ZINC REPLENISHMENT REDUCES ESOPHAGEAL CELL-PROLIFERATION AND N-NITROSOMETHYLBENZYLAMINE (NMBA)-INDUCED ESOPHAGEAL TUMOR-INCIDENCE IN ZINC-DEFICIENT RATS

Previous work has shown that sustained increased and decreased cell pr oliferation, induced by dietary zinc deficiency and caloric restrictio n respectively, influence the course of N-nitrosomethylbenzylamine (NM BA)-induced esophageal carcinogenesis in rats, The present study consi dered whether the increased cell proliferation and esophageal tumor in cidence induced by zinc deficiency are reversed upon zinc replenishmen t, Weanling rats were maintained initially on a deficient diet contain ing 4 p.p.m. zinc. After 5 weeks, carcinogen-treated animals were give n six intragastric doses of NMBA (2 mg/kg twice weekly). Controls were untreated. After the second NMBA dose, the rats were divided into thr ee dietary groups. One group was continued on the deficient diet, whil e the other two groups were switched to diets containing either 75 or 200 p.p.m. zinc, with half of the members in each group fed ad libitum and half pair-fed with deficient rats. NMBA-untreated controls were s imilarly replenished, At various time points, esophageal cell prolifer ation was assessed in five animals from each group by immunohistochemi cal detection of cells in S phase, with in vivo 5-bromo-2'-deoxyuridin e labeling, At II weeks after the first dose, esophageal tumor inciden ce was greatly reduced, from 100% in the deficient group to 26 and 14% respectively in the replenished groups fed ad libitum 75 and 200 p.p. m. zinc and to 14 and 11% respectively in the replenished groups pair- fed 75 and 200 p.p.m. zinc, In addition, the number of tumors per esop hagus was reduced from 9.93 +/- 4.25 in deficient rats, to a range of 0.11 +/- 0.31-0.30 +/- 0.54 in replenished animals. Following zinc rep lenishment, esophageal cell proliferation, as measured by labeling ind ex (LI), the number of labeled cells and the total number of cells, wa s markedly decreased in NMBA-untreated and -treated esophagi as compar ed with those in corresponding deficient esophagi, Thus, the esophagea l cell proliferation induced by zinc deficiency is reversed by zinc re plenishment and replenished animals have a markedly lower incidence of esophageal tumors.