Comparison of rat olfactory mucosal responses to carcinogenic and non-carcinogenic chloracetanilides.
Alachlor and butachlor are chloracetanilide herbicides that induce olfactory tumors in rats, whereas propachlor does not. The mechanism by which alachlor induces tumors is distinct from many other nasal carcinogens, in that alachlor induces a gradual de-differentiation of the olfactory mucosa (OM) to a more respiratory-like epithelium, in contrast to other agents that induce cytotoxicity, followed by an aberrant regenerative response. We studied biochemical and genomic effects of these compounds to identify processes that occur in common between alachlor- and butachlor-treated rats. Because we have previously shown that matrix metalloproteinase-2 (MMP2) is activated in OM by alachlor, in the present studies we evaluated both MMP2 activation and changes in OM gene expression in response to carcinogenic and non-carcinogenic chloracetanilide treatments. All three chloracetanilides activated MMP2, and >300 genes were significantly up- or downregulated between control and alachlor-treated rats. The most significantly regulated gene was vomeromodulin, which was dramatically upregulated by alachlor and butachlor treatment (>60-fold), but not by propachlor treatment. Except for similar gene responses in alachlor- and butachlor-treated rats, we did not identify clear-cut differences that would predict OM carcinogenicity in this study.
Department of Environmental Health and Center for Environmental Genetics, 3223 Eden Ave., ML 670056, University of Cincinnati, Cincinnati, OH 45267-0056, United States. marybeth.genter@uc.edu
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MB
Genter
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Warner
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Medvedovic
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Sartor
D000081:Acetamides / Q000494:pharmacology / Q000633:toxicity; D000083:Acetanilides / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology* / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006540:Herbicides / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D009669:Nose Neoplasms / Q000139:chemically induced; D009831:Olfactory Mucosa / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D051381:Rats; D020318:Rats, Long-Evans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects
D000081:Acetamides; D000083:Acetanilides; D002273:Carcinogens; D006023:Glycoproteins; D006540:Herbicides; D036341:Intercellular Signaling Peptides and Proteins; C092201:LOC690507; D026901:Membrane Transport Proteins; C011088:propachlor; C000188:alachlor; C054409:butachlor; D020778:Matrix Metalloproteinase 2