Enhancing effects of various gastric carcinogens on development of pepsinogen-altered pyloric glands in rats

Abstract

To assess the possibility of establishing an in vivo, medium-term bioassay system for gastric carcinogens and promoters, a total of 220 male WKY rats were divided into two groups. Group 1 animals were treated first with a single dose of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) (160 mg/kg body wt) and starting 2 weeks later administrated one of five gastric carcinogens, a gastric promoter, one of five non-gastric carcinogens or no treatment, as a control, for 14 weeks. Saturated sodium chloride solution (1 ml) treatments were given by gastric intubation at weeks 4, 6, 8 and 10. Group 2 rats received 1 ml of DMSO instead of MNNG and were then treated in the same way as group 1. Analysis of pyloric mucosa sections for pepsinogen altered pyloric glands (PAPG) detected immunohistochemically after the animals were killed at week 16 revealed increased lesion numbers in group 1, with all gastric carcinogens and promoters examined. However, none of the five non-gastric carcinogens exerted any significant modification of PAPG development. The results strongly suggest that the experimental protocol consisting of the following four components: (i) adoption of PAPG as the end-point marker lesion; (ii) single dose of MNNG as initiator; (iii) test chemical administration for 14 weeks; and (iv) administration of saturated sodium chloride solution during the test chemical exposure, could be used effectively for the detection of gastric carcinogens as well as promoters of gastric carcinogenesis in a relatively short time period.

Hexosaminidase‐altered Aberrant Crypts, Carrying Decreased Hexosaminidase α and β Subunit mRNAs, in Colon of 1,2‐Dimethylhydrazine‐treated Rats

“…[34][35][36][37][38][39][40] Enzyme alterations are also observed in the glandular stomach in carcinogen-treated rodents, so-called pepsinogen-altered pyloric glands (PAPG), also considered as a stomach precancerous lesion. [41][42][43][44][45][46][47] We confirmed alteration of hexosaminidase activity by staining of paraformaldehydefixed whole mounted colonic mucosa. In contrast to the normal-shaped crypts bearing red grains, ACF remained lightly yellowish.…”

Dose-dependent Induction of Glandular Stomach Preneoplastic and Neoplastic Lesions in Male F344 Rats Treated with Catechol Chronically

“…However, although submucosal hyperplasias of the pyloric glands induced by catechol largely disappear after withdrawal, some of them have the potential to develop into adenomas or adenocarcinomas (18). Although it has been reported that rats exposed to a 0.8% catechol diet for a relatively short period develop submucosal hyperplasias (40,41) or pepsinogen-altered pyloric glands (PAPG) (48), no dose-response study has hitherto been performed.…”

“…It has been reported to also possess cocarcinogenic effects in N-methyl-N-amylnitrosamine (MNAM)-induced rat esophageal carcinogenesis (30,31,55) and benzo[a]pyrene (B[a]P)-induced mouse skin carcinogenesis (12,54). In addition, catechol acts as a promotor of N-methyl-N -nitro-Nnitrosoguanidine (MNNG)-initiated forestomach and glandular stomach tumor development (13,14,16,17,24,48). A dietary level of 0.8% catechol induces glandular stomach adenomas or adenocarcinomas in rats and mice after 2 years of treatment (15).…”

The Safety Assessment of Piperonyl Butoxide

“…Because of the high-dose levels used and resulting toxicity, it is difficult to interpret the carcinogenicity findings and their relevance for hazard assessment. Moreover, several investigators have reported that hepatotoxicity, and the resulting regenerative hyperplasia, can contribute to the formation of liver tumors by nongenotoxic mechanisms (Kociba et al, 1978;McClean et al, 1990;Mutai et al, 1990;Tatematsu et al, 1990;Van Miller et al, 1977). This and other mechanistic aspects of this oncogenicity response are discussed in Section 99.3.5.…”