Review
Lessons learned from perinatal exposure to diethylstilbestrol

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Abstract

The synthetic estrogen diethylstilbestrol (DES) is well documented to be a perinatal carcinogen in both humans and experimental animals. Exposure to DES during critical periods of differentiation permanently alters the programming of estrogen target tissues resulting in benign and malignant abnormalities in the reproductive tract later in life. Using the perinatal DES-exposed rodent model, cellular and molecular mechanisms have been identified that play a role in these carcinogenic effects. Although DES is a potent estrogenic chemical, effects of low doses of the compound are being used to predict health risks of weaker environmental estrogens. Therefore, it is of particular interest that developmental exposure to very low doses of DES has been found to adversely affect fertility and to increase tumor incidence in murine reproductive tract tissues. These adverse effects are seen at environmentally relevant estrogen dose levels. New studies from our lab verify that DES effects are not unique; when numerous environmental chemicals with weak estrogenic activity are tested in the experimental neonatal mouse model, developmental exposure results in an increased incidence of benign and malignant tumors including uterine leiomyomas and adenocarcinomas that are similar to those shown following DES exposure. Finally, growing evidence in experimental animals suggests that some adverse effects can be passed on to subsequent generations, although the mechanisms involved in these trans-generational events remain unknown. Although the complete spectrum of risks to DES-exposed humans are uncertain at this time, the scientific community continues to learn more about cellular and molecular mechanisms by which perinatal carcinogenesis occurs. These advances in knowledge of both genetic and epigenetic mechanisms will be significant in ultimately predicting risks to other environmental estrogens and understanding more about the role of estrogens in normal and abnormal development.

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

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