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

Abstract

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-

Neonatal Exposure to a Combination of N -Methyl-d-aspartate and γ-Aminobutyric Acid Type A Receptor Anesthetic Agents Potentiates Apoptotic Neurodegeneration and Persistent Behavioral Deficits

“…52 Hyperactivity and RAM acquisition deficits have also been reported related to olfactory mucosal metaplasia after treatment with methylsulphonyl-dichlorobenzene in mice and rats. 53,54 Both a subgroup of adults with residual attention deficithyperactivity disorder with hyperactivity 55 and one third of first-episode psychosis 56,57 have a measurable olfactory identification deficit on a smell identification test. Reduced olfactory sensitivity, discrimination, and identification in patients with alcohol dependence have also been reported.…”

Effects of dichlorobenzene on acetylcholine receptors in human neuroblastoma SH-SY5Y cells

“…The primary route for the contact of DCB is inhalation, and olfactory mucosal lesions induced by DCB had been found (Bahrami et al, 1999). A major DCB metabolite, 2,6-dichlorophenol, has been detected in olfactory bulb and olfactory mucosa, and has been linked to increased glial fibrillary acidic protein in the olfactory bulb of mice (Carlsson et al, 2003). The nasal cavity contains an olfactory neuron, which links with an interneuron and is used to relay information to the brain; therefore, neuronal signal transduction is important.…”