed to nicotine (66 μg/kg b.w.) twice daily on postnatal day (PND) 10, 10–11, 10–12 or 10–13 (nicotine only). At 2 months of age the animals were tested for spontaneous behavior in a novel home environment, habituation capacity and nicotine-induced behavior. Results: Fractionated irradiation and co-exposure to radiation and nicotine on three consecutive days disrupted behavior and habituation and altered susceptibility of the cholinergic system. All observed effects were significantly more pronounced in mice co-exposed to both radiation and nicotine. Conclusions: The fractionated irradiation regime affects behavior/cognitive function in a similar manner as has previously been observed for single-dose exposures. Neonatal co-exposure to radiation and nicotine, during a critical period of brain development in general and cholinergic system development in particular, enhance these behavioral defects suggesting that the cholinergic system can be a target system for this type of developmental neurotoxic effects.
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| 9. |
- Buratovic, Sonja, et al.
(författare)
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Developmental exposure to PBDE 209 : sex, neuroprotein and neurobehavioural analyses
- 2012
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Ingår i: Toxicology Letters. - 0378-4274 .- 1879-3169. ; 211:supplement, s. S90-
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Tidskriftsartikel (refereegranskat)abstract
- Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame-retardants in polymers products.Newborns and toddlers can be indirectly and directly exposed to PBDEs during a period of critical rapid brain development. The present study was undertaken to investigate neurotoxic effects after neonatal exposure to PBDE 209 on sex differences, cognitive function, neuroproteins and altered susceptibility to toxicants in adults. 3-day-old NMRI mice were exposed to PBDE 209 (2,2´,3,3´,4,4´,5,5´,6,6´-decaBDE at 0, 1.4, 6.0 and 14 µmol/kg bw). At 2 months of age male mice were exposed to paraoxon (0.25 mg/kg bw, every 2nd day for 7 days) and female mice exposed to nicotine (80 µg nicotine base/kg bw). At the age of 2 and 4 months mice were observed for spontaneous behaviour, before and after adult exposure to paraoxon (male) and nicotine (female). Male mice aged 5 and 7 months were observed for memory and learning. Neuroproteins CaMKII, GAP-43, synaptophysin and tau in cerebral cortex and hippocampus from 7-months old male and female mice were analyzed. The present study shows that neonatal exposure to PBDE 209 can induce developmental neurobehavioural defects in both male and female mice. Neonatal exposure to PBDE 209 also caused increased susceptibility in adult mice to paraoxon and nicotine. All these effects were dose response related. Further, neonatal exposure to PBDE 209 caused persistent defects in memory and learning in adult male mice and increased levels of important neuroproteins e.g. tau in adult male and female mice.
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| 10. |
- Buratovic, Sonja, et al.
(författare)
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Developmental exposure to PBDE 209 alters adult susceptibility to paraoxon and nicotine : gender and neurobehavioural analysis
- 2011
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Konferensbidrag (refereegranskat)abstract
- Newborns, infants and children can be indirectly and directly exposed to PBDEs. This exposure coincides with a period of rapid brain development. Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame-retardants in polymers, especially in electric appliances.A concern is that these compounds are present at a higher level in newborns and toddlers than in the average adult individual, especially the highly brominated PBDEs. We have earlier reported that neonatal exposure to toxicants can lead to an increased susceptibility of the cholinergic system at adult age. The present study was undertaken to investigate whether neonatal exposure of male and female mice to PBDE 209 alters the adult susceptibility to the organophosphorous compound, paraoxon, and to nicotine, respectively.. Neonatal, 3-day-old, NMRI mice were exposed to PBDE 209 (2,2´,3,3´,4,4´,5,5´,6,6´-decaBDE at 1.4, 6.0 and 14 µmol/kg bw). At two months of age male mice were exposed to paraoxon (0.25 mg/kg bw, every 2nd day for 7 days) and female mice exposed to nicotine. At the age of 2 months male and female mice were observed for spontaneous behaviour in a novel home environment, before and after adult exposure to paraoxon and nicotine, respectively. Adult male and female mice neonatally exposed to PBDE 209 showed significant impaired spontaneous behaviour. Male mice neonatally exposed to PBDE 209 and to paraoxon as adults developed additional defect spontaneous behaviour and lack of habituation. Female mice neonatally exposed to PBDE 209 showed an increased susceptibility to nicotine, where PBDE 209 exposed mice responded with a decrease in activity to nicotine whereas control mice responded with increased activity. The present study shows that PBDE 209 can induce developmental neurobehavioural defects in both male and female mice. Neonatal exposure to PBDE 209 caused also increased susceptibility in adult mice to paraoxon and nicotine. All these effects were dose response related.
