IDENTITY AND PATHOGENESIS OF STOMACH TUMORS IN SPRAGUE-DAWLEY RATS ASSOCIATED WITH THE DIETARY ADMINISTRATION OF BUTACHLOR

Macroscopic stomach tumors induced in Sprague-Dawley rats during two c hronic bioassays with the acetanilide herbicide butachlor at a dietary concentration of 3000 ppm, were evaluated histologically and immunohi stochemically in order to determine their identity and pathogenesis. T he tumors, which occurred primarily in female rats, were a heterogeneo us series, including a few consisting wholly or partly of classic soli d or anaplastic epithelium, but with the majority containing diffusely distributed primitive neoplastic cells. The latter had either the gen eral appearance of undifferentiated epithelium or presented a more ''m esenchyme-like'' pattern where the cells were epithelioid, bla stema-l ike, neuroendocrine-like or sarcoma-like with fascicular disposition. Gastric glandular profiles were also present, usually located near the periphery of the tumors, but in some cases extending into the diffuse tumor tissue. Most of the tumors displayed variable immunohistochemic al reactivity for cytokeratin, vimentin and neuron-specific enolase bu t were negative for muscle-specific actin or desmin except in the stro mal tracts. Detailed examination of all available gastric tissue revea led the presence of additional microscopic neoplasms and precursor hyp erplastic lesions. All of these were typical gastric neuroendocrine ce ll lesions (gastric carcinoids) originating in the fundic mucosa but o ccasionally invading submucosally, and consisting of epithelial cells in organized clusters, rosettes or primitive tubules. The enterochroma ffin-like (ECL) nature of these microscopic neoplasms and precursor le sions was substantiated by strong immunohistochemical reactivity for c ytokeratin, neuron-specific enolase and chromogranin A, and a negative reaction for vimentin. One microscopic tumor showed a transition from differentiated neuroendocrine type in the fundic mucosa to a disperse d ''mesenchyme-like'' pattern in the submucosal extension. An addition al finding in the butachlor-treated male and female rats was atrophy o f the fundic mucosa involving, in particular, reduction in the numbers of parietal cells. This effect was dose-related, being most severe in the high-dose (3000 ppm) females. On the basis of their morphological characteristics, coupled with the continuity evident in the microscop ic lesions, it is concluded that the macroscopic stomach tumors associ ated with the dietary administration of butachlor are poorly different iated gastric carcinoids, in some cases admired with a non-neuroendocr ine epithelial element. Fundic ECL and stem cells are known to be unde r the trophic influence of gastrin, which is apparently responsible fo r the induction of the tumors associated with butachlor administration . Gastric tumor development involving gastrin is recognized as a secon dary, hormonal mechanism of carcinogenesis, demonstrating a dose-thres hold phenomenon. In the butachlor studies, this is further supported b y the absence of gastric neoplasia in rats given the mid-dose (1000 pp m) of butachlor.