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Neurotoxic Effects of Nicotine During Neonatal Brain Development: Critical Period and Adult Susceptibility
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis examined neurotoxic effects of nicotine exposure during a defined critical period of neonatal brain development in mice.

In our environment there are numerous hazardous contaminants that an individual can be exposed to during its entire lifetime. In many mammalian species the neonatal period is characterised by a rapid development of the brain. The present studies have identified a defined critical period during the neonatal brain development in mice, where exposure to low doses of nicotine causes permanent disturbances in the cholinergic nicotinic receptors and altered behaviour response to nicotine at adult age. This adult reaction to nicotine, a hypoactive response, was the opposite of that observed in control animals and animals exposed to nicotine before or after this period. Animals showing a hypoactive response to nicotine lacked nicotinic low affinity binding sites in the cerebral cortex. Furthermore, neonatal exposure to nicotine affected learning and memory in adult animals, an effect that was time-dependent. This thesis also showed that neonatal exposure to nicotine increased adult susceptibility to a repeated exposure of nicotine, manifested as an even more pronounced effect in spontaneous behaviour after challenging doses of nicotine. In these animals the nicotinic receptors in the cerebral cortex, assayed by a-bungarotoxin, was decreased.

Neonatal exposure to nicotine was also shown to increase adult susceptibility to the organophosphate paraoxon, a known cholinergic agent, and to the brominated flame retardant 2,2´,4,4´,5-pentabromodiphenyl ether, a novel environmental agent, at adult age. This was seen at doses that did not affect behaviour in control animals, and was manifested as deranged spontaneous behaviour and reduced habituation, aberrations that also worsened with age.

The results indicate that differences in adult susceptibility to environmental pollutants are not necessarily an inherited condition. Rather they may well be acquired by low dose exposure to toxic agents during early life.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 48
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 907
Keywords [en]
Biology, nicotine, neonatal development, behaviour, nicotinic receptors, susceptibility, cholinergic system, paraoxon, PBDE
Keywords [sv]
Biologi
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-3770ISBN: 91-554-5800-9 (print)OAI: oai:DiVA.org:uu-3770DiVA, id: diva2:163637
Public defence
2003-12-05, Lindahlsalen, EBC, Norbyv. 18A, Uppsala, 09:00
Opponent
Supervisors
Available from: 2003-11-11 Created: 2003-11-11Bibliographically approved
List of papers
1. Exposure to nicotine during a defined period in neonatal life induces permanent changes in brain nicotinic receptors and in behaviour of adult mice
Open this publication in new window or tab >>Exposure to nicotine during a defined period in neonatal life induces permanent changes in brain nicotinic receptors and in behaviour of adult mice
2000 In: Brain Research, Vol. 853, p. 41-48Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91050 (URN)
Available from: 2003-11-11 Created: 2003-11-11Bibliographically approved
2. Neurobehavioural defects in adult mice neonatally exposed to nicotine: changes in nicotine-induced behaviour and maze learning performance
Open this publication in new window or tab >>Neurobehavioural defects in adult mice neonatally exposed to nicotine: changes in nicotine-induced behaviour and maze learning performance
2001 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 123, no 2, p. 185-192Article in journal (Refereed) Published
Abstract [en]

Neonatal exposure to low doses of nicotine has been shown to disturb the development of low-affinity nicotinic binding sites in the cerebral cortex and to elicit a deviant behavioural response to nicotine in adult mice. In this study, 10-day-old male NMRI mice were exposed to one of three different doses of nicotine (3.3, 33, or 66 μg nicotine-base/kg body wt.) s.c. twice daily on 5 consecutive days to study dose–response effects of nicotine on adult spontaneous and nicotine-induced motor behaviour. The nicotine-induced behaviour test revealed a hypoactive response to nicotine in 4-month-old mice neonatally exposed to 33 or 66 μg nicotine-base, whereas the response to nicotine in control animals and mice exposed to 3.3 μg nicotine-base was an increased activity. Learning and memory functions were also investigated in adult animals neonatally exposed to 66 μg nicotine-base/kg body wt. in the same manner, in the Morris water maze and in the Radial arm maze. In the swim maze and the Radial arm maze tests, no significant differences were observed between nicotine-treated and control animals at the age of 4 months. At 7 months, however, a significant difference in performance was evident, indicating a time-response/time-dependent effect. Furthermore, it was shown that in mice exposed neonatally to a nicotine dose known to inhibit the development of the nicotinic low affinity-binding site (LA), the response to nicotine could not cause any increase in spontaneous motor activity as seen in controls.

