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Physiol. Genomics (November 5, 2002). doi:10.1152/physiolgenomics.00120.2002
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Articles in PresS, published online ahead of print November 5, 2002
Physiol Genomics, 10.1152/physiolgenomics.00120.2002
Submitted on September 18, 2002
Accepted on October 24, 2002

Genomic Analysis of Alachlor-Induced Oncogenesis in Rat Olfactory Mucosa

Mary Beth Genter1*, Dawn M Burman1, Soundarapandian Vijayakumar2, Cathy L Ebert3, and Bruce J Aronow3

1 Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA
2 Department of Medicine, Columbia University, New York, NY, USA
3 Department of Pediatrics/Developmental Biology, Children's Hospital, Cincinnati, OH, USA

* To whom correspondence should be addressed. E-mail: MaryBeth.Genter{at}UC.edu.

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 up-regulation 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.




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