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| 11. |
- Buratovic, Sonja, et al.
(författare)
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Developmental exposure to the polybrominated diphenyl ether PBDE 209 : Neurobehavioural and neuroprotein analysis in adult male and female mice
- 2014
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Ingår i: Environmental Toxicology and Pharmacology. - : Elsevier BV. - 1382-6689 .- 1872-7077. ; 38:2, s. 570-585
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Tidskriftsartikel (refereegranskat)abstract
- Polybrominated diphenyl ethers (PBDEs), used as flame retardants in polymer products, are reported to cause developmental neurotoxic effects in mammals. The present study have investigated neurotoxic effects arising from neonatal exposure to PBDE 209, including alterations in sex differences, spontaneous behaviour, learning and memory, neuroproteins and altered susceptibility of the cholinergic system in adults. Three-day-old NMRI mice, of both sexes, were exposed to PBDE 209 (2,2',3,3',4,4',5,5',6,6'-decaBDE at 0, 1.4, 6.0 and 14.0 mu mol/kg b.w.). At adult age (2-7 months) a similar developmental neurotoxic effects in both male and female mice were seen, including lack of or reduced habituation to a novel home environment, learning and memory defects, modified response to the cholinergic agent's paraoxon (males) and nicotine (females) indicating increased susceptibility of the cholinergic system. The behavioural defects were dose-response related and persistent. In mice of both sexes and showing behavioural defects, neuroprotein tau was increased. (C) 2014 Elsevier B.V. All rights reserved.
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| 12. |
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| 13. |
- Buratovic, Sonja, 1986-, et al.
(författare)
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Effects on adult cognitive function after neonatal exposure to clinically relevant doses of ionising radiation and ketamine in mice
- 2018
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Ingår i: British Journal of Anaesthesia. - : ELSEVIER SCI LTD. - 0007-0912 .- 1471-6771. ; 120:3, s. 546-554
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Tidskriftsartikel (refereegranskat)abstract
- Background: Radiological methods for screening, diagnostics and therapy are frequently used in healthcare. In infants and children, anaesthesia/sedation is often used in these situations to relieve the patients' perception of stress or pain. Both ionising radiation (IR) and ketamine have been shown to induce developmental neurotoxic effects and this study aimed to identify the combined effects of these in a murine model. Methods: Male mice were exposed to a single dose of ketamine (7.5 mg kg(-1) body weight) s.c. on postnatal day 10. One hour after ketamine exposure, mice were whole body irradiated with 50-200 mGy gamma radiation (Cs-137). Behavioural observations were performed at 2, 4 and 5 months of age. At 6 months of age, cerebral cortex and hippocampus tissue were analysed for neuroprotein levels. Results: Animals co-exposed to IR and ketamine displayed significant (P <= 0.01) lack of habituation in the spontaneous behaviour test, when compared with controls and single agent exposed mice. In the Morris Water Maze test, co-exposed animals showed significant (P <= 0.05) impaired learning and memory capacity in both the spatial acquisition task and the relearning test compared with controls and single agent exposed mice. Furthermore, in co-exposed mice a significantly (P <= 0.05) elevated level of tau protein in cerebral cortex was observed. Single agent exposure did not cause any significant effects on the investigated endpoints. Conclusion: Co-exposure to IR and ketamine can aggravate developmental neurotoxic effects at doses where the single agent exposure does not impact on the measured variables. These findings show that estimation of risk after paediatric low-dose IR exposure, based upon radiation dose alone, may underestimate the consequences for this vulnerable population.
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| 14. |
- Buratovic, Sonja, et al.
