EFFECTS OF SUBACUTE ETHINYLESTRADIOL ADMINISTRATION ON CELL PROLIFERATION OF 5 ORGANS, INCLUDING TUMORIGENIC TARGET AND NON-TARGET ORGANS, IN MALE F344 RATS

The effect of ethinylestradiol (EE), a synthetic estrogen which is tumorigenic to the mammary gland, pituitary gland, and liver, on the cell proliferation in 5 organs was investigated in male rats. Cell proliferation was estimated by bromodeoxyuridine (BrdU) immunohistochemistry after 72 hr continuous administration of BrdU through an osmotic minipump prior to sacrifice. Two experimental protocols were applied. In one, EE was administered to rats at l ppm in feed for 3, 7, 14, 28, and 91 days. The BrdU labeling indices (LI) in the pars distalis of the pituitary gland were significantly increased in the EE-treated rats compared to the control rats throughout the experimental period. The LI in the Harderian gland, a non-target organ of EE tumorigenesis, were also higher in the EE-treated rats on day 14 and thereafter. Other non-target organs, including the adrenal cortex and medulla, kidneys, and pancreas, showed variable or consistently lower LI in the EE-treated rats. In the other protocol, EE wa administered to rats at 0.1, 0.5, and 2 ppm in feed for 3, 7, and 14 days, and the serum prolactin (PRL) concentration and LI in the pars distalis were compared. EE treatment increased the serum PRL concentration, the LI in the pars distalis, and the numerical density (No. of cells/mm2) of BrdU-labeled PRL cells in a dose-dependent manner with complete parallelism among them. The increase in LI was observed within 14 days after the start of EE treatment, and the profiles of cell proliferation were unique to each organ, including tumorigenic target and non-target organs.