Behavioural changes related to olfactory mucosal metaplasia and bulbar glial fibrillary acidic protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice.
Methylsulphonyl-2,6-dichlorobenzene [2,6-(diCl-MeSO(2)-B)], and its 2,5-chlorinated isomer [2,5-(diCl-MeSO(2)-B)] bind firmly in the olfactory mucosa of mice. Both isomers are also selectively localised in the olfactory bulb. Persistent olfactory mucosal metaplasia is induced by 2,6-(diCl-MeSO(2)-B) whereas 2,5-(diCl-MeSO(2)-B) has no effects. Furthermore, a strong induction of glial fibrillary acidic protein (GFAP) restricted to the olfactory bulb has been reported in 2,6-(diCl-MeSO(2)-B)-treated mice. To explore whether these lesions give rise to early or long-lasting changes in behaviour, spontaneous motor activity and radial arm maze (RAM) learning were examined at 1, 2, 4 and 12 weeks following an intraperitoneal injection of a single low (32 mg/kg) or high (65 mg/kg) dose of 2,6-(diCl-MeSO(2)-B). 2,5-(DiCl-MeSO(2)-B) (65 mg/kg) was used as a negative control. Hyperactivity was observed in all treatment groups while deficits in the RAM performance was only seen in the 2,6-(diCl-MeSO(2)-B)-treated groups. Alterations in motor activity and impaired performance in the RAM-test induced by 2,6-(diCl-MeSO(2)-B) persisted up to 2 weeks in the low-dose group and 12 weeks in the high-dose group. The low-dose group consistently showed a less pronounced effect than the high-dose group. The 2,5-(diCl-MeSO(2)-B)-induced changes in motor activity declined rapidly and did not remain after 2 weeks. As determined by immunohistochemistry, 2,6-(diCl-MeSO(2)-B)-induced GFAP immunoreactivity was mainly confined to the glomerular layer of the olfactory bulb. We propose that the behavioural deficits caused by 2,6-(diCl-MeSO(2)-B) result from a primary loss of sensory neurons in the olfactory mucosa with consequent astrocyte proliferation in the glomerular layer of the olfactory bulb. A targeted uptake of metabolites into the olfactory bulb could also contribute to the GFAP induction and/or behaviour response.
Carlsson
Carina
C
Department of Environmental Toxicology, Uppsala University, Norbyvägen 18A, 752 36, Uppsala, Sweden. Carina.Carlsson@ebc.uu.se
Bahrami
Fariba
F
Fredriksson
Anders
A
Brandt
Ingvar
I
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001555:Benzene Derivatives / Q000633:toxicity*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D018782:Maze Learning / Q000187:drug effects; D008679:Metaplasia; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D009831:Olfactory Mucosa / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
D001555:Benzene Derivatives; D005904:Glial Fibrillary Acidic Protein; C120874:methylsulfonyl-2,5-dichlorobenzene; C120875:methylsulfonyl-2,6-dichlorobenzene