INDUCTION OF CELL-PROLIFERATION IN THE FORESTOMACH OF F344 RATS FOLLOWING SUBCHRONIC ADMINISTRATION OF STYRENE 7,8-OXIDE AND BUTYLATED HYDROXYANISOLE

The question addressed was whether stimulation of cell proliferation c ould be responsible for tumor induction in the forestomach by styrene 7,8-oxide (SO). Male F344 rats were treated for 4 weeks with 0, 137, 2 75, and 550 mg/kg SO by p.o. gavage 3 times/week. Positive controls re ceived 0, 0.5, 1, and 2% butylated hydroxyanisole (BHA) in the diet fo r 4 weeks. Twenty-four h before termination of the experiment, the rat s were implanted s.c. with an osmotic minipump delivering 5-bromo-2'-d eoxyuridine (BrdU). Cell proliferation in the forestomach was assessed by immunohistochemistry for BrdU incorporated into DNA. Cell number/m m section length and fraction of replicating cells (labeling index) we re determined in 3 domains of the forestomach, the saccus caecus, the midregion, and the prefundic region. With the exception of the prefund ic region of the low-dose SO group, a significant increase of the labe ling index was found in all regions both with SO and BHA. Rats treated with BHA showed, in addition, a dose-dependent increase in number and size of hyperplastic lesions. This was most pronounced in the prefund ic region where carcinomas were reported to be localized. In this regi on, the number of dividing cells/mm section length was increased up to 17-fold. With SO, only marginal morphological changes were occasional ly observed, despite the fact that the respective long-term treatment had been reported to result in a higher carcinoma incidence than treat ment with BHA. It is concluded that the rate of replicating cells alon e, numerically expressed by the labeling index, is an insufficient too l for interpreting the role of cell division in carcinogenesis. It is postulated that SO and BHA induce forestomach tumors via different mec hanisms. While hyperplasia in the prefundic region most likely dominat es the carcinogenicity of BHA, a mechanism combining marginal genotoxi city with strong promotion by increased cell proliferation appears to be involved in the tumorigenic action of SO.