POTENTIATION OF DIETHYLSTILBESTROL-INDUCED ALTERATIONS IN THE FEMALE MOUSE REPRODUCTIVE-TRACT BY TRANSFORMING GROWTH-FACTOR-ALPHA TRANSGENEEXPRESSION

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 epig enetic and involves the modulation of a number of estrogen-regulated g enes including epidermal growth factor (EGF). Because of the evidence that there is an integral relationship between the EGF family, estroge n action, and the regulation of the growth and differentiation of the reproductive tract, we used transforming growth factor-alpha (TGF alph a) transgenic mice to investigate the interaction of constitutive TGF alpha expression with the potent estrogen diethylstilbestrol (DES) in the induction of reproductive-tract alterations. Our study was designe d to determine whether TGF alpha expression could modulate DES-induced carcinogenesis of the female mouse reproductive tract. The animals we re homozygous TGF alpha transgenic female mice from the MT42 line and the parental CD-1 outbred mice. The presence of the TGF alpha transgen e significantly increased the incidence of DES-induced vaginal adenosi s, uterine endometrial hyperplasia, uterine polyps, hypospadia, benign ovarian cysts, and pituitary adenomas. However, constitutive TGF alph a expression did not promote reproductive-tract neoplasia. This study demonstrates that TGF alpha participates in the regulation of developm ental and morphogenic events in the Mullerian duct and urogenital sinu s, suggesting a role for TGF alpha in the pathogenesis of reproductive -tract diseases. Furthermore, we showed that although constitutive exp ression of the TGF alpha transgene did have an effect on the reproduct ive tract, TGF alpha overexpression alone could not substitute for DES as a reproductive-tract carcinogen or as a promoter of uterine neopla sia, indicating that DES-induced carcinogenesis requires events in add ition to the overexpression of this single peptide growth factor. (C) 1996 Wiley-Liss, Inc.