Effects of carcinogen dosage on experimental colonic carcinogenesis by azoxymethane: an ultrastructural study of grossly normal colonic mucosa.

The transmission electron microscopic features of grossly normal colonic mucosa in the azoxymethane [(AOM) CAS: 25843-45-2]-treated rat model of colonic carcinogenesis were studied by the method of concomitant variation. Ten-week-old male F344 rats were given 10 weekly sc injections of AOM at doses of 3, 7, or 14 mg/kg body weight and were killed 1 week or 15 weeks after the last AOM dose. Grossly normal distal left colon was examined using transmission electron microscopy. Three transient dose-dependent features of colonic epithelial cells were identified: a) mitochondrial injury, b) nuclear pleomorphism and loss of polarity, and c) increased numbers of mitotic figures in the lower third of the crypts. Because these dose-dependent features were present only shortly after AOM administration, they appeared to be manifestations of carcinogen toxicity and associated reactive, regenerative epithelial changes. By contrast, four persistent dose-dependent features were identified: a) increased numbers of epithelial cells with enlarged nucleoli, b) increased numbers of mitotic figures in the middle third of crypts, c) reduced numbers of goblet cells, and d) reduced numbers of apical cytoplasmic vacuoles in the upper third of the crypts. Because these features persisted in a dose-dependent manner for many weeks after the last dose of AOM and were present after the latent period to tumor formation, they appear to be morphologic precursors to colonic carcinogenesis in the model.