Uterine adenocarcinoma in mice following developmental treatment with estrogens: a model for hormonal carcinogenesis.
In order to study the effects of perinatal exposure to estrogens on the developing reproductive tract, outbred female mice were treated neonatally (days 1 to 5) with varying doses of diethylstilbestrol (DES) and sacrificed from 1 to 18 months of age. Uterine adenocarcinoma was observed in a time- and dose-related manner after DES treatment; at 18 months, neoplastic lesions were seen in 90% of the mice exposed neonatally to 2 micrograms/pup of DES/day, while none was observed in the corresponding control mice. These DES-induced uterine tumors were estrogen dependent; when DES-treated mice were ovariectomized before puberty, no uterine tumors developed. As a marker for neoplasia, uterine tumors were transplanted and carried as serial transplants in nude mice. The transplanted tissue retained some differentiated uterine gland structure and function and also required estrogen supplementation for maintenance. Additional groups of neonatal mice were treated with various DES analogues (hexestrol and tetrafluorodiethylstilbestrol) and steroidal estrogens. The compounds were ranked according to developmental estrogenic potency (hexestrol greater than trifluorodiethylstilbestrol greater than DES greater than 17 beta-estradiol). The combined prevalence of uterine atypical hyperplasia and adenocarcinoma follows the order of estrogenic potency. The experimental induction of these tumors will provide the basis for additional studies in mechanisms of hormonal carcinogenesis.
Newbold
R R
RR
Developmental Endocrinology and Pharmacology Section, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709.
Bullock
B C
BC
McLachlan
J A
JA
D000230:Adenocarcinoma / Q000209:etiology* / Q000473:pathology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced; D004054:Diethylstilbestrol / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004715:Endometriosis / Q000139:chemically induced; D004848:Epithelium / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006589:Hexestrol / Q000494:pharmacology; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011374:Progesterone / Q000494:pharmacology; D014594:Uterine Neoplasms / Q000209:etiology* / Q000473:pathology; D014599:Uterus / Q000473:pathology; D014621:Vagina / Q000187:drug effects
D004967:Estrogens; D013196:Dihydrotestosterone; D006589:Hexestrol; D011374:Progesterone; D004958:Estradiol; D004054:Diethylstilbestrol