Association of salmonella mutants with germfree rats: site specific model to detect carcinogens as mutagens

Abstract

An association of the histidine auxotroph of Salmonella typhimurium (strain TA1538) within the gastrointestinal tract of otherwise germfree Sprague-Dawley rats is maintained during periods of observation lasting as long as 7 months. The bacteria are found at levels exceeding 10(7) per g in the forestomach and at levels greater than 10(8) per g in the lower bowel and in the feces. Only approximately 10(4) bacteria per g are found in the posterior stomach and in the upper small intestine. The association of the salmonella mutants is maintained when the bacterial association is increased by the addition of other bacteria characteristic of the gastrointestinal flora. Carcinogenic amines, which cause strain TA1538 to revert to histidine independence in Ames' in vitro assays, increase the number of revertants in the feces when fed to the salmonella-associated rats. In contrast, the number of revertants in the feces does not increase when the rats are fed structurally related compounds which are not mutagenic to the bacteria in vitro and for which no evidence of carcinogenicity exists. Sacrifice of rats after feeding the carcinogen 2-nitrofluorene indicates that the number of revertants is increased in the cecum and colon as well as in the feces. The apparent proximity of the bacterial mutagenic response to the location of the tumor response in the colon suggests that the rat associated with the histidine auxotroph may provide a useful model for further investigation of the possible association between bacterial mutagenesis and carcinogenesis within the gastrointestinal tract. In addition, with this model it may be possible to evaluate selectively the effects of various constituents of the flora on the activation of compounds provoking the revertant response.