(författare)
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Exposure to a single dose of ionising radiation during brain development can cause cognitive defects and increased levels of tau in mice
- 2012
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Konferensbidrag (refereegranskat)abstract
- Ionising radiation (IR) is widely used in the medical field for treating tumours, including tumours in the central nervous system, and for imaging techniques such as computed tomography (CT). There is a lack of knowledge and increasing concern about effects and consequences from low dose exposure during critical phases of perinatal and/or neonatal brain development compared to prenatal irradiation. It is known that IR causes neurotoxicological and neurobehavioural defects in mammals. Further, an epidemiological study has suggested that low doses of IR to the human brain during infancy can have a negative effect on cognitive abilities in adulthood. The rapid brain growth spurt (BGS) occurs in humans as well as mice. In humans the BGS starts during the third trimester of pregnancy and continues throughout the first two years of life. In mouse and rat the BGS is neonatal, spanning the first 3-4 weeks of life. The BGS is characterized by maturation of axonal and dendritic outgrowth, establishment of neural connections and acquisition of many new motor and sensory abilities. By using the neonatal mouse as an animal model we are able to study the effect of IR during early periods of brain development and which consequences it has for the adult animal. Disturbances in development caused by nicotine, MeHg, PCBs and PBDEs have previously been shown to alter adult spontaneous behaviour and/or neuroprotein levels in mice.Neonatal NMRI male mice were irradiated (0; 0.35 and 0.5 Gy) at one single occasion on postnatal day 10. Mice serving as controls were placed in plastic dishes for a time-period corresponding to the irradiation. Spontaneous behaviour was tested in a novel home environment at 2- and 4-months of age and parameters observed were locomotion, rearing and total activity. Analyses of important neuroprotein levels were performed on 6-month-old control and 0.5 Gy irradiated mice.Spontaneous behaviour test (locomotion, rearing, total activity revealed a significantly deranged behaviour in 2- and 4-month old mice irradiated with 0.35 or 0.5 Gy in a dose-response related manner, when compared to controls. The behavioural alterations were manifested as a reduced activity during at the beginning of the observational period and a higher activity at the end of the observational period. Analyses of the neuroprotein tau, which in human medicine is used as a biomarker for Alzheimer’s disease, showed a significantly higher level in mice irradiated with 0.5 Gy compared to controls. This demonstrates that a single dose of gamma radiation, given at a defined critical time period during brain development, is sufficient to cause persistently reduced cognitive functions and increased levels of tau in mice.
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| 15. |
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| 16. |
- Buratovic, Sonja, 1986-
(författare)
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Low-Dose Ionizing Radiation Induces Neurotoxicity in the Neonate : Acute or fractionated doses and interaction with xenobiotics in mice
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis examines the developmental neurotoxic effects of exposure to low-dose ionizing radiation (IR), alone or together with xenobiotics, during a critical period of neonatal brain development in mice.During mammalian brain development there is a period called the brain growth spurt (BGS), which involves extensive growth and maturation of the brain. It is known that neonatal exposure during the BGS to xenobiotics can have a negative impact on neonatal brain development, resulting in impaired cognitive function in the adult mouse. In humans, the BGS starts during the third trimester of pregnancy and continues for approximately 2 years in the child. The present thesis has identified a defined critical period, during the BGS, when IR can induce developmental neurotoxicity in mice. The observed neurotoxicity was not dependent on sex or strain and manifested as altered neurobehaviour in the adult mouse. Furthermore, fractionated dose exposures appear to be as potent as a higher acute dose. The cholinergic system can be a target system for developmental neurotoxicity of IR, since alterations in adult mouse cholinergic system susceptibility were observed. Co-exposure to IR and nicotine exacerbated the behavioural disturbances and cholinergic system dysfunction. Furthermore, co-exposure with the environmental agent paraquat has indicated that the dopaminergic system can be a potential target. In this thesis, clinically relevant doses of IR and a sedative/anesthetic agent (ketamine) were shown to interact and exacerbate defects in adult mouse neurobehaviour, learning and memory, following neonatal exposure, at doses where the single agents did not have any impact on the measured variables. This indicates a shift in the dose-response curve for IR, towards lower doses, if exposure occurs during the neonatal brain development. In addition, co-exposed mice, showing cognitive defects, expressed elevated levels of tau protein in the cerebral cortex. Furthermore, exacerbation of neurochemical deviations were observed following co-exposure compared to irradiation alone.Further investigations of neurotoxic effects following fractionated or acute low-dose IR, modelling the clinical situation during repeated CT scans or levels of radiation deposited in non-target tissue during radiotherapy, and possible interaction effects with xenobiotics, is of great importance in the field of radioprotection.
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| 17. |
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| 18. |
- Buratovic, Sonja, et al.
