Behavioural changes related to olfactory mucosal metaplasia and bulbar glial fibrillary acidic protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice

Carlsson, Carina; Bahrami, Fariba; Fredriksson, Anders; Brandt, Ingvar

doi:10.1007/s00204-002-0363-5

Cited by 4 publications

(10 citation statements)

References 32 publications

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“…We have previously reported that 2,6‐diClPh‐MeSO 2 causes long lasting, but transient, behavioural deficits in mice (Carlsson et al 2002). We proposed that these effects originated mainly from the loss of olfactory neuroepithelium, deterioration of nerve bundles, and a subsequent loss of odorant perception.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in the low dosed groups acquisition deficits were evident at the third day in female and male rats and in male but not female mice. We have previously concluded that at least part of the increased motor activity was not dependent on olfactory mucosal deficits (Carlsson et al 2002). The dramatic differences in histopathological alterations for the two species combined with the behavioural results strengthen this conclusion.…”

Section: Discussionmentioning

confidence: 99%

“…Based on these changes in the olfactory mucosa and brain, we hypothesized that 2,6‐diClPh‐MeSO 2 is a neurotoxic chemical that can also give rise to neurobehavioural disturbances. Indeed, we were able to demonstrate that 2,6‐diClPh‐MeSO 2 induces dose‐dependent (32 and 65 mg/kg as a single intraperitoneal injection) and long‐lasting (≥12 weeks) changes in spontaneous motor activity and radial arm maze acquisition in mice (Carlsson et al 2002). In contrast to 2,6‐diClPh‐MeSO 2 , the 2,5‐chlorinated isomer does not induce histological changes in the olfactory mucosa or increased glial fibrillary acidic protein levels in the olfactory bulb (Bahrami et al 1999 & 2000b).…”

mentioning

confidence: 96%

“…In contrast to 2,6‐diClPh‐MeSO 2 , the 2,5‐chlorinated isomer does not induce histological changes in the olfactory mucosa or increased glial fibrillary acidic protein levels in the olfactory bulb (Bahrami et al 1999 & 2000b). Accordingly, the 2,5‐chlorinated isomer failed to affect the radial arm maze learning, although it gave rise to a transient increase (2 weeks) in spontaneous motor activity in mice (Carlsson et al 2002). Based on these observations, the deficits in radial arm maze learning in 2,6‐diClPh‐MeSO 2 dosed mice were proposed to be related to the olfactory mucosal lesions.…”

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confidence: 99%

“…Within two weeks after dosing (≥16 mg/kg), a persistent metaplastic remodelling of the lamina propria starts to develop, characterised by massive fibrosis, cartilage/bone formation in the fibrotic masses, and polyposis (Bahrami et al 2000a). In addition, a long‐lasting but transient induction of glial fibrillary acidic protein is observed, predominantly localised to the glomerular layer of the olfactory bulb (Bahrami et al 2000a; Carlsson et al 2002). Based on these changes in the olfactory mucosa and brain, we hypothesized that 2,6‐diClPh‐MeSO 2 is a neurotoxic chemical that can also give rise to neurobehavioural disturbances.…”

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2,6‐Dichlorophenyl Methylsulphone Induced Behavioural Impairments in Rats and Mice in Relation to Olfactory Mucosal Metaplasia

