ReviewLessons learned from perinatal exposure to diethylstilbestrol
Introduction
The developing organism is extremely vulnerable to perturbation by chemicals, especially those with hormone-like activity (Bern, 1992). Rapid cell proliferation and cell differentiation coupled with complex patterns of cell signaling and cell migration occurring during development help contribute to its unique sensitivity. Further, fetuses and neonates have high metabolic rates, undeveloped liver detoxifying mechanisms, and undifferentiated immune systems as compared to adults making them more prone to chemical insult. Unlike adult exposures that can result in reversible alterations, exposure to chemicals during critical stages of development and differentiation may cause irreversible long-lasting consequences. Some of these consequences may not be noticeable or expressed until much later in life. The adverse consequences resulting from prenatal exposure to diethylstilbestrol (DES) is one example.
Ample evidence exists in multiple species including rodents and humans to link prenatal exposure to DES, a synthetic estrogen used for treatment of miscarriage, with numerous detrimental effects including reproductive tract abnormalities and a low but significant increase in vaginal cancer. In fact, DES holds the dubious position of being the only definitely established transplacental chemical carcinogen in humans Herbst and Bern, 1981, Tomatis, 1989. Observations in our lab for over three decades and from other laboratories using DES-exposed experimental animal models, combined with similar findings in DES-exposed humans, have added to the substantial literature base documenting the potential adverse consequences of developmental exposure to environmental chemicals with estrogenic activity. These experimental studies provide unique opportunity to study the underlying mechanisms associated with the complex issues related to perinatal carcinogenesis. The aim of this review is to update what is currently known about the consequences of DES exposure in humans and experimental animals, and to discuss the cellular and molecular findings that are contributing to our understanding of perinatal toxicity and carcinogenicity.
Section snippets
Historical perspective of DES
DES, a synthetic nonsteroidal compound with estrogenic activity, was heavily prescribed from the late 1940s through the 1970s to women with high-risk pregnancies with the mistaken belief that it would prevent miscarriage and other complications of pregnancy. In 1971, a landmark report associated prenatal DES exposure with a rare form of reproductive tract cancer, “vaginal clear cell adenocarcinoma”, that was detected in a small number (<0.1%) of adolescent daughters of women who had taken the
Prenatal model
One extensively described experimental model is the prenatal DES exposure model in which timed pregnant, outbred CD-1 mice are treated subcutaneously with DES dissolved in corn oil on days 9–16 of gestation. This time of in utero DES exposure for the offspring encompasses the major period of organogenesis of the reproductive tract in the mouse (Tuchmann-Duplessis and Haegel, 1982). After the mice are born, they are followed for up to 18 months of age. The doses of DES range from 0.01 to 100
Cellular and molecular mechanisms
Numerous studies have demonstrated that developmental exposure to DES interferes with normal differentiation of the Müllerian duct and regression of the Wolffian duct. Although the mechanisms are not completely understood, a molecular component in the malformation of the tissues and perhaps in the cellular changes may be responsible. Studies by Taylor et al. (1997) report that HOX genes are involved in the structural differentiation of the reproductive tract. Further studies from Ma et al.
Multigenerational carcinogenesis
Ongoing mechanistic studies continue to provide support that estrogens cause both genetic and epigenetic alterations in developing target tissues (Li et al., 2003). This then raises the possibility that changes seen following prenatal or neonatal DES treatment may be transmitted to subsequent generations. In fact, when the granddaughters and grandsons of DES-treated female mice were examined late in life at 18 months of age, they had an increased incidence of tumors in reproductive tract
DES as a predictor of risks to other environmental estrogens
There has been increasing concern that environmental and dietary chemicals with estrogenic activity are causing adverse reproductive health consequences by altering normal developmental processes Colborn and Clement, 1992, Colborn et al., 1993, Colborn et al., 1996, McLachlan, 1985. Initial attention focused only on chemicals with estrogenic activity, but now concern has broadened to include numerous chemicals that mimic or interfere with the normal actions of all endocrine hormones. These
Summary and conclusion
Sufficient evidence has been accumulated through the years by many laboratories to show that exposure of the developing fetus to exogenous estrogens adversely affects the differentiation of the genital tract. Experimental data demonstrate that reproductive tract structure and function are altered, and long-term cellular changes occur including both benign and malignant abnormalities. Cellular changes were seen in aged DES-exposed mice at all doses examined; the severity of specific lesions was
Acknowledgements
The author is greatly indebted to Ms. Wendy Jefferson and Elizabeth Padilla-Banks of NIEHS for skillful technical expertise in the conduct of the DES experiments and their critical editorial comments in the preparation of this paper. Also, the insightful diagnosis of the pathological lesions by Dr. Bill Bullock, Wake Forest University Medical School, Winston Salem, NC, is greatly appreciated. Finally, the long-standing association with Dr. John McLachlan, Tulane University, New Orleans, LA
References (61)
- et al.