(författare)
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Neonatal exposure to a moderate dose of ionizing radiation causes behavioural defects and altered levels of tau protein in mice
- 2014
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Ingår i: Neurotoxicology. - : Elsevier BV. - 0161-813X .- 1872-9711. ; 45, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- Medical use of ionizing radiation (IR) has great benefits for treatment and diagnostic imaging, butprocedures as computerized tomography (CT) may deliver a significant radiation dose to the patient.Recently, awareness has been raised about possible non-cancer consequences from low dose exposure toIR during critical phases of perinatal and/or neonatal brain development.In the present study neonatal NMRI mice were whole body irradiated with a single dose of gammaradiation (0; 350 and 500 mGy) on postnatal day 10 (PND 10). At 2 and 4 months of age, mice of bothsexes were observed for spontaneous behaviour in a novel home environment. The neuroproteinsCaMKII, GAP-43, synaptophysin and total tau in male mouse cerebral cortex and hippocampus wereanalysed 24 h post-irradiation and in adults at 6 months of age exposed to 0 or 500 mGy on PND 10.A significantly dose-response related deranged spontaneous behaviour in 2- and 4-month-old micewas observed, where both males and females displayed a modified habituation, indicating reducedcognitive function. The dose of 350 mGy seems to be a tentative threshold. Six-month-old male miceshowed a significantly increased level of total tau in cerebral cortex after irradiation to 500 mGy compared to controls. This demonstrates that a single moderate dose of IR, given during a defined criticalperiod of brain development, is sufficient to cause persistently reduced cognitive function. Moreover, anelevation of tau protein was observed in male mice displaying reduced cognitive function.
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| 19. |
- Buratovic, Sonja, et al.
(författare)
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Neonatal exposure to a single low dose of ionising radiation causes persistent disruptions in cognitive abilities and increased levels of tau in mice
- 2013
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Ionising radiation (IR) is extensively used in the medical field for treatment and diagnostics. Concern has been raised about possible negative consequences from low dose exposure to IR during critical phases of perinatal and/or neonatal brain development. The brain growth spurt, which is characterized by maturation of axonal and dendritic outgrowth, establishment of neural connections and acquisition of new motor and sensory abilities, occurs perinatally in humans and neonatally in mice. By using the neonatal mouse as an animal model we are able to study the effect of IR during early periods of brain development and which consequences it has for the adult animal.Neonatal NMRI mice were irradiated (0; 0.35 and 0.5 Gy) at one single occasion on postnatal day 10. At 2- and 4-months of age, spontaneous behaviour was tested in a novel home environment and parameters observed were locomotion, rearing and total activity. Analyses of important neuroproteins in cerebral cortex were performed 24h following irradiation (0 and 0.5 Gy) and at 6-months of age.Observations of spontaneous behaviour revealed a significantly deranged behaviour in 2- and 4-month old mice of both sexes irradiated with 0.35 or 0.5 Gy in a dose response related manner. The observed reduced activity during the beginning of the test period and increased activity at the end of the test period indicates a lack of habituation capacity and disrupted cognitive functions. Neuroprotein analyses of cerebral cortex 24h after irradiation and at 6-months of age showed a significantly increased level of tau in mice irradiated with 0.5 Gy compared to controls. This demonstrates that a single dose of IR, given at a defined critical period during brain development, is sufficient to cause persistently reduced cognitive functions and increased levels of tau in mice.
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| 20. |
- Buratovic, Sonja
(författare)
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Neonatal Exposure to Low-Dose Ionizing Radiation in Mice : Developmental Neurotoxic Effects of Single and Fractionated Doses and Interaction with Nicotine
- 2015
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis aims to investigate the developmental neurotoxic effects of low-dose exposure to ionizing radiation, alone or together with nicotine, during a defined critical period of neonatal brain development in mice. Investigation of neurotoxic effects following fractionated or acute low-dose radiation, resembling the clinical situation during repeated CT scans or radiation delivered to non-target tissue during radiotherapy, and possible interaction effects with other agents, is of great importance for risk and safety evaluation.During mammalian brain development there are defined critical periods for induction of developmental neurotoxic effects. One of these critical periods is called the brain growth spurt (BGS) and involves extensive growth and maturation of the brain. It is known that neonatal exposure during the BGS to low doses of radiation, as well as nicotine, can have a negative impact on neonatal brain development, resulting in impaired cognitive function in the adult mouse. The present studies have shown that developmental neurotoxicity following low-dose irradiation can be induced during the same critical period of brain development as previously has been shown for chemicals. The observed neurotoxicity was manifested as altered spontaneous behaviour and habituation capacity, independent of sex, as well as elevated levels of an Alzheimer-related neuroprotein in the adult mouse. Furthermore, fractionated dose regimes seem to be as potent for induction of neurotoxicity and behavioural disturbances as an equivalent single acute dose. The cholinergic system can be a target system for developmental neurotoxicity of ionizing radiation, either alone or in combination with the cholinergic agent nicotine. Co-exposure to ionizing radiation and nicotine exacerbated the behavioural disturbances and cholinergic system dysfunction observed in these studies.Further studies on developmental neurotoxic effects of low-dose neonatal irradiation and interaction with medical drugs and environmental pollutants are important for the field of radioprotection.
