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Evolution of Alachlor-Induced Nasal Neoplasms in the Long-Evans Rat

Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio 45267-0056, MaryBeth.Genter{at}UC.edu

Dawn M. Burman

Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio 45267-0056

Michael W. Dingeldein

Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio 45267-0056

Ian Clough

Center for Biostatistical Services, University of Cincinnati, Cincinnati, Ohio 45267-0056

Brad Bolon

Department of Pathology, Amgen, Inc, Thousand Oaks, California 91320-1789

The chloracetanilide herbicide alachlor (2-chloro-2',6-diethyl-N-(methoxymethyl)-acetanilide) induces nasal neoplasms in rats following chronic dietary exposure. The present study sought to identify the cellular origin and mechanisms of tumor induction and progression. Male Long-Evans rats were fed alachlor (0 or 126 mg/kg/day) beginning at 6 weeks of age. Following 1 month of alachlor ingestion, neither histological abnormalities nor enhanced cell division (assessed by BrdU incorporation) occurred in any region of the nasal cavity. Six months of alachlor exposure resulted in proliferation of basal and nonbasal cells in the olfactory mucosa while inducing nasal masses in 7 of 15 animals. Tumors ranged from dysplastic plaques to polypoid adenomas and originated in the olfactory regions of the nasal cavity. Neoplasms were associated with regions of respiratory metaplasia and were often covered with a low cuboidal, poorly ciliated epithelium. Tumor cells did not express characteristics of the olfactory mucosa, including olfactory marker protein (OMP, for neurons) and NMa (antibody recognizing cytochrome P450 [CYP] 2A3, found in Bowman's glands). Sites of plaque and tumor development coincided with regions of NMa immunoreactivity. These data suggest that local metabolism is important in alachlor-induced olfactory tumors and support the concept that metaplastic respiratory epithelial cells give rise to the observed neoplasms.

Key Words: Bioactivation • cytochromes P450 • herbicide • metabolism • nasal • olfactory toxicity • alachlor • polypoid adenoma • metaplasia

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