17 beta-estradiol modulates gastroduodenal preneoplastic alterations in rats exposed to the carcinogen N-methyl-N '-nitro-nitrosoguanidine

Gastric cancers are a significant cause of morbidity worldwide. Epidemiolog ical studies and animal models show that males have higher incidences of ga stric cancers compared with females, suggesting that sex hormones may modul ate gastric cancer risk. An animal model of the initiation phase of gastric cancer was used to determine the effects of systemic estrogen administrati on on morphological progression of preneoplastic lesions and to define cell populations at which estrogens may act. Preneoplastic progression in antra l and duodenal mucosa was examined in male rats that received the chemical carcinogen, N-methyl-N'-nitro-nitrosoguanidine (MNNG), during treatment wit h implants containing 17 beta-estradiol or oil vehicle. Histopathological c hanges in antral and duodenal gland morphology, numbers of proliferating ce lls and apoptotic bodies, and antral gastrin cell numbers and protein stora ge levels were determined 4 weeks later. With MNNG treatment, duodenal vill ous heights were significantly decreased, and epithelial cells displayed hi stological features of hyperplasia and dysplasia. Antral glands showed epit helial hyperplasia and dysplasia, increased mucosal height, and decreased m ucin levels. Antral gastrin storage protein levels were decreased by MNNG. Systemic treatment with 17 beta-estradiol significantly reversed MNNG-induc ed alterations in duodenal gland heights while increasing mucin and gastrin levels in antral glands. Cell proliferation and apoptosis rates were not s ignificantly different between groups. The present results indicate that sy stemic 17 beta-estradiol treatment influences antral and duodenal gland dif ferentiation during the initiation phase of chemical gastroduodenal carcino genesis in male rats. These results explain, in part, a potential pathway t hrough which protective effects of estrogens on chemical carcinogenesis are mediated in the upper gastrointestinal tract.