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| 21. |
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| 22. |
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| 23. |
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| 24. |
- Eriksson, Per, et al.
(författare)
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Neonatal exposure to whole body ionizing radiation induces adult neurobehavioural defects : Critical period, dose-response effects and strain and sex comparison
- 2016
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328 .- 1872-7549. ; 304, s. 11-19
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Tidskriftsartikel (refereegranskat)abstract
- Development of the brain includes periods which can be critical for its normal maturation. The present study investigates specifically vulnerable peri-/postnatal periods in mice which are essential for understanding the etiology behind radiation induced neurotoxicity and functional defects, including evaluation of neurotoxicity between sexes or commonly used laboratory mouse strains following low/moderate doses of ionizing radiation (IR). Male Naval Medical Research Institute (NMRI) mice, whole body irradiated to a single 500 mGy IR dose, on postnatal day (PND) 3 or PND 10 showed an altered adult spontaneous behaviour and impaired habituation capacity, whereas irradiation on PND 19 did not have any impact on the studied variables. Both NMRI and C57bl/6 male and female mice showed an altered adult spontaneous behaviour and impaired habituation following a single whole body irradiation of 500 or 1000 mGy, but not after 20 or 100 mGy, on PND 10. The present study shows that exposure to low/moderate doses of IR during critical life stages might be involved in the induction of neurological/neurodegenerative disorder/disease. A specifically vulnerable period for radiation induced neurotoxicity seems to be around PND 3-10 in mice. Further studies are needed to investigate mechanisms involved in induction of developmental neurotoxicity following low dose irradiation.
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| 25. |
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| 26. |
- Eriksson, Per, 1951-, et al.
(författare)
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Perfluorinated chemicals (PFOA) can, by interacting with highly brominated diphenyl ethers (PBDE 209) during a defined period of neonatal brain development, exacerbate neurobehavioural defects
- 2023
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Ingår i: Neurotoxicology and Teratology. - : Elsevier. - 0892-0362 .- 1872-9738. ; 96
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Tidskriftsartikel (refereegranskat)abstract
- Perfluorinated compounds (PFCs) and polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent environmental compounds, present in humans and at higher levels in infants/children than in adults. This study shows that co-exposure to pentadecafluorooctanoic acid (PFOA) and 2,2 ',3,3 ',4,4 ',5,5 ',6,6'-decaBDE (PBDE 209) can significantly exacerbate developmental neurobehavioural defects. Neonatal male NMRI mice, 3 and 10 days old, were exposed perorally to PBDE 209 (1.4 or 8.0 mu mol/kg bw), PFOA (1.4 or 14 mu mol/kg bw), co-exposed to PBDE 209 and PFOA (at the given doses), or a vehicle (20% fat emulsion) and observed for spontaneous behaviour in a novel home environment when 2 and 4 months old. The behavioural defects observed included hyperactivity and reduced habituation indicating cognitive defects. This interaction appears most likely dependent on the presence of PBDE 209 and/or its metabolites together with PFOA, during a defined critical period of neonatal brain development, corresponding to the perinatal and newborn period in humans.
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| 27. |
- Hallgren, Stefan, 1978-, et al.
