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Rapid Induction of Ovarian Granulosa Cell Tumors by 7,12-Dimethylbenz(a)anthracene in Neonatally Estrogenized Mice¹

Laboratory of Experimental Pathology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya 464, Japan [O. T., Y. N.]; and Department of Biological Sciences, University Center at Binghamton, State University of New York, Binghamton, New York 13901 [S. D. M.]

Groups of female C3H/HeMs x 129/J F₁ mice were given injections of either 20 µg of 17ß-estradiol or sesame oil (vehicle) for the first 5 days after birth. Half of each group was then given gastric intubations of 20 mg/kg of 7,12-dimethylbenz(a)anthracene (DMBA) at 70, 77, and 84 days of age. The other half of each group was given sesame oil. Thus, this design yielded four experimental groups: oil + oil; 17ß-estradiol + oil; oil + DMBA; and 17ß-estradiol + DMBA. They were sacrificed at approximately 144 days of age (Experiment 1) or the day of palpable ovarian tumor detection or 360 days of age (Experiment 2). In Experiment 1, the total number of oocytes (follicles) per ovary in mice of the 17ß-estradiol + oil group was maintained at the same level as mice of the oil + oil group. A significant reduction of oocytes, however, was observed in mice of the 17ß-estradiol + DMBA group in comparison with mice of the oil + DMBA group (P < 0.01), and neoplastic nodules of the granulosa cell type developed in the unilateral ovary in 10 of 17 mice of the 17ß-estradiol + DMBA group. No tumors were detected in the mice of the other groups. The plasma levels of both follicle-stimulating and luteinizing hormones as determined by radioimmunoassay were significantly higher (P < 0.01) in mice of the 17ß-estradiol + oil group than in mice of the oil + oil group. In Experiment 2, more ovarian tumors of the granulosa cell type were detected before 360 days of age in mice of the 17ß-estradiol + DMBA group (14 of 18) than in mice of the oil + DMBA group (5 of 15) (P < 0.05). No tumors developed in mice of the other two groups. These results strongly indicate that an abnormal endocrine milieu caused by neonatal treatment with estrogen may induce a high frequency of transformation of some ovarian tissues and rapid growth of the ovarian tumors after DMBA treatment.

¹ This work was supported in part by a Grant-in-Aid for Scientific Research and Cancer Research from the Ministry of Education, Science, and Culture, Japan, and by NIH Grant CA-34344.

² To whom requests for reprints should be addressed.

Received 12/10/86. Revised 9/30/87. Accepted 10/ 5/87.

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