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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
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
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.
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2016 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 304, 11-19 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 304, 11-19 p.
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-282365DOI: 10.1016/j.bbr.2016.02.008ISI: 000372939400002PubMedID: 26876140OAI: oai:DiVA.org:uu-282365DiVA: diva2:916929
Funder
Swedish Radiation Safety AuthorityEU, FP7, Seventh Framework Programme, 29552
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2017-11-30Bibliographically approved
In thesis
1. 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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Eriksson, PerBuratovic, SonjaFredriksson, AndersStenerlöw, Bo

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