Prenatal exposure to diethylstilbestrol (DES)

The scientiﬁc community now recognizes that exposure tocertain environmental chemicals can adversely affect thedeveloping organism, and subsequently result in a lifetimerisk of chronic disease (the developmental basis of adulthealth and disease). Prenatal exposure to diethylstilbestrol(DES) was the ﬁrst documented example where exposureof the fetus resulted in long-term changes in the offspringthat were not apparent until much later in life, usually afterthe onset of puberty. Diethylstilbestrol was prescribed forpregnant women from the late 1940s to 1970s, with themistaken belief that it would prevent miscarriage. World-wide estimates suggest that 2 to 8 million pregnancies mayhave been treated with DES. Today, we know DES asa ‘‘transplacental carcinogen,’’ because it crossed themother’s placenta and caused reproductive cancer in her off-spring. Although the prevalence of neoplasia is estimated tobe very low in the DES-exposed population (0.1%), numer-ous other abnormalities including subfertility/infertilityhave a high prevalence (>90%) and occur in both sons anddaughters. Together, these reproductive tract abnormalitiescomprise ‘‘the DES syndrome’’ (1).For over 3 decades, research from our lab and others usingexperimental animals have replicated the changes observedin DES-exposed humans. In some cases, experimentalanimals have predicted changes later found in DES-exposedhumans such as oviductal malformations (2), and increasedincidence of uterine ﬁbroids (3–5). Molecular studies haveshown that many of the DES-associated structural and cellu-larabnormalitiesarecausedbyalteredprogrammingofgenessuch as Hox and Wnt, which play important roles in repro-ductive tract differentiation (6–8).Through the years, not only have we gained insights intothe mechanisms involved in DES-associated abnormalities,but we have also learned that many problems incurred byDES-exposed men and women may be examples of develop-mental (prenatal/neonatal/early childhood) exposure to otherenvironmental chemicals with endocrine-disrupting activity.Environmental‘‘hormonemimics,’’whethersyntheticornat-urally occurring, can disrupt developing organ systems and,like DES, cause abnormalities that may not be apparent untilmuch later in life (9). In fact, developmental exposure to en-docrine-disrupting chemicals has been proposed to be linkedto endometriosis, ﬁbroids, and breast cancer in women, poorsperm quality and increased incidence of cryptorchism inmen,andsubfertility/infertilityinmenandwomen.Itisinter-esting to note that abnormalities characterizing the DESsyndrome are similar to those described following exposureto other endocrine-disrupting chemicals (1).Prenatal DES exposure is a continuing story, with indica-tions that vaginal cancer continues to be found in daughtersas they age. Further, second-generation effects are surfacingwith reports of increased menstrual irregularities (10) andovarian cancer (11) in DES granddaughters, and increasedhypospadias in DES grandsons (12, 13). These trans-generational ﬁndings are consistent with changes previouslyreported in DES-exposed mice (14, 15). This has importantimplications because it suggests that maternal exposure toan endocrine-disrupting substance like DES, can directlyalter the reproductive tract of the person exposed as a fetus,andalsotheaffectthehealthofanothergeneration.Althoughwe do not fully understand the mechanisms involved in thetransmission of disease from one generation to another, itlikely involves persistent epigenetic changes in some genessuch that the fate of tissues or organs are altered. This isan important area of new investigation and critical researchdirection.REFERENCES