Quantitation of an epithelial S-phase response in the rat forestomach and glandular stomach following gavage dosing with ethyl acrylate.
Gavage dosing of the irritant, ethyl acrylate (EA), has been found to induce hyperplasia in the rat forestomach, but no signs of toxicity in the glandular stomach or in organs remote from the site of dosing. To quantitatively describe this effect as a background for subsequent modeling studies, pulse measurements of the number of S-phase cells were made following a single gavage dose of EA. The time-course of the S-phase response in the forestomach epithelium following a high dose (200 mg/kg or a 4% solution in corn oil) indicated that the number of S-phase nuclei was decreased relative to control animals immediately following gavage dosing with a minimum at 6 hr, but that the number of S-phase nuclei increased significantly above control values by 20 hr and remained significantly elevated until at least 48 hr following the gavage dose. A single-dose dose-response study with gavage doses of 0, 2, 10, 20, 50, 100, or 200 mg/kg EA and S-phase analysis at 24 hr following gavage dosing indicated that a significant increase in S-phase nuclei was evident at doses of 20 mg/kg or higher. Dosing with EA for 2 weeks at dose levels of 0, 10, 50, or 200 mg/kg caused a prolonged elevation of S-phase nuclei only at the 200 mg/kg dose level during the 24 hr following the last gavage dose. Lower doses did not induce a significant increase in the S-phase nuclei. In contrast to the forestomach, the S-phase response of the glandular stomach was transient following a single 200 mg/kg gavage dose, and only a marginal response was observed following multiple 200 mg/kg doses. No effects were observed at lower doses. Comparison of these results to prior determinations of the effect of EA on the concentration of nonprotein sulfhydryls (primarily glutathione) in the forestomach and glandular stomach indicate a correlation of the stimulation in S-phase activity in the forestomach with the repletion and overshoot of tissue nonprotein sulfhydryl levels.
Gillette
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Toxicology Department, Rohm and Haas Company, Spring House, Pennsylvania 19477.
Frederick
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D000179:Acrylates / Q000633:toxicity*; D000818:Animals; D001973:Bromodeoxyuridine; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D016196:S Phase / Q000187:drug effects; D013270:Stomach / Q000166:cytology* / Q000187:drug effects*; D013997:Time Factors
D000179:Acrylates; C040833:ethyl acrylate; D001973:Bromodeoxyuridine