Keywords
nicotine, neonatal, development, spontaneous behaviour, adult, maze
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-91051 (URN)10.1016/S0166-4328(01)00207-8 (DOI)
Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2017-12-14Bibliographically approved
3. Increased susceptibility to adult paraoxon exposure in mice neonatally exposed to nicotine
Open this publication in new window or tab >>Increased susceptibility to adult paraoxon exposure in mice neonatally exposed to nicotine
2004 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 82, no 2, p. 555-561Article in journal (Refereed) Published
Abstract [en]

Low-dose exposure of neonatal mice to nicotine has earlier been shown to induce an altered behavioral response to nicotine in adulthood. Organophosphorus insecticides are known to affect the cholinergic system by inhibition of acetylcholinesterase. This study was undertaken to investigate whether neonatal exposure to nicotine makes mice more susceptible to a known cholinergic agent. Neonatal, 10-day-old, male mice were exposed to nicotine-base (33 microg/kg body weight) or saline s.c. twice daily on five consecutive days. At 5 months of age the animals were exposed to paraoxon (0.17 or 0.25 mg/kg body weight [29% and 37% inhibition of cholinesterase, respectively]) or saline sc every second day for 7 days. Before the first paraoxon injection, the animals were observed for spontaneous motor behavior. The spontaneous motor behavior test did not reveal any differences in behavior between the treatment groups. Immediately after the spontaneous behavior test, the animals received the first injection of paraoxon and were observed for acute effects of paraoxon on spontaneous motor behavior. The acute response to paraoxon in the spontaneous motor behavior test was a decreased level of activity in mice neonatally exposed to nicotine. Control animals showed no change in activity. Two months after the paraoxon treatment, the animals were again tested for spontaneous motor behavior. Animals neonatally exposed to nicotine and exposed to paraoxon as adults showed a deranged spontaneous motor behavior, including hyperactivity and lack of habituation.

Keywords
Animals, Animals; Newborn/*physiology, Behavior; Animal/drug effects, Cholinesterase Inhibitors/*toxicity, Cholinesterases/metabolism, Habituation (Psychophysiology)/drug effects, Insecticides/*toxicity, Male, Mice, Motor Activity/drug effects, Nicotine/*pharmacology, Nicotinic Agonists/*pharmacology, Paraoxon/*toxicity, Receptors; Muscarinic/drug effects, Receptors; Nicotinic/drug effects, Research Support; Non-U.S. Gov't
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-91052 (URN)10.1093/toxsci/kfh274 (DOI)15356346 (PubMedID)
Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2017-12-14Bibliographically approved
4. Increased adult susceptibility to paraoxon in mice neonatally exposed to nicotine
Open this publication in new window or tab >>Increased adult susceptibility to paraoxon in mice neonatally exposed to nicotine
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91053 (URN)
Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2010-01-13Bibliographically approved
5. Increased adult susceptibility to a brominated flame retardant, 2,2´4,4´,5-pentabromodiphenyl ether (PBDE 99) in mice neonatally exposed to nicotine
Open this publication in new window or tab >>Increased adult susceptibility to a brominated flame retardant, 2,2´4,4´,5-pentabromodiphenyl ether (PBDE 99) in mice neonatally exposed to nicotine
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91054 (URN)
Available from: 2003-11-11 Created: 2003-11-11 Last updated: 2010-01-13Bibliographically approved

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