Alachlor induces olfactory mucosal tumors in rats in a highly ordered temporal process. We used GeneChip analysis to test the hypothesis that histological progression and oncogenic transformation are accompanied by gene expression changes that might yield clues as to the molecular pathogenesis of tumor formation. Acute alachlor exposure caused upregulation of matrix metalloproteinases (MMP)-2 and -9, tissue inhibitor of metalloproteinase-1, carboxypeptidase Z, and other genes related to extracellular matrix homeostasis. Heme oxygenase was upregulated acutely and maintained elevated expression. Expression of ebnerin, related to the putative human tumor suppressor gene DMBT1, progressively increased in alachlor-treated olfactory mucosa. Progression from adenomas to adenocarcinoma was correlated with upregulation of genes in the wnt signaling pathway. Activated wnt signaling was confirmed by immunohistochemical localization of beta-catenin to nuclei of adenocarcinomas, but not earlier lesions. These observations suggest that initiation and progression of alachlor-induced olfactory mucosal tumors is associated with alterations in extracellular matrix components, induction of oxidative stress, upregulation of ebnerin, and final transformation to a malignant state by wnt pathway activation.

The chloracetanilide herbicide alachlor (2-chloro-2',6-diethyl-N -(methoxymethyl)-acetanilide) induces

Summary. Alachlor is an herbicide used primarily in the production of corn (maize), peanuts, and soybeans and is associated with cancer of the nasal cavity, thyroid, and stomach in rats. Previous work from our laboratory demonstrated that the nasal cavity tumours originate from the olfactory mucosa, and that neoplasms were present following 6 months of exposure (126 mg/kg/day in the diet). The studies presented herein were conducted to determine more precisely the earliest time point at which alachlor-induced tumours were present, and to describe the histological changes that occur en route to tumour formation. We determined that dramatic histological changes, including respiratory metaplasia of the olfactory mucosa, were present following 3 months of exposure, and the earliest alachlor-induced olfactory mucosal tumours were detected following 5 months of treatment. Because alachlor is positive in short-term mutagenicity assays with olfactory mucosal activation, and because of the relatively short time-to-tumour formation observed with alachlor, we also conducted a`stop' study in which rats were treated with alachlor for 1 month and then held without further treatment for an additional 5 months. This study demonstrated that abbreviated alachlor exposure did not result in subsequent tumour formation within the 6-month observation period.

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