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Developmental effects of neonatal fractionated co-exposure to low-dose gamma radiation and paraquat on behaviour in adult mice
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.ORCID iD: 0000-0003-2024-1824
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.
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2019 (English)In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 39, no 4, p. 582-589Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 39, no 4, p. 582-589
National Category
Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-282374DOI: 10.1002/jat.3748ISI: 000461835200003PubMedID: 30426514OAI: oai:DiVA.org:uu-282374DiVA, id: diva2:916959
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2019-04-05Bibliographically 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. p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1366
Keywords
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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Philippot, GaetanStenerlöw, BoFredriksson, AndersEriksson, Per

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