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Toxicant-induced ER-stress and caspase activation in the olfactory mucosa
1Department of Pharmaceutical Biosciences, Uppsala University, 594, 751-24 Uppsala, Sweden.
Abstract:
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.
Insights
The olfactory toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO(2)) causes cell death in mouse olfactory glands. This damage involves endoplasmic reticulum stress and apoptotic signaling, primarily in Bowman
Area of Science:
- Toxicology
- Cell Biology
- Neuroscience
Background:
- 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO(2)) is a potent olfactory toxicant.
- This toxicant causes cell death and metaplastic changes in rodent olfactory regions.
- Damage is linked to cytochrome P450 (CYP)-mediated metabolic activation to reactive intermediates.
Purpose of the Study:
- To investigate the early, cell-specific changes leading to cell death in the olfactory mucosa of mice exposed to 2,6-diClPh-MeSO(2).
- To examine the role of endoplasmic reticulum (ER) stress and apoptotic pathways in 2,6-diClPh-MeSO(2)-induced toxicity.
Main Methods:
- Examined expression of the ER-specific stress protein GRP78.
- Assessed the presence of secretory glycoproteins.
- Measured cellular activation of initiator caspase 12 and effector caspase 3.
Main Results:
- 2,6-diClPh-MeSO(2) induced rapid, cell-specific expression of GRP78 in Bowman's glands.
- Activated caspases 12 and 3 were observed in Bowman's glands, but not the neuroepithelium, early after exposure.
- Bowman's glands exhibited oncotic morphology, suggesting a blocked terminal phase of apoptosis.
Conclusions:
- Lesions are initiated in Bowman's glands, where metabolic activation of 2,6-diClPh-MeSO(2) triggers an ER-stress response and apoptotic signaling.
- The terminal phase of apoptosis appears blocked, with Bowman's glands succumbing to alternative cell death pathways.
- Findings highlight Bowman's glands as the primary site of early olfactory toxicity from 2,6-diClPh-MeSO(2).
