Richard A. Hajek,1,6 Audra D. Robertson,1 Dennis A. Johnston,3 Nguyen T. Van,2 Robert K. Tcholakian,6 Laura A. Wagner,7 Claudio J. Conti,4 Marvin L. Meistrich,5 Nancy Contreras,8 Creighton L. Edwards,1 and Lovell A. Jones1,9
1Experimental Gynecology-Endocrinology Laboratory, Departments
of Gynecologic Oncology, 2Hematology, 3Biomathematics, 4Carcinogenesis, 5Experimental Radiotherapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; 6Departments of OB/GYN Reproductive Sciences and 7Planning; The University of Texas Health Science Center at Houston, Houston, Texas; and 8Departamento de Morfología, Universidad Centro de Venezuela, Carracas, Venezuela
Neonatal administration of estradiol-17ß (E2-17ß) increases the nuclear DNA content in the mouse reproductive tract. Similar responses have been demonstrated for synthetic estrogens such as diethylstilbestrol. One of the questions raised regarding environmental estrogens such as organochlorines is whether they are potent enough to result in abnormal changes such as those demonstrated by both natural and synthetic estrogens. To test this hypothesis, female BALB/c mice were treated neonatally (days 1-5) with either E2-17ß or estradiol- 17
(E2- 17), an inactive stereoisomer in adult reproductive tissues. We also proposed whether neonatal administration of (E2- 17) was tumorigenic and whether the effects were age dependent. To answer these questions, one set each of 10-day-old treated and control mice received short-term secondary administration of E2-17ß, E2- 17, or cholesterol. Cervicovaginal tracts from intact BALB/c mice were examined histologically and by flow cytometry at 70 days of age and by histology alone at 18 to 22 months of age. The results include several important findings: a) like E2-17ß, neonatal E2- 17 treatment induced persistent vaginal cornification, hypospadias, vaginal concretions, and hyperproliferation in nearly 100% of the animals regardless of the secondary treatment for most groups; b) neonatal E2- 17 treatment increased the nuclear DNA content of cervicovaginal epithelium at one-half both the level (mean DNA index of 1.02 vs 1.04) and incidence (22 vs 46% of the animals) of E2-17ß; c) short-term secondary treatment with E2- 17, unlike E2-17ß, did not significantly augment the increase in DNA content (13% for E2- 17 vs 37 and 56% for control and E2-17ß, respectively); and d) neonatal administration with E2- 17 induced adenosquamous tumors in the reproductive tract in 25% of the animals. Therefore, the biological effects (estrogenic potency) of E2- 17 may be age dependent. -- Environ Health Perspect 105(Suppl 3):577-581 (1997)
Key words: carcinogen, cervicovaginal, endocrine disruptor, estradiol, estrogen, development, neonatal, mouse
This paper was presented in part at the Workshop on Hormones, Hormone Metabolism, Environment, and Breast Cancer held 28-29 September 1995 in New Orleans, Louisiana. Manuscript received at EHP 6 June 1996; manuscript accepted 30 August 1996.
We wish to thank S.K. Grigsby, B. Nehete, and R.P. Rhodes for their help in the laboratory. In addition, we thank M.A. Hajek and S.C. Patterson for their technical and editorial assistance.
This work was supported in part by the Ann Rife Cox Chair in Gynecology, The Tenneco Core Facility, and National Institutes of Health grants CA44591, CA16672, and HD07324.
Address correspondence to Dr. L.A. Jones, Experimental Gynecology/Endocrinology Laboratory, Department of Gynecologic Oncology, Box 304, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Telephone: (713) 792-3316. Fax: (713) 792-3575. E-mail: lovell_jones@gynonc.mdacc.tmc.edu
Abbreviations used: ANOVA, analysis of variance; CV, cervicovaginal; DI, DNA index; E2- 17
, 17-estradiol; E2-17ß, 17-ß estradiol; INIT, type of initial treatment; K-W, Kruskal-Wallis; SCND, type of secondary treatment.
Last Update: April 10, 1997