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17ß-Estradiol Modulates Gastroduodenal Preneoplastic Alterations in Rats Exposed to the Carcinogen N-Methyl-N'-Nitro-Nitrosoguanidine¹

Departments of Medicine (M.C.-T., K.Y.R., J.C.), Pathology, Immunology and Laboratory Medicine (G.Y.L.), and Pharmacology and Therapeutics (K.T.S.), College of Medicine, University of Florida, Gainesville, Florida 32610

Address all correspondence and requests for reprints to: Martha Campbell-Thompson, Box 100214 JHMHC, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610. E-mail: thompmc{at}medicine.ufl.edu

Gastric cancers are a significant cause of morbidity worldwide. Epidemiological studies and animal models show that males have higher incidences of gastric cancers compared with females, suggesting that sex hormones may modulate gastric cancer risk. An animal model of the initiation phase of gastric cancer was used to determine the effects of systemic estrogen administration on morphological progression of preneoplastic lesions and to define cell populations at which estrogens may act. Preneoplastic progression in antral and duodenal mucosa was examined in male rats that received the chemical carcinogen, N-methyl-N'-nitro-nitrosoguanidine (MNNG), during treatment with implants containing 17ß-estradiol or oil vehicle. Histopathological changes in antral and duodenal gland morphology, numbers of proliferating cells and apoptotic bodies, and antral gastrin cell numbers and protein storage levels were determined 4 weeks later. With MNNG treatment, duodenal villous heights were significantly decreased, and epithelial cells displayed histological features of hyperplasia and dysplasia. Antral glands showed epithelial hyperplasia and dysplasia, increased mucosal height, and decreased mucin levels. Antral gastrin storage protein levels were decreased by MNNG. Systemic treatment with 17ß-estradiol significantly reversed MNNG-induced alterations in duodenal gland heights while increasing mucin and gastrin levels in antral glands. Cell proliferation and apoptosis rates were not significantly different between groups. The present results indicate that systemic 17ß-estradiol treatment influences antral and duodenal gland differentiation during the initiation phase of chemical gastroduodenal carcinogenesis in male rats. These results explain, in part, a potential pathway through which protective effects of estrogens on chemical carcinogenesis are mediated in the upper gastrointestinal tract.

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