Effects of Dichlobenil on Ultrastructural Morphology and Cell Replication in the Mouse Olfactory Mucosa

Mancuso, Mariateresa; Giovanetti, Anna; Brittebo, Eva B.

doi:10.1177/019262339702500208

Cited by 17 publications

(11 citation statements)

References 29 publications

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“…27 Herbicides, such as the dioxins and chlorthiamid, are selectively taken up by the olfactory neuroepithelium even when administered systemically or to the surface of the cornea 28,29 and can damage the olfactory mucosa by causing necrosis of Bowman's glands. 30 The pathological infectious prion protein P r P Sc is consistently found in the olfactory cilia, receptor cells, bulbs, tracts, and primary olfactory cortices of patients with Creutzfeldt-Jakob disease, but not in the retina, optic nerves, or respiratory mucosa. 31 A number of patients with this disease first present to the clinician with anosmia or complaints of taste and smell loss.…”

Section: Evidence That Xenobiotics Can Enter the Brain Via The Olfactmentioning

confidence: 99%

The olfactory vector hypothesis of neurodegenerative disease: Is it viable?

Doty

2008

Annals of Neurology

355

279

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Environmental agents, including viruses, prions, and toxins, have been implicated in the cause of a number of neurodegenerative diseases, most notably Alzheimer's and Parkinson's diseases. The presence of smell loss and the pathological involvement of the olfactory pathways in the formative stages of Alzheimer's and Parkinson's diseases, together with evidence that xenobiotics, some epidemiologically linked to these diseases, can readily enter the brain via the olfactory mucosa, have led to the hypothesis that Alzheimer's and Parkinson's diseases may be caused or catalyzed by agents that enter the brain via this route. Evidence for and against this concept, the “olfactory vector hypothesis,” is addressed in this review. Ann Neurol 2008;63:7–15

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Section: Evidence That Xenobiotics Can Enter the Brain Via The Olfactmentioning

confidence: 99%

The olfactory vector hypothesis of neurodegenerative disease: Is it viable?

Doty

2008

Annals of Neurology

355

279

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“…Both compounds induce dose-dependent decreases in the levels of nonprotein sulfhydryl residues (mainly glutathione, GSH), as well as detachment of neuroepithelium and tissue damage in the lamina propria (Brittebo, 1995; Bergstrom et al, 2003). A notable difference, however, is that while MMZ induces cell death in the OE primarily through apoptosis (Sakamoto et al, 2007), which is associated with minimal inflammatory response, DCBN-induced cell death in the OE was accompanied by excessive nasal inflammation and necrosis (Brandt et al, 1990; Bergman et al, 2002; Franzén et al, 2006; Mancuso et al, 1997). Nevertheless, the precise mechanism of the differential effects of the two olfactory toxicants on ORN regeneration, including the role of nasal inflammation, and the involvement of olfactory stem cells, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of permanent loss of olfactory receptor neurons induced by the herbicide 2,6-dichlorobenzonitrile: Effects on stem cells and noninvolvement of acute induction of the inflammatory cytokine IL-6

Xie

Fang

Schnittke

et al. 2013

Toxicology and Applied Pharmacology

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We explored the mechanisms underlying the differential effects of two olfactory toxicants, the herbicide 2,6-dichlorobenzonitrile (DCBN) and the anti-thyroid drug methimazole (MMZ), on olfactory receptor neuron (ORN) regeneration in mouse olfactory epithelium (OE). DCBN, but not MMZ, induced inflammation-like pathological changes in OE, and DCBN increased interleukin IL-6 levels in nasal-wash fluid to much greater magnitude and duration than did MMZ. At 24 h after DCBN injection, the population of horizontal basal cells (HBCs; reserve, normally quiescent OE stem cells) lining the DMM became severely depleted as some of them detached from the basal lamina, and sloughed into the nasal cavity along with the globose basal cells (GBCs; heterogeneous population of stem and progenitor cells), neurons, and sustentacular cells of the neuroepithelium. In contrast, the layer of HBCs remained intact in MMZ-treated mice, as only the mature elements of the neuroepithelium were shed. Despite the respiratory metaplasia accompanying the greater severity of the DCBN lesion, residual HBCs that survived intoxication were activated by the injury and contributed to the metaplastic respiratory epithelium, as shown by tracing their descendants in a K5CreErT2∷fl(stop)TdTomato strain of mice in which recombination causes HBCs to express TdTomato in advance of the lesion. But, contrary to published observations with MMZ, the HBCs failed to form ORNs. A role for IL-6 in suppressing ORN regeneration in DCBN-treated mice was rejected by the failure of the anti-inflammatory drug dexamethasone to prevent the subsequent respiratory metaplasia in the DMM, suggesting that other factors lead to HBC neuro-incompetence.

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“…DCBN (25 mg/kg) and chlorthiamid (12 mg/kg) were toxic to the OE of mice with oral administration (Eriksson and Brittebo, 1995b;Mancuso et al, 1997). The injury produced by acute doses of DCBN persisted for up to 6 months.…”

Section: Introductionmentioning

confidence: 99%

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

2006

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Toxicity and carcinogenicity in the mucosa of the nasal passages in rodents has been produced by a variety of organic chemicals which are systemically distributed. In this review, 14 such chemicals or classes were identified that produced rodent nasal cytotoxicity, but not carcinogenicity, and 11 were identified that produced nasal carcinogenicity. Most chemicals that affect the nasal mucosa were either concentrated in that tissue or readily activated there, or both. All chemicals with effects in the nasal mucosa that were DNA-reactive, were also carcinogenic, if adequately tested. None of the rodent nasal cytotoxins has been identified as a human systemic nasal toxin. This may reflect the lesser biotransformation activity of human nasal mucosa compared to rodent and the much lower levels of human exposures. None of the rodent carcinogens lacking DNA reactivity has been identified as a nasal carcinogen or other cancer hazard to humans. Some DNA-reactive rodent carcinogens that affect the nasal mucosa, as well as other tissues, have been associated with cancer at various sites in humans, but not the nasal cavity. Thus, findings in only the rodent nasal mucosa do not necessarily predict either a toxic or carcinogenic hazard to that tissue in humans.

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Effects of Dichlobenil on Ultrastructural Morphology and Cell Replication in the Mouse Olfactory Mucosa

Cited by 17 publications

References 29 publications

The olfactory vector hypothesis of neurodegenerative disease: Is it viable?

The olfactory vector hypothesis of neurodegenerative disease: Is it viable?

Mechanisms of permanent loss of olfactory receptor neurons induced by the herbicide 2,6-dichlorobenzonitrile: Effects on stem cells and noninvolvement of acute induction of the inflammatory cytokine IL-6

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

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