Mechanisms of DES carcinogenicity: effects of the TGF alpha transgene.

Inappropriate estrogen exposure during critical periods of development will cause numerous abnormalities in the female reproductive tract. Epigenetic effects on the expression of estrogen-regulated genes is proposed to be one of the mechanisms by which neonatal estrogen elicits teratogenic and carcinogenic effects. Of note is the existence of an integral relationship between the regulation of members of the epidermal growth factor (EGF) gene family and estrogen effects on the growth and differentiation of the reproductive tract. To determine whether the EGF gene family plays a critical role in mediating the pathogenic effects of estrogen, we have used transforming growth factor-alpha (TGF alpha) transgenic mice to investigate the effects of constitutive TGF alpha expression in the reproductive tract and whether TGF alpha would potentiate carcinogenesis induced by the potent estrogen, diethylstilbestrol (DES), and by the carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA). The animals were homozygous TGF alpha transgenic female mice from the MT42 line and the parental CD-1 outbred mice. Constitutive TGF alpha expression was found to augment the effects of both DES and DMBA in eliciting hyperplastic and differentiation changes in the reproductive tract. The presence of the TGF alpha transgene significantly increased the incidence of DES-induced vaginal adenosis, uterine endometrial hyperplasia, hypaspadia, and benign ovarian cysts. In addition TGF alpha potentiated the effects of DMBA in eliciting uterine polyps and benign ovarian cysts, and in the retention of Wolffian Duct remnants. However, the incidence of reproductive tract neoplasia was not promoted by the presence of the TGF alpha transgene. This study indicates that TGF alpha plays a role in the developmental and morphogenic events of both the Müllerian duct and urogenital sinus, and that deregulation is associated with pathogenesis of these tissues. Furthermore, the fact that constitutive expression of the TGF alpha did not substitute for DES as a reproductive tract carcinogen or act as a promoter of DES-induced uterine neoplasia suggest that DES carcinogenesis involves more than aberrant expression of this single growth factor.