Toxicant-induced ER-stress and caspase activation in the olfactory mucosa.
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.
Franzén
Anna
A
Department of Pharmaceutical Biosciences, Uppsala University, 594, 751-24 Uppsala, Sweden.
Brittebo
Eva B
EB
D000818:Animals; D017209:Apoptosis; D001555:Benzene Derivatives / Q000008:administration & dosage / Q000633:toxicity*; D053454:Caspase 12; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000633:toxicity*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism; D009336:Necrosis; D046569:Neuroepithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013450:Sulfones; D013997:Time Factors
C507859:2,6-dichlorophenyl methylsulfone; D001555:Benzene Derivatives; D002722:Chlorobenzenes; D000091342:Endoplasmic Reticulum Chaperone BiP; D006023:Glycoproteins; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D013450:Sulfones; C506440:Casp12 protein, mouse; C505409:Casp3 protein, mouse; D053454:Caspase 12; D053148:Caspase 3; D020169:Caspases