Self-reported allergy, infection, and autoimmune diseases among men and women exposed in utero to diethylstilbestrol
J. Clin. Epidemiol.
(1996) - et al.
Screening of adolescents exposed to diethylstilbestrol in utero
Pediatr. Clin. North Am.
(1981) - et al.
Estrogen receptor-alpha knockout mice exhibit resistance to the developmental effects of neonatal diethylstilbestrol exposure on the female reproductive tract
Dev. Biol.
(2001) - et al.
Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities
J. Urol.
(1979) - et al.
Risk factors for the development of diethylstilbestrol-associated clear cell adenocarcinoma: a case-control study
Am. J. Obstet. Gynecol.
(1986) - et al.
Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in mullerian duct by the synthetic estrogen diethylstilbestrol (DES)
Dev. Biol.
(1998) - et al.
Testicular tumors in mice exposed in utero to diethylstilbestrol
J. Urol.
(1987) - et al.
Effects of diethylstilbestrol exposure in utero on the genital tracts of female ACI rats
Exp. Mol. Pathol.
(1988) - et al.
Alterations in immune responsiveness in women exposed to diethylstilbestrol in utero
Fertil. Steril.
(1987) - et al.
Cancer development in male reproductive tract in rats given diethylstilbestrol at neonatal age
Gann
(1978)
The fragile fetus
Diethylstilbestrol and risk of fatal breast cancer in a prospective cohort of US women
Am. J. Epidemiol.
Chemically-Induced Alterations in Sexual and Functional Development: The Wildlife/Human Connection
Developmental effects of endocrine-disrupting chemicals in wildlife and humans
Environ. Health Perspect.
Our Stolen Future
Seminoma and epididymal cysts in a young man with known diethylstilbestrol exposure in utero
J. Am. Med. Assoc.
Accelerated onset of uterine tumors in transgenic mice with aberrant expression of the estrogen receptor after neonatal exposure to diethylstilbestrol
Mol. Carcinog.
Cancer risk in women exposed to diethylstilbestrol in utero
J. Am. Med. Assoc.
Developmental Effects of Diethylstilbestrol (DES) in Pregnancy
Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women
N. Engl. J. Med.
Estrogen-induced Leydig cell tumor in the mouse: a model system for the study of carcinogenesis and hormone dependency
J. Toxicol. Environ. Health
Development of vaginal adenosis-like lesions and uterine epithelial stratification in mice exposed perinatally to diethylstilbestrol
Proc. Soc. Exp. Biol. Med.
Expression of estrogen receptor beta is developmentally regulated in reproductive tissues of male and female mice
Biol. Reprod.
Neonatal exposure to genistein induces estrogen receptor (ER)alpha expression and multioocyte follicles in the maturing mouse ovary: evidence for ERbeta-mediated and nonestrogenic actions
Biol. Reprod.
Long-term effects of neonatal DES treatment on plasma prolactin in female mice
Endocr. Res. Commun.
Metabolic activation of pesticides with proestrogenic activity
Fed. Proc.
Etiology of DES-induced uterine tumors in the Syrian hamster
Adv. Exp. Med. Biol.
Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus
Cancer Res.
Promoter CpG methylation of Hox-a10 and Hox-a11 in mouse uterus not altered upon neonatal diethylstilbestrol exposure
Mol. Carcinog.
Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus
Mol. Carcinog.
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