(författare)
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Adult dose-response-related behavioral effects of 4 different pesticides, after neonatal exposure
- 2014
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- There are several different types of pesticides globally used, all with their own characteristics and toxicological potency. In the present study we have exposed male mice neonatally to different doses of four different types of pesticides, carbaryl (carbamate) chlorpyrifos (organophosphate), cypermethrin (pyrethroid) and endosulfan (organochlorine), and tested them for spontaneous behavior in a novel home environment at adult age. The doses used were 0.5 – 20 mg carbaryl/kg bw, 0.1 – 5.0 mg chlorpyrifos/kg bw, 0.1 – 5.0 mg cypermethrin/kg bw and 0.05 – 20 mg endosulfan/kg bw. All four pesticides induced adult disturbances in the spontaneous behavior in a novel home environment, affecting cognitive function, at 2 months of age. Carbaryl induced a dose-response related effect on spontaneous behavior from 5 mg/kg bw and up, while chlorpyrifos only induced a weak effect with the highest dose tested (5 mg/kg bw). The pyrethroid cypermethrin induced dose-response related neurotoxicity from 0.5 mg/kg bw and up. The organochlorine endosulfan also induced dose-response related neurotoxicity from 0.1 mg/kg bw and up These disturbances also persisted when the animals were re-observed at 4 months of age, indicating that these effects are long-lasting or even irreversible. From this study we conclude that endosulfan seem to be the most potent, of these four compounds, to induce cognitive behavioral effects in the adult after neonatal exposure, while carbaryl has the lowest potency to induce these types of neurotoxic effects.
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| 28. |
- Hladik, Daniela, et al.
(författare)
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Combined Treatment with Low-Dose Ionizing Radiation and Ketamine Induces Adverse Changes in CA1 Neuronal Structure in Male Murine Hippocampi
- 2019
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 20:23
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Tidskriftsartikel (refereegranskat)abstract
- In children, ketamine sedation is often used during radiological procedures. Combined exposure of ketamine and radiation at doses that alone did not affect learning and memory induced permanent cognitive impairment in mice. The aim of this study was to elucidate the mechanism behind this adverse outcome. Neonatal male NMRI mice were administered ketamine (7.5 mg kg(-1)) and irradiated (whole-body, 100 mGy or 200 mGy, Cs-137) one hour after ketamine exposure on postnatal day 10. The control mice were injected with saline and sham-irradiated. The hippocampi were analyzed using label-free proteomics, immunoblotting, and Golgi staining of CA1 neurons six months after treatment. Mice co-exposed to ketamine and low-dose radiation showed alterations in hippocampal proteins related to neuronal shaping and synaptic plasticity. The expression of brain-derived neurotrophic factor, activity-regulated cytoskeleton-associated protein, and postsynaptic density protein 95 were significantly altered only after the combined treatment (100 mGy or 200 mGy combined with ketamine, respectively). Increased numbers of basal dendrites and branching were observed only after the co-exposure, thereby constituting a possible reason for the displayed alterations in behavior. These data suggest that the risk of radiation-induced neurotoxic effects in the pediatric population may be underestimated if based only on the radiation dose.
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| 29. |
- Kempf, Stefan J., et al.
(författare)
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Ionising Radiation Immediately Impairs Synaptic Plasticity-Associated Cytoskeletal Signalling Pathways in HT22 Cells and in Mouse Brain : An In Vitro/In Vivo Comparison Study
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10, s. e110464-
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Tidskriftsartikel (refereegranskat)abstract
- Patients suffering from brain malignancies are treated with high-dose ionising radiation. However, this may lead to severe learning and memory impairment. Preventive treatments to minimise these side effects have not been possible due to the lack of knowledge of the involved signalling pathways and molecular targets. Mouse hippocampal neuronal HT22 cells were irradiated with acute gamma doses of 0.5 Gy, 1.0 Gy and 4.0 Gy. Changes in the cellular proteome were investigated by isotope-coded protein label technology and tandem mass spectrometry after 4 and 24 hours. To compare the findings with the in vivo response, male NMRI mice were irradiated on postnatal day 10 with a gamma dose of 1.0 Gy, followed by evaluation of the cellular proteome of hippocampus and cortex 24 hours post-irradiation. Analysis of the in vitro proteome showed that signalling pathways related to synaptic actin-remodelling were significantly affected at 1.0 Gy and 4.0 Gy but not at 0.5 Gy after 4 and 24 hours. We observed radiation-induced reduction of the miR-132 and Rac1 levels; miR-132 is known to regulate Rac1 activity by blocking the GTPase-activating protein p250GAP. In the irradiated hippocampus and cortex we observed alterations in the signalling pathways similar to those in vitro. The decreased expression of miR-132 and Rac1 was associated with an increase in hippocampal cofilin and phospho-cofilin. The Rac1-Cofilin pathway is involved in the modulation of synaptic actin filament formation that is necessary for correct spine and synapse morphology to enable processes of learning and memory. We suggest that acute radiation exposure leads to rapid dendritic spine and synapse morphology alterations via aberrant cytoskeletal signalling and processing and that this is associated with the immediate neurocognitive side effects observed in patients treated with ionising radiation.
