- Title
- Alachlor-Induced Oxidative Stress in Rat Olfactory Muscosa
- Author
- BURMAN, DAWN MARIE
- Degree
- MS, University of Cincinnati,
Medicine : Environmental Health Sciences, 2001.
- Advisor
- Mary Beth Genter
- Pages
- 60p.
- Abstract
- Alachlor (2-choro-2',6'-diethyl-N-(methoxymethyl)acetanilide) is a chloracetanilide herbicide that induces nasal tumors after chronic dietary exposure in rats. This research examines oxidative stress as a result of antioxidant depletion as a possible mechanism for alachlor-related olfactory mucosal carcinogenicity. Male Long-Evans rats were fed alachlor (0, 10, 31.5, 63, or 126 mg/kg/day) for 0,1, 2, 4, 10, or 30 days. At each timepoint, intracellular reduced glutathione and ascorbate levels were measured in olfactory mucosa and liver. Glutathione was significantly depleted in olfactory mucosa after one day of dietary exposure at 10 or 126 mg/kg/day (p=0.041 and 0.007, respectively) with a rebound in the high dose group 2-4 days thereafter. To examine the etiology of increased glutathione levels after 2-4 days in the high dose group, glutamate-cysteine ligase (GCL) catalytic and modifying subunit protein levels were measured in olfactory mucosa and liver; GCL is regarded as the rate-limiting enzyme in glutathione synthesis. Expression of the modifying subunit increased in olfactory mucosa after one day of treatment (126 mg/kg/day) and remained elevated after 10 days of treatment. Olfactory mucosal ascorbate was significantly depleted after one day of treatment at all doses (p<0.05), possibly contributing to abnormal cell growth by disrupting normal expression of extracellular matrix proteins important for cell orientation. Ascorbate depletion was not observed in the liver. Due to the high levels of olfactory mucosal ascorbate, ascorbate synthetase activity was examined in olfactory mucosa, liver, and lung. Ascorbate synthetase activity was not detected in lung or olfactory mucosa whereas the liver displayed measurable activity. Levels of cytochrome P450 2A3, an enzyme in the olfactory mucosa hypothesized to participate in the bioactivation of alachlor, as well as a potential marker for oxidative stress, decreased (western blot) analysis in the olfactory mucosa of alachlor-treated rats. Decrease in olfactory mucosal glutathione and ascorbate observed in this study suggests that oral exposure to alachlor leads to antioxidant depletion in the olfactory mucosa, but not liver, potentially contributing to tissue specific tumor formation.
- Subject Headings
- Health Sciences, Toxicology
- Keywords
- alachlor; chloracetanilide; oxidative stress; glutathione; ascorbate
Document number: ucin1006204005.
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