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Endometrial Hyperplasia and Apoptosis following Neonatal Diethylstilbestrol Exposure and Subsequent Estrogen Stimulation in both Host and Transplanted Hamster Uteri¹

Department of Biological Sciences, Wichita State University, Wichita, Kansas 67260-0026 [W. J. H., X. Z., W. W. L.], and Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, Arkansas 72079 [W. S. B., D. M. S.]

Prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) causes morphogenetic alterations and neoplasia in the human reproductive tract. In the hamster, neonatal DES exposure alters early uterine morphogenesis and induces endometrial adenocarcinomas in adults. We now demonstrate that the preneoplastic stages of this phenomenon in the hamster reflect an abnormal uterotropic response to estrogen that is characterized by hyperplastic lesions in the endometrial epithelium and includes an immune and/or inflammatory component. Interestingly, biochemical and in situ analysis revealed that the hyperplastic epithelium is also an active site of cell death by apoptosis. To further probe the mechanism of this phenomenon, uteri from 7-day-old control or DES-exposed donors were transplanted into the cheek pouches of control or neonatally DES-exposed adult hosts, and both host groups were treated to provide high circulating levels of estradiol. Among the four ectopic scenarios, histopathological lesions (epithelial hyperplasia, dysplasia, and apoptosis), segregated almost exclusively to the two that consisted of neonatally DES-exposed uteri. The virtual absence of lesions in control uteri transplanted to DES hosts eliminated host systemic factors as causative agents. Therefore, we conclude that DES or its metabolites alter the cellular physiology and/or composition of the developing uterus (initiating event) in such a way that it thereafter responds abnormally to estrogenic stimulation (promoting event). These observations serve to further define a unique experimental system for probing: (a) various aspects of the clinical "DES Syndrome"; (b) how estrogen regulates normal uterine growth and morphogenesis; and (c) how this process can degenerate to the unregulated neoplastic state.

¹ This work was supported in part by an institutional Pilot Study Program funded through the American Cancer Society and the Arkansas Cancer Research Center, Grant HD 28074 from the National Institute of Child Health and Human Development, Grant CA60250 from the National Cancer Institute, a gift from the Flossie West Memorial Trust Foundation, and a grant from the United States Food and Drug Administration.

² To whom requests for reprints should be addressed, at Department of Biological Sciences, Wichita State University, 1845 Fairmount, Wichita, KS 67260-0026. Phone: (316) 978-3111; Fax: (316) 978-3772; E-mail: hendry@wsuhub.uc.twsu.edu.

³ Present address: Howard Hughes Medical Institute, Washington University School of Medicine, 660 South Euclid Avenue, Box 8022, St. Louis, MO 63110.

Received 6/ 6/96. Accepted 3/17/97.

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