Our goal is to understand the cellular mechanism by which prenatal and neonatal DES exposure permanently alters the cell growth and differentiation of male and female reproductive tracts. Current research involves the elucidation of the role of peptide growth factors (IGF-1, EGF, TGFalpha, TGFbeta1, TGFbeta2, and lactoferrin) in the regulation of reproductive function and steroid hormone action. Our studies have now provided considerable evidence that EGF-like peptides (EGF and TGFalpha) and the EGF-receptor play crucial roles in mediating estrogen action in the adult female mouse reproductive tract. In addition, the growth of the undifferentiated neonatal mouse reproductive tract (a stage of development that is exquisitely sensitive to DES-induced carcinogenesis) is also regulated in part by EGF and TGFalpha. Interestingly, the EGF receptor is ontogenically a much earlier constituent of the epithelium of the developing uterus than is the estrogen receptor which appears relatively late in development. These data suggest that EGF/TGFalpha are intimately associated with the normal development and functioning of the reproductive tract and may play a role in DES-induced carcinogenesis and teratogenesis. Recent in vivo experiments clearly demonstrate that EGF has a significant effect on the male reproductive tract. Also, in vivo studies have identified TGF-beta1 and -beta2 as potential regulators of uterine and vaginal growth. Lactoferrin, an estrogen-inducible iron-binding protein, may play a critical role in the growth and differentiation of the reproductive tract and mammary gland. At present, there are still many important questions regarding the role of growth factors on reproduction. Our future plans are to continue to characterize and define the role of peptide mediators of estrogen-induced growth, determine the cell type responsible for the synthesis of these factors, locate the cellular target where these factors act, elucidate whether these factors act alone, synergistically, or temporally, and investigate the second messenger systems that transduce the growth factor signal.
