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Toxicologic Pathology
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Articles

Reduction of Alachlor-Induced Olfactory Mucosal Neoplasms by the Matrix Metalloproteinase Inhibitor Ro 28-2653

Mary Beth Genter1
Blake M. Warner1
Hans-Willi Krell2
Brad Bolon3

1 Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, USA
2 Roche Diagnostics GmbH, Pharma Research, Penzberg, Germany
3 GEMpath Inc., Cedar City, Utah, USA

Correspondence: Address correspondence to: Dr. Mary Beth Genter, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, USA; e-mail:MaryBeth.Genter{at}UC.edu

Chronic exposure to the chloracetanilide herbicide alachlor has been shown to cause olfactory mucosal neoplasms. Genomic analysis of olfactory mucosa from rats given alachlor (126 mg/kg/d) for from 1 day to 18 mo suggested that matrix metalloproteinases MMP-2 and MMP-9 were upregulated in the month following initiation of treatment. The present studies were designed to confirm this latter finding and to explore the potential role of MMPs in alachlor-induced olfactory carcinogenesis. Zymographic analysis of olfactory mucosal extracts confirmed that MMP-2 activity is higher in the olfactory mucosa of alachlor-treated rats. Therefore, rats were fed alachlor (126 mg/kg/d in the diet for 1 year) either with or without the MMP-2/MMP-9 inhibitor Ro 28-2653 (100 mg/kg daily by gavage for the first 2 months of alachlor treatment). The number of olfactory mucosal neoplasms was reduced by 25% after 1 year of alachlor treatment in rats that received both alachlor and Ro 28-2653. The morphology of alachlor-induced olfactory tumors was similar whether or not Ro 28-2653 had been given; the MMP inhibitor itself had no impact on olfactory mucosal histology. These data confirm that olfactory mucosal MMP-2 activity is increased following short-term alachlor exposure and show that administration of an MMP-2/9 inhibitor reduced the incidence of olfactory neoplasms in alachlor-treated rats, thereby implicating MMP-2 activity as a mediator of alachlor-induced carcinogenicity.

Key Words: Alachlor • herbicide • matrix metalloproteinase • MMP-2 • neoplasm • olfactory • rat

Toxicologic Pathology, Vol. 33, No. 5, 593-599 (2005)
DOI: 10.1080/01926230500244522
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[Abstract] [Full Text] [PDF]