E-DRUG: DES (DIETHYLSTILBESTROL) MAY SUPPRESS GENE IMPORTANT
TO NORMAL FEMALE REPRODUCTIVE TRACT DEVELOPMENT
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U.S. NATIONAL INSTITUTES OF HEALTH, National Institute on Aging
Press release
Exposure to a synthetic estrogen-like hormone, DES, during a critical
gestational period appears to suppress a gene that controls reproductive
tract development in mice causing changes in the uterus and vagina that
are similar to those found in women exposed to DES before birth.
Scientists at the Mt. Sinai School of Medicine, New York City, found
that defects in the reproductive tracts of mice exposed in utero to DES
are similar to those in mice missing the Wnt7a gene, one of a family of
genes that regulate cell interactions in the development of the body and
specific organs in living organisms from fruit flies to humans.
Between 1947 and 1971 over 1,000,000 American women were exposed to DES
when their mothers took the drug during pregnancy to prevent
miscarriage. Women exposed to DES during the first three months of in
utero development often exhibit changes in the tissue and/or structure
of their uterus, cervix, or vagina. These changes resulted in later
infertility problems and also place them at risk of developing a rare
form of cancer, clear cell adenocarcinoma of the vagina or cervix, at a
young age.
"These animal studies should greatly enhance our understanding of the
molecular effects of DES exposure, and possibly that of other estrogenic
compounds, whether found in the environment or used for medical
treatment," explained Dr. Francis Bellino, Acting Associate Director of
the Biology of Aging Program at the National Institute on Aging (NIA).
Because the risk of uterine cancer increases with age, the NIA is
interested in understanding the molecular response to estrogen and
estrogen-like substances used to treat menopause or to prevent breast
cancer and how they may contribute to this risk.
These results were reported in the November 1998 issue of the journal,
Nature Genetics.* The study, conducted by David A. Sassoon, Ph.D., Cary
Miller, and Karl Degenhardt, at Mt. Sinai's Brookdale Center for
Developmental and Molecular Biology, was supported by the National
Institute on Aging, the National Institute of Dental and Craniofacial
Research (NIDCR), and the National Institute of General Medical Sciences
(NIGMS).
Initially, the scientists exposed pregnant mice to 200 micrograms/day of
DES suspended in sesame oil or to the oil alone on days 15 to 18 of
their pregnancy. Samples of reproductive tract tissue from the resulting
DES-exposed female offspring were compared to similar samples from Wnt7a
mutant mice and the control group. As compared with the control mice,
both the DES mice and the Wnt7a group showed similar changes in the
epithelium (outer layer of tissue), stroma (the underlying tissue), and
the smooth muscle in their uteri. These similarities suggested that
Wnt7a was involved in the DES response. In fact, they saw that DES
exposure blocks the expression of Wnt7a in the uterus during a time
period critical to uterine development in mice. Although expression of
Wnt7a does return to normal 5 days after birth, irreversible changes in
the organization of the reproductive tract have already occurred.
The scientists also observed structural changes in the reproductive
tracts of DES-treated and Wnt7a mutant mice including poorly formed
oviducts and vaginal fornices (the area in the vagina near the cervix),
as well as hardened areas and abnormal glandular material in the vagina.
*C. Miller, K. Degenhardt, and D.A. Sassoon, "Fetal Exposure to DES
Results in De-regulation of Wnt7a During A Critical Period of Uterine
Morphogenesis," Nature Genetics, 20:3, pp. 228-230, 1998
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