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Effects of postnatal DES treatment on uterine growth, development, and estrogen receptor levels
K L Medlock1, D M Sheehan, C J Nelson
1Food and Drug Administration, National Center for Toxicological Research, Jefferson, AR 72079.
Insights
Neonatal rats exposed to diethylstilbestrol (DES) showed altered uterine growth and estrogen receptor levels. Early DES exposure caused lasting hypoplasia, impacting reproductive tract development.
Area of Science:
- Reproductive Toxicology
- Developmental Biology
- Endocrinology
Background:
- Neonatal exposure to endocrine-disrupting chemicals can impact reproductive development.
- Diethylstilbestrol (DES) is a synthetic estrogen with known developmental toxicity.
- Understanding the effects of early-life estrogen exposure is crucial for reproductive health.
Purpose of the Study:
- To investigate the effects of neonatal diethylstilbestrol (DES) exposure on reproductive tract development in rats.
- To evaluate the impact of DES on uterine growth, estrogen receptor levels, and gland morphogenesis.
- To determine if neonatal rodents are a suitable model for studying estrogen toxicity.
Main Methods:
- Newborn rats were administered diethylstilbestrol (DES) at human therapeutic doses during two critical developmental windows (postnatal days 1-5 and 1-25).
- Uterine weight, DNA content, estrogen receptor levels, and gland morphology were assessed at various time points.
- Control groups received no DES treatment.
Main Results:
- Short-term DES exposure (days 1-5) doubled uterine weight initially but led to subsequent growth failure.
- Continuous DES exposure (days 1-25) resulted in a 4-fold increase in uterine weight and doubled DNA content.
- DES significantly reduced uterine estrogen receptor levels and inhibited uterine gland development, with effects varying based on exposure duration.
Conclusions:
- Neonatal rodent models are appropriate for studying estrogen toxicity in the developing reproductive tract.
- Neonatal DES exposure disrupts normal uterine growth patterns, estrogen receptor regulation, and morphogenesis.
- These findings highlight the potential for endocrine disruptors to cause lasting reproductive abnormalities, mirroring clinical observations in DES-exposed humans.
Abstract:
The neonatal rodent appears to be an appropriate animal model for estrogen toxicity in the developing reproductive tract. Newborn rats were treated with diethylstilbestrol (DES) at human therapeutic doses (approx 1 mg/kg) during two ontogenetic periods (postnatal days 1-5 and 1-25). Treatment on days 1-5 doubled uterine wt by day 5; however, these uteri failed to grow after discontinuation of DES treatment. In contrast, uterine wt was 4-fold higher and DNA content was 2-fold higher than controls on days 10-25 with continued DES treatment. Total uterine estrogen receptor levels, depressed 60% by day 5 of DES treatment, partially recovered after discontinuation of DES treatment but remained 25% below controls on day 25. Receptor levels following DES on days 1-25 decreased to about 15% of the controls by day 15. Short-term DES treatment approximately halved uterine gland content while continued treatment almost completely inhibited gland appearance. DES effects on glands appear related to continued hypertrophy of the luminal epithelium, from which uterine glands are derived. Subsequent failure of uterine growth caused by DES treatment on days 1-5 is similar to clinical findings of hypoplastic uteri in DES-treated patients. Disruption of the normal ontogenetic patterns of estrogen receptor by DES may be involved. These data demonstrate abnormal patterns of growth, estrogen receptor levels and morphogenesis in uteri of rats treated postnatally with DES.