Diet and Epithelial Hyperplasia in the Forestomach of Rats and Mice

Since Singer (19) in 1913 observed hyperplasia and ulceration of the forestomach epithelium in rats fed bread and wood shavings, there have been numerous studies to determine the etiology of the lesions. Pappenheimer and Larimore (14) showed that a faulty diet would produce the changes, but there is still divergence of opinion as to the nature of the deficiency and the mechanism of lesion formation. While benign changes have been described by" most authors, Fibiger (6) reported that squamous carcinoma of the forestomach epithelium was produced in rats and mice by feeding cockroaches infected with Gongylonema neoplasticum (Spiroptera neoplastica). He believed the evidence was conclusive that Spiroptera could serve as the etiologic agent of both benign and malignant changes. Carcinoma was thought to be a more advanced stage of the benign hyperplasia. Studies performed since the discovery of accessory food factors have shown that Fibiger's diet was nutritionally poor and that even without the worms it would induce some alterations (15). With an improved diet, Passey, Leese, and Knox (15) were able to increase the life span of infected animals without the production of extensive changes. Cramer (4) accepted Fibiger's interpretation of carcinoma in a few cases but made the reservation that something more than Spiroptera and poor diet was necessary to produce it. Hoelzel and Da Costa ( i i ) found ulcers in the epithelium of both the forestomach and the glandular portion in rats and mice when low protein diets were fed and also when the animals were fasted every second day. Since gastric stasis resulted from either method, they suggested that irritation from unbuffered acid produced the changes. Some support for this hypothesis was provided when Matzner and his associates (13) demonstrated that pepsin and hydrochloric acid could induce ulceropapillomas. These investigators observed that more extensive lesions developed when pepsin and hydrochloric acid were fed together than when either was given alone. Irritation either by parasites or gastric juice is the only explanation that has been advanced for the mechanism of lesion formation, though without attempting to elucidate this mechanism numerous reports have suggested that the changes are a result of vitamin deficiency. Thus stomach lesions were found in rats suffering from vitamin B1 deficiency by DaUdorf and Kellogg (5) and Sure and Thatcher (2o), while Findlay (7) obtained them only with vitamin Bz deficiency. These studies were made, however before the synthetic vitamins became available and other deficiencies also may have been present. Howes and Vivier (12) demonstrated that lesions occurred despite adequate protein intake if there was a vitamin B deficiency, and concluded that the whole vitamin B complex is necessary to maintain normal forestomach epithelium. Althgugh Wolbach and Howe (22) proved that vitamin A is essential for the maintenance of normal epithelium in general, they did not find forestomach changes in vitamin A deficient animals. On the other hand, extensive lesions at this site were described by Fujimaki (9), and attributed to vitamin A deficiency, but further study (io) showed that undetermined factors were also important in their production. From a recent report of well controlled studies started by Fibiger (8) we learn that vitamin A deficiency under favorable conditions will increase the incidence of lesions, but that additional unknown factors are necessary completely to prevent their formation. While they offer no explanation of the mechanism of formation, Brunschwig and Rasmussen ( i ) suggest that when a certain degree of malnutrition exists in the rat, such malnutrition not necessarily being synonymous with absolute loss of weight nor with the lack of any specific type of food or vitamin, the forestomach mucosa reacts by localized loci of cellular proliferation. Hyperplasia and ulceration are the normal reactions of the forestomach epithelium to mechanical or chemical irritation. Bullock and Rohdenburg (2) inserted into the forestomach by gastrotomy either a celluloid ball covered with pin points or pieces of cork with protruding pig bristles, and observed extensive changes, similar in many respects to those obtained by Fibiger with parasites. Chemical irritation with a piece of rubber sponge impregnated with Scharlach R, or pine tar oil introduced in a similar manner,