PARENT SESSION
BIOLOGY OF THE FEMALE REPRODUCTIVE TRACT
Harborside C
7:30 AM-10:00 AM

(543) LOW DOSES OF ESTROGENIC CHEMICALS LIKE DIETHYLSTILBESTROL (DES) DURING DEVELOPMENT RESULT IN PERMANENT ALTERATIONS IN THE REPRODUCTIVE TRACT.

Newbold, Retha¹, Padilla-Banks, Elizabeth¹, Jefferson, Wendy¹, ¹ Developmental Endocrinology Section, Research Triangle Park, NC

ABSTRACT- Adverse human health consequences may result from exposure to chemicals that interact with the endocrine system as documented in experimental animals and wildlife. Since the developing organism is uniquely sensitive to perturbation by chemicals with hormone-like activity, the present study addresses whether exposure to these chemicals during critical stages of differentiation will permanently alter the developmental program of tissues, so that they respond atypically to further stimuli later in life. Outbred CD-1 mice were treated by subcutaneous injections with diethylstilbestrol (DES .0001 - 1,000 g/kg) dissolved in corn oil or corn oil alone (control) on days 1-5 of neonatal life. Mice were weaned at 17 days prior to puberty, housed 4/cage, and challenged with 3 daily doses of 17-estradiol (500 g/kg) or DES (10 g/kg). On the 4th day, uterine wt./body wt. ratios were determined. Uterine tissues were microscopically evaluated for changes in epithelial cell height and number, gland number, and induction of estrogen-responsive proteins including lactoferrin (LF), progesterone receptor (PR) and c-fos. Neonatal DES exposure resulted in altered uterine response to estrogen at puberty. Of particular interest was that the response varied depending on the dose of neonatal exposure; neonatal exposure to DES 0.01 caused an enhanced response to estrogen at puberty as compared to controls, whereas higher neonatal doses of DES caused reduced uterine response. To determine if these effects were permanent, an additional group of mice was neonatally treated with DES (0.001-10 g/kg) and housed until 4-5 months of age. These adult mice were ovariectomized and challenged 7 days later as described for the immature mice. The adult mice exhibited similar results (enhanced uterine wet weight response at the .01 dose and a dampened response at the high doses of 1 and 10 g/kg. Mechanisms responsible for this altered response involved ER mediated events. We conclude that altered uterine responses were permanently imprinted by developmental exposure to estrogens. Other environmental estrogens are being tested and compared to DES to determine if similar altered uterine responses occur.

KEY WORDS: endocrine disrupter, diethylstilbestrol (DES), female reproductive tract, development