Carlsson

Fredriksson

Brandt

2003

Pharmacology & Toxicology

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2,6-Dichlorophenyl methylsulphone (2,6-diClPh-MeSO 2 ) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6-diClPh-MeSO 2 gives rise to a long-lasting hyperactivity along with an impaired radial arm maze performance. To study cause-effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re-examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6-diClPh-MeSO 2 (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose-dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6-diClPhMeSO 2 gave rise to significantly increased motor-activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein-induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6-diClPh-MeSO 2 in the brain rather than being a consequence of the olfactory mucosal lesion.The olfactory mucosa has a high metabolic capacity. Several substances including the herbicides dichlobenil (2,6-dichlorobenzonitrile), chlorthiamid (2,6-dichlorothiobenzamide) and the environmental dichlobenil metabolite 2,6-dichlorobenzamide, induce olfactory mucosal toxicity following metabolic activation and covalent binding in the Bowman's glands (Brandt et al. 1990) (Brittebo et al. & 1992. Methylsulphonyl-2,6-dichlorobenzene (2,6-diClPh-MeSO 2 ) is another olfactory toxicant sharing the 2,6-dichlorinated benzene structure (Bahrami et al. 1999(Bahrami et al. & 2000b. Based on the high toxic potency, 2,6-diClPh-MeSO 2 has been used as a model compound to examine the mechanism of action and the longterm toxicity in the olfactory system in rodents. The nontoxic 2,5-dichlorinated isomer (2,5-diClPh-MeSO 2 ) has served as a negative control. Following a single toxic dose of 2,6-diClPh-MeSO 2 (Ø4 mg/kg), degeneration and necrosis of the Bowman' s glands will develop. Subsequent to this primary toxic event, degeneration and shedding of the olfactory neuroepithelium is observed (Ø8 mg/kg), followed by a repopulation of the basement membrane with an atypical, respiratory-like epithelium. Within two weeks after dos-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 96%

mentioning

confidence: 99%

mentioning

confidence: 99%

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2,6‐Dichlorophenyl Methylsulphone Induced Behavioural Impairments in Rats and Mice in Relation to Olfactory Mucosal Metaplasia

Carlsson

Fredriksson

Brandt

2003

Pharmacology & Toxicology

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Toxicant-induced ER-stress and caspase activation in the olfactory mucosa

Franzén

Brittebo

2005

Arch Toxicol

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The potent olfactory toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO(2)) induces rapid cell death and long-term metaplastic changes in the olfactory regions of rodents. The damage is related to a tissue-specific and extensive cytochrome P450 (CYP)-mediated metabolic activation of the compound to reactive intermediates. The aim of the present study was to examine the early, cell-specific changes leading to cell death in the olfactory mucosa of mice exposed to 2,6-diClPh-MeSO(2). We have examined the expression of the ER-specific stress protein GRP78, the presence of secretory glycoproteins, and the cellular activation of the initiator caspase 12 and the downstream effector caspase 3. 2,6-DiClPh-MeSO(2) induced rapid and cell-specific expression of GRP78, and activation of caspases 12 and 3 in the Bowman's glands. No similar early onset changes in the neuroepithelium were observed. Based on these results, we propose that extensive lesions are initiated in the Bowman's glands and that the metabolic activation of 2,6-diClPh-MeSO(2) elicits ER-stress response and subsequent apoptotic signaling at this site. Since most of the Bowman's glands had oncotic morphology, the results suggest that the terminal phase of apoptosis was blocked and that these glands finally succumb to other routes of cell death.

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Differential gene expression in the olfactory bulb following exposure to the olfactory toxicant 2,6-dichlorophenyl methylsulphone and its 2,5-dichlorinated isomer in mice

et al. 2007

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Behavioural changes related to olfactory mucosal metaplasia and bulbar glial fibrillary acidic protein (GFAP) induction in methylsulphonyl-dichlorobenzene-treated mice

Cited by 4 publications

References 32 publications

2,6‐Dichlorophenyl Methylsulphone Induced Behavioural Impairments in Rats and Mice in Relation to Olfactory Mucosal Metaplasia

2,6‐Dichlorophenyl Methylsulphone Induced Behavioural Impairments in Rats and Mice in Relation to Olfactory Mucosal Metaplasia

Toxicant-induced ER-stress and caspase activation in the olfactory mucosa

Differential gene expression in the olfactory bulb following exposure to the olfactory toxicant 2,6-dichlorophenyl methylsulphone and its 2,5-dichlorinated isomer in mice

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