Effect of ethanol and vitamin A deficiency on epithelial cell proliferation and structure in the rat esophagus

An increased risk of cancer of the esophagus has been reported in alcoholics and in populations with low dietary vitamin A consumption. As cancer is a disorder of cell proliferation and differentiation, we have assessed the combined effects of ethanol and vitamin A deficiency on cell proliferation and structure of the esophagus. Weanling male rats were fed liquid diets with either a standard amount of vitamin A or lacking vitamin A for 8 wk. Littermates were pair-fed the same diets with carbohydrate (36% of calories) replaced by ethanol. Rats were given [3H]thymidine 1 h before death, and the labeling index of the proliferative basal cells was determined on radioautographs. In rats fed the normal vitamin A diet with or without ethanol, plasma vitamin A was normal. Hepatic vitamin A was markedly decreased, whereas esophageal vitamin A was increased after ethanol feeding. Ethanol feeding resulted in a twofold increase in basal cell labeling index (14.6 +/- 0.7 vs. 6.8 +/- 0.8; p less than 0.001). The thickness of the epithelium and the morphology of basal cells were not altered by ethanol feeding. In rats fed the vitamin A-deficient diet with or without ethanol, plasma vitamin A was extremely low, and hepatic and esophageal vitamin A were unmeasurable. The epithelium was thin (with a 50% reduction in thickness) and showed abnormalities of basal cells and increased production of keratohyalin granules, changes suggesting a disorder in the epithelial differentiation. This altered differentiation caused by vitamin A deficiency was not affected by ethanol consumption. Ethanol feeding again resulted in an increase in the basal cell labeling index (13.2 +/- 1.6 vs. 4.8 +/- 0.7; p less than 0.001). Vitamin A deficiency had no effect on basal cell proliferation. Therefore, the stimulatory effect of ethanol on cell proliferation is independent of vitamin A deficiency. Nevertheless, the combined actions of ethanol and vitamin A deficiency may have a synergistic effect on the susceptibility of the esophagus to carcinogens.