Diethylstilbestrol exposure in utero: A paradigm for mechanisms leading to adult disease

Abstract

The synthetic estrogen diethylstilbestrol (DES) was administered to pregnant women between the 1940s and the mid-1970s and is believed to be responsible for numerous uterine/cervical/vaginal malformations and cancers that appeared after birth and in young adult life. This medical tragedy has served as one of the prototypical examples of a phenomenon known as "endocrine disruption," in which either environmental agents or other compounds disrupt normal hormonal signaling in the body. Whereas DES signals through estrogen receptors, the subsequent molecular targets were largely unknown. We had identified Wnt7a as a target in this pathway and have used genetic analyses of mutant mice to demonstrate that disruption of Wnt7a is the key event leading to the DES phenotypes and cancers. We find that Wnt7a expression is only transiently deregulated in response to DES exposure, leading to the conclusion that critical events during early reproductive tract development results in a permanent change or "reprogramming" in subsequent development. © 2005 Wiley-Liss, Inc.