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.
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 24h 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 K5CreEr(T2)::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.
Laboratory of Molecular Toxicology, Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA; School of Public Health, State University of New York at Albany, NY 12201, USA.
Fang
F
Xie
Cheng
C
Fang
Nikolai
N
Schnittke
James E
JE
Schwob
Xinxin
X
Ding
D000818:Animals; D002452:Cell Count; D006540:Herbicides / Q000633:toxicity*; D018836:Inflammation Mediators / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009570:Nitriles / Q000633:toxicity*; D009831:Olfactory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018034:Olfactory Receptor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D006540:Herbicides; D018836:Inflammation Mediators; D015850:Interleukin-6; D009570:Nitriles; C577686:interleukin-6, mouse; C055869:dichlobanil
2,6-dichlorobenzonitrile (or dichlobenil); DCBN; DEX; DMM; Dichlobenil; HBCs; IFN; IL; Inflammatory cytokines; K5; MMZ; Methimazole; Neurodegeneration; OE; OMP; ORNs; Olfactory stem cells; PBS; Regeneration; TNF; dexamethasone; dorsal medial meatus; horizontal basal cells; interferon; interleukin; keratin 5; methimazole; olfactory epithelium; olfactory marker protein; olfactory receptor neurons; phosphate-buffered saline; tumor necrosis factor