title: Antioxidant perturbations in the olfactory mucosa of alachlor-treated rats.
abstract: The chloracetanilide herbicide alachlor (2-chloro-2',6'-diethyl-N-(methoxymethyl)acetanilide) induces olfactory mucosal tumors in rats following chronic dietary exposure. Previous reports demonstrated that alachlor exposure was associated with depletion of glutathione (GSH) in liver in vivo and in vitro, but did not address this issue in the target tissue for the carcinogenic response. In this study we investigated a potential oxidative stress pathway in olfactory tissue by examining perturbations in olfactory mucosal antioxidants. Male Long-Evans rats were fed alachlor for up to 10 days (10-126 mg/kg per day), and intracellular reduced GSH and ascorbate levels were measured in olfactory mucosa. Both GSH and ascorbate rapidly decreased in olfactory mucosa following alachlor exposure, with a subsequent increase in both antioxidants to approximately 160% of control levels in the high dose group, and recovery of GSH to control levels in all groups by 10 days. Using Western blot analysis, we found that the modifier subunit of the rate-limiting enzyme in GSH synthesis, glutamate-cysteine ligase, increased in olfactory mucosa and remained elevated (126 mg/kg per day group). Two ascorbate transporters were detected by RT-PCR in olfactory mucosa, but neither appeared to be upregulated by alachlor exposure, and ascorbate synthesis was not stimulated in olfactory mucosa by alachlor treatment. Dietary exposure to alachlor depletes olfactory mucosa antioxidants, which may contribute to DNA damage and tissue-specific tumor formation.
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267-0056, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Burman
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
authors.forename: Albert P
authors.initials: AP
authors.lastname: Senft
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dalton
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Genter
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006540:Herbicides / Q000494:pharmacology*; D050544:L-Gulonolactone Oxidase; D008297:Male; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D060347:Sodium-Coupled Vitamin C Transporters; D013401:Sugar Alcohol Dehydrogenases / Q000378:metabolism; D027981:Symporters / Q000378:metabolism
chemical_list: D000081:Acetamides; D000975:Antioxidants; D006540:Herbicides; D029363:Organic Anion Transporters, Sodium-Dependent; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters; C000188:alachlor; D013401:Sugar Alcohol Dehydrogenases; D050544:L-Gulonolactone Oxidase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D001205:Ascorbic Acid