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.
The National Institute on Aging leads the Federal effort supporting basic, clinical, epidemiological and social research on aging and the special needs of older people. The National Institute of Dental and Craniofacial Research seeks to improve and promote craniofacial, oral and dental health through research, and the National Institute of General Medical Sciences supports basic biomedical research in order to advance our understanding of fundamental life processes. These are three of the Institutes and Centers at the National Institutes of Health, the leading Federal biomedical research agency.
*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