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| 30. |
- Kempf, Stefan J., et al.
(författare)
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The cognitive defects of neonatally irradiated miceare accompanied by changed synaptic plasticity,adult neurogenesis and neuroinflammation
- 2014
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Ingår i: Molecular Neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 9, s. 57-
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Tidskriftsartikel (refereegranskat)abstract
- Background/purpose of the study: Epidemiological evidence suggests that low doses of ionising radiation(≤1.0 Gy) produce persistent alterations in cognition if the exposure occurs at a young age. The mechanismsunderlying such alterations are unknown. We investigated the long-term effects of low doses of total body gammaradiation on neonatally exposed NMRI mice on the molecular and cellular level to elucidate neurodegeneration.Results: Significant alterations in spontaneous behaviour were observed at 2 and 4 months following a single 0.5or 1.0 Gy exposure. Alterations in the brain proteome, transcriptome, and several miRNAs were analysed 6–7months post-irradiation in the hippocampus, dentate gyrus (DG) and cortex. Signalling pathways related to synapticactin remodelling such as the Rac1-Cofilin pathway were altered in the cortex and hippocampus. Further, synapticproteins MAP-2 and PSD-95 were increased in the DG and hippocampus (1.0 Gy). The expression of synapticplasticity genes Arc, c-Fos and CREB was persistently reduced at 1.0 Gy in the hippocampus and cortex. Thesechanges were coupled to epigenetic modulation via increased levels of microRNAs (miR-132/miR-212, miR-134).Astrogliosis, activation of insulin-growth factor/insulin signalling and increased level of microglial cytokine TNFαindicated radiation-induced neuroinflammation. In addition, adult neurogenesis within the DG was persistentlynegatively affected after irradiation, particularly at 1.0 Gy.Conclusion: These data suggest that neurocognitive disorders may be induced in adults when exposed at a youngage to low and moderate cranial doses of radiation. This raises concerns about radiation safety standards andregulatory practices.
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| 31. |
- Lee, Iwa, et al.
(författare)
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Developmental neurotoxic effects of two pesticides : behavior and biomolecular studies on chlorpyrifos and carbaryl
- 2015
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 288:3, s. 429-438
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Tidskriftsartikel (refereegranskat)abstract
- In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. We studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5 mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0 mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8–12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development.
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| 32. |
- Lee, Iwa, et al.
(författare)
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Developmental neurotoxic effects of two pesticides : behavior and neuroprotein studies on endosulfan and cypermethrin
- 2015
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 335, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Developmental neurotoxicity of industrial chemicals and pharmaceuticals have been of growing interest in recent years due to the increasing reports of neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and autism. Exposure to these substances during early development may lead to adverse behavior effects manifested at a later phase of life. Pesticides are a wide group of chemicals which are still actively used and residues are found in the environment and in food products.The present study investigated the potential developmental neurotoxic effects of two different types of pesticides, endosulfan and cypermethrin, after a single neonatal exposure during a critical period of brain development. Ten-day-old male NMRI mice were administrated an oral dose of endosulfan or cypermethrin (0.1 or 0.5 mg/kg body weight, respectively). Levels of proteins were measured in the neonatal and adult brain, and adult behavioral testing was performed. The results indicate that both pesticides may induce altered levels of neuroproteins, important for normal brain development, and neurobehavioral abnormalities manifested as altered adult spontaneous behavior and ability to habituate to a novel home environment. The neurotoxic behavioral effects were also presentseveral months after the initial testing, indicating long-lasting or even persistent irreversible effects. Also, the present study suggests a possible link between the altered levels of neuroprotein and changes in behavior when exposed during a critical period of brain development.
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| 33. |
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| 34. |
- Philippot, Gaetan, et al.
