Potentiation of diethylstilbestrol‐induced alterations in the female mouse reproductive tract by transforming growth factor‐α transgene expression

Abstract

Neonatal estrogen exposure causes numerous abnormalities in the female reproductive tract, including carcinogenesis. One mechanism by which neonatal estrogen elicits teratogenic and carcinogenic effects is epigenetic and involves the modulation of a number of estrogen-regulated genes including epidermal growth factor (EGF). Because of the evidence that there is an integral relationship between the EGF family, estrogen action, and the regulation of the growth and differentiation of the reproductive tract, we used transforming growth factor-α (TGFα) transgenic mice to investigate the interaction of constitutive TGFα expression with the potent estrogen diethylstilbestrol (DES) in the induction of reproductive-tract alterations. Our study was designed to determine whether TGFα expression could modulate DES-induced carcinogenesis of the female mouse reproductive tract. The animals were homozygous TGFα transgenic female mice from the MT42 line and the parental CD-1 outbred mice. The presence of the TGFα transgene significantly increased the incidence of DES-induced vaginal adenosis, uterine endometrial hyperplasia, uterine polyps, hypospadia, benign ovarian cysts, and pituitary adenomas. However, constitutive TGFα expression did not promote reproductive-tract neoplasia. This study demonstrates that TGFα participates in the regulation of developmental and morphogenic events in the Müllerian duct and urogenital sinus, suggesting a role for TGFα in the pathogenesis of reproductive-tract diseases. Furthermore, we showed that although constitutive expression of the TGFα transgene did have an effect on the reproductive tract, TGFα overexpression alone could not substitute for DES as a reproductive-tract carcinogen or as a promoter of uterine neoplasia, indicating that DES-induced carcinogenesis requires events in addition to the overexpression of this single peptide growth factor. © 1996 Wiley-Liss, Inc. 1 This article is a US Government work and, as such, is in the public domain in the United States of America.