Induction of Glandular Stomach Cancers in Helicobacter pylori‐sensitive Mongolian Gerbils Treated with N‐Methyl‐N‐nitrosourea and N‐Methyl‐N′‐nitro‐N‐nitrosoguanidine in Drinking Water

Abstract

An animal model of stomach carcinogenesis was established using Mongolian gerbils with Nmethyl-N-nitrosourea (MNU) and N-methyl-N′ ′ ′ ′-nitro-N-nitrosoguanidine (MNNG) as the carcinogens. In addition, the sensitivity of these gerbils to Helicobacter pylori (H. pylori) was confirmed. One hundred and sixty specific pathogen-free male MGS/Sea animals, 7 weeks old, were treated with MNU in the drinking water (30 ppm for alternate weeks to give 10 weeks exposure, or 10 ppm or 3 ppm for 20 weeks continuous exposure), or given MNNG in the drinking water at 400 ppm or 200 ppm for 20 weeks, or orally inoculated with ATCC43504 H. pylori (1.7× × × ×10 8 CFUs/animal). Adenocarcinomas in the glandular stomach were found in 2 out of 12 effective animals (2/ 12) treated with 30 ppm MNU at week 20, although all were dead or moribund by week 30 due to MNU toxicity. At week 50, the incidences of gastric adenocarcinomas in groups treated with 10 ppm MNU, 3 ppm MNU, 400 ppm MNNG, and 200 ppm MNNG were 2/21 (9.5%), 1/23 (4.3%), 7/ 11 (63.6%), and 1/10 (10.0%). The lesions were generally well differentiated, although poorly differentiated adenocarcinoma was also found in a single gerbil in each of the 10 ppm MNU and 400 ppm MNNG groups. In control animals no tumors were found. In the infection study, the animals were killed at week 20, and H. pylori was detected in all cases, causing multiple erosions with marked inflammatory cell infiltration in the lamina propria and submucosa, and frequent formation of lymphoid follicles. Thus, MNU and MNNG in the drinking water induced neoplastic lesions in the glandular stomach epithelium of H. pylori-sensitive gerbils.

Earlier Helicobacter pylori Infection Increases the Risk for the N‐Methyl‐N‐nitrosourea‐induced Stomach Carcinogenesis in Mongolian Gerbils

“…The incidence of adenocarcinomas was significantly higher in the early (H. pylori+MNU) group A than the early MNU-alone group D. In the MNU-alone groups, adenocarcinomas were detected only in early exposed gerbils, indicating that MNU-induced chemical gastric carcinogenesis depends not only on the concentration, 5) but also on the timing of administration in this model. Nonetheless, there was no significant difference in the incidences of gastric cancers among the MNU-alone groups D, E, and F. Thus, the early H. pylori infection was considered as a strong promoter for gastric carcinogenesis, even though administration of MNU at an early age also possibly contributed to the high incidence of adenocarcinomas in group A.…”

“…3,4) Our previous studies have proven that N-methyl-N-nitrosourea (MNU) and Nmethyl-N′-nitro-N-nitrosoguanidine (MNNG) can induce glandular stomach cancers in Mongolian gerbils (MGs), and further demonstrated promoting effects due to H. pylori infection on tumor development. [5][6][7] Since there has been no experimental investigation to determine the significance of H. pylori infection in children in relation to the risk of development of gastric cancer in adult life, we here examined the effects of H. pylori infection acquisition time on incidence of adenocarcinomas, serum anti-H. pylori IgG antibodies and gastrin levels in MGs.…”

Prevention of Helicobacter pylori–Induced Gastric Cancers in Gerbils by a DNA Demethylating Agent

“…Sections of 3 mm thickness were prepared and stained with hematoxylin and eosin. Neoplastic lesions in the stomach were diagnosed as previously described (36). The size of a gastric cancer was determined as the maximum diameter of the gastric cancer in the neighboring sections.…”

Helicobacter pylori-Induced Chronic Active Gastritis, Intestinal Metaplasia, and Gastric Ulcer in Mongolian Gerbils

“…More recently, Tatematsu et al 9 have established a Mongolian gerbil model in which gastric carcinogenesis is induced by N-methyl-N-nitorosourea (MNU), and Sugiyama et al 10 have demonstrated that H. pylori has both co-initiating and promoting effects on MNU-induced gastric carcinogenesis in this model. However, the evolution of the histopathological changes taking place in the gastric mucosa of experimentally infected Mongolian gerbils has not been described in a systematic fashion.…”