Exposure to endocrine disrupting compounds (EDC's) has been linked to cancer, steady decline of sperm counts, premature onset of puberty, and abnormal development of the reproductive tract and other developmental impacts to humans and wildlife. Diethylstilbestrol (DES) is a synthetic estrogen that was prescribed to millions of pregnant women to prevent miscarriage and other pregnancy abnormalities. In the mouse model, genital tract abnormalities also develop after prenatal or neonatal DES exposure. However, how DES alters normal reproductive tract development remains obscure. Recently, DES has been shown to potently repress developmental expression of Hoxa-lO, Hoxa-ll and Wnt-7a genes. In this proposal, we propose to use DES as a model to study the effect of EDC's on normal uterine development. We showed that neonatal DES exposure alters the luminal epithelial cell fate by inducing the expression of a family of Small Proline Rich Proteins (Sprr) genes, offering a molecular basis for alteration of development and differentiation by early exposure to DES. This proposal will further investigate the molecular mechanisms underlying DES-induced uterine metaplasia using Sprr genes as an entry point. ? ?
