Persistent Olfactory Mucosal Metaplasia and Increased Olfactory Bulb Glial Fibrillary Acidic Protein Levels Following a Single Dose of Methylsulfonyl-dichlorobenzene in Mice: Comparison of the 2,5- and 2,6-Dichlorinated Isomers

Abstract

Histopathology was used to characterize long-term toxic effects in the olfactory system following a single ip dose (4–65 mg/kg) of methylsulfonyl-2,6-dichlorobenzene, (2,6-(diCl-MeSO2-B)), in female NMRI mice. The effects of 2,6-(diCl-MeSO2-B) and its 2,5-chlorinated isomer, (2,5-(diCl-MeSO2-B)), on the levels of glial fibrillary acidic protein (GFAP; a biomarker for neurotoxicity) in different brain regions were examined by an enzyme-linked immunosorbent assay (ELISA). The histopathologic effects of 2,6-(diCl-MeSO2-B) were dose-, time-, and tissue-dependent. At the highest doses (16–65 mg/kg), the initial effect of 2,6-(diCl-MeSO2-B) was necrosis of the Bowman's glands, followed by a sequence of secondary events including degeneration of the olfactory neuroepithelium, repopulation of the basement membrane by a ciliated respiratorylike epithelium, fibrosis and ossification in the lamina propria, formation of bilateral polyps, angiogenesis, and disappearance of nerve bundles. Remodeling was most pronounced in the dorsal meatus of the olfactory mucosa and persisted for the duration of the experiment (46 weeks). A dose-dependent induction of GFAP in the olfactory bulb of mice treated with 2,6-(diCl-MeSO2-B) was observed at all doses examined (16–65 mg/kg). GFAP levels were highest 2 weeks after treatment (eightfold induction at 65 mg/kg) and then gradually decreased to normal within 26 weeks. The 2,5-substituted isomer (65 mg/kg) did not induce GFAP in the olfactory bulb and or toxicity in the olfactory mucosa. In conclusion, a single dose of 2,6-(diCl-MeSO2-B) results in persistent metaplasia and remodeling of the olfactory mucosa, and a long-lasting but transient induction of GFAP in the olfactory bulb. It is proposed that methylsulfonyl-2,6-dichlorobenzene may serve as an experimental tool with a unique ability to produce persistent primary and/or secondary lesions in the olfactory system of mice.