(författare)
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Developmental effects of neonatal fractionated co-exposure to low-dose gamma radiation and paraquat on behaviour in adult mice
- 2019
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Ingår i: Journal of Applied Toxicology. - : Wiley. - 0260-437X .- 1099-1263. ; 39:4, s. 582-589
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Tidskriftsartikel (refereegranskat)abstract
- Radiological methods for screening, diagnostics and therapy are often used in healthcare; however, it has recently been reported that developmental exposure to low-dose ionizing radiation (IR) causes neurotoxicity. Environmental chemicals also have the potential to affect the developing brain and the concomitant effects caused by IR and chemicals are of high interest today. We therefore aim to investigate if low-dose IR can interact with the known neurotoxicant paraquat to induce neurotoxicity in the neonatal mouse model. Using the same model, we also aim to investigate if fractionated low-dose IR can be as neurotoxic as higher acute doses. Male mice were exposed to a single dose of paraquat (0.2 or 0.02 mg/kg) on postnatal day 10 and 11. Two hours following paraquat exposure, mice were whole body irradiated with 100 or 300 mGy gamma radiation (Cs-137). Behavioural observations were performed at 2 and 3 months of age. Following behavioural testing, we evaluated striatal dopaminergic gene transcription. Animals co-exposed to IR and paraquat generally displayed altered spontaneous behaviour compared to controls and single agent exposed mice. Stronger effects by combined exposure were also observed on adult memory and learning. However, dopaminergic gene transcript levels remained unchanged by treatment. Co-exposure to low-dose IR and paraquat can interact to exacerbate neurotoxic effects and to impair cognitive function. Furthermore, fractionation of the radiation dose was observed to be as potent as higher acute exposure for induction of developmental neurotoxicity.
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| 35. |
- Philippot, Gaëtan, et al.
(författare)
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Paracetamol (Acetaminophen) and its Effect on the Developing Mouse Brain
- 2022
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Ingår i: Frontiers in Toxicology. - : Frontiers Media S.A.. - 2673-3080. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol, or acetaminophen (AAP), is the most commonly used analgesic during pregnancy and early life. While therapeutic doses of AAP are considered harmless during these periods, recent findings in both humans and rodents suggest a link between developmental exposure to AAP and behavioral consequences later in life. The aim of this study is to evaluate the impact of neonatal exposure to clinically relevant doses of AAP on adult spontaneous behavior, habituation, memory, learning, and cognitive flexibility later in life using a mouse model. Markers of oxidative stress, axon outgrowth, and glutamatergic transmission were also investigated in the hippocampus during the first 24 h after exposure. In addition, potential long-term effects on synaptic density in the hippocampus have been investigated. In a home cage setting, mice neonatally exposed to AAP (30 + 30 mg/kg, 4 h apart) on postnatal day 10 displayed altered spontaneous behavior and changed habituation patterns later in life compared to controls. These mice also displayed reduced memory, learning and cognitive flexibility compared to control animals in the Morris water maze. An increase of markers for oxidative stress was observed in the hippocampus 6 h after AAP exposure. As AAP is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for risk assessment. Here we show that AAP can have persistent negative effects on brain development and suggest that AAP, despite the relatively low doses, is capable to induce acute oxidative stress in the hippocampus.
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| 36. |
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| 37. |
- Viberg, Henrik, et al.
(författare)
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Dose-dependent behavioral disturbances after a single neonatal Bisphenol A dose
- 2011
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 209:2-3, s. 188-195
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Tidskriftsartikel (refereegranskat)abstract
- Bisphenol A is widely used in polymer products for food and beverage packaging, baby bottles, dental sealants, and fillings, adhesives, protective coatings, flame retardants, water supply pipes, and compact discs, and is found in the environment and in placental tissue, fetuses and breast milk. We have recently reported that neonatal exposure to other environmental pollutants can induce persistent aberrations in spontaneous behavior and also affect learning and memory functions in the adult animal. Furthermore, recent reports indicate that pre- and perinatal exposure to Bisphenol A can induce neurotoxic effects. The present study indicates that a single exposure to Bisphenol A on postnatal day 10 can alter adult spontaneous behavior and cognitive function in mice, effects that are both dose–response related and long-lasting/irreversible. Earlier studies on neonatal exposure to persistent organic pollutants (POPs) have shown the cholinergic system to be a target of neurotoxicity, but here only minor effects on the nicotine-induced behavior was seen. Furthermore, Morris swim-maze and the elevated plus-maze did not reveal any effects on spatial learning and anxiety-like behaviors. The present findings show similarities with effects earlier reported after pre- and perinatal exposure to Bisphenol A, and also with effects seen after a single postnatal exposure to other POPs, such as PBDEs, PCBs and PFCs.
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| 38. |
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