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Neonatal exposure to a moderate dose of ionizing radiation causes behavioural defects and altered levels of tau protein in mice
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö.
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2014 (English)In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 45, 48-55 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 45, 48-55 p.
National Category
Other Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-240576DOI: 10.1016/j.neuro.2014.09.002ISI: 000346955100006PubMedID: 25265567OAI: oai:DiVA.org:uu-240576DiVA: diva2:776723
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2017-06-30Bibliographically approved
In thesis
1. Neonatal Exposure to Low-Dose Ionizing Radiation in Mice: Developmental Neurotoxic Effects of Single and Fractionated Doses and Interaction with Nicotine
Open this publication in new window or tab >>Neonatal Exposure to Low-Dose Ionizing Radiation in Mice: Developmental Neurotoxic Effects of Single and Fractionated Doses and Interaction with Nicotine
2015 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

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. 

Place, publisher, year, edition, pages
Uppsala: , 2015. 38 p.
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-242816 (URN)
Presentation
2015-03-16, Hörstadius, Norbyvägen 18a, Uppsala, 10:15 (English)
Opponent
Supervisors
Funder
EU, FP7, Seventh Framework Programme, 29552Swedish Radiation Safety Authority
Available from: 2015-03-19 Created: 2015-02-02 Last updated: 2015-03-19Bibliographically approved
2. Low-Dose Ionizing Radiation Induces Neurotoxicity in the Neonate: Acute or fractionated doses and interaction with xenobiotics in mice
Open this publication in new window or tab >>Low-Dose Ionizing Radiation Induces Neurotoxicity in the Neonate: Acute or fractionated doses and interaction with xenobiotics in mice
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1366
Keyword
Ionizing radiation, Neonatal, Neurotoxicity, Behaviour, Nicotine, Ketamine, Mouse, Cognition, Acute irradiation, Fractionated irradiation
National Category
Other Biological Topics
Identifiers
urn:nbn:se:uu:diva-282625 (URN)978-91-554-9545-9 (ISBN)
Public defence
2016-05-26, Lindahlsalen, EBC, Norbyvägen 18 A, 75236, Uppsala, 09:30 (English)
Opponent
Supervisors
Funder
Swedish Radiation Safety AuthorityEU, FP7, Seventh Framework Programme, 29552
Available from: 2016-05-03 Created: 2016-04-06 Last updated: 2016-05-12

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Buratovic, SonjaStenerlöw, BoFredriksson, AndersViberg, HenrikEriksson, Per

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