Potentiation of diethylstilbestrol-induced alterations in the female mouse reproductive tract by transforming growth factor-alpha transgene expression.
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-alpha (TGF alpha) 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 designed to determine whether TGF alpha expression could modulate DES-induced carcinogenesis of the female mouse reproductive tract. The animals were homozygous TGF alpha transgenic female mice from the MT42 line and the parental CD-1 outbred mice. The presence of the TGF alpha transgene significantly increased the incidence of DES-induced vaginal adenosis, uterine endometrial hyperplasia, uterine polyps, hypospadia, benign ovarian cysts, and pituitary adenomas. However, constitutive TGF alpha expression did not promote reproductive-tract neoplasia. This study demonstrates that TGF alpha participates in the regulation of developmental and morphogenic events in the Müllerian duct and urogenital sinus, suggesting a role for TGF alpha in the pathogenesis of reproductive-tract diseases. Furthermore, we showed that although constitutive expression of the TGF alpha transgene did have an effect on the reproductive tract, TGF alpha 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.
Gray
K
K
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Bullock
B
B
Dickson
R
R
Raszmann
K
K
Walmer
D
D
McLachlan
J
J
Merlino
G
G
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D003043:Cocarcinogenesis; D004054:Diethylstilbestrol / Q000633:toxicity*; D005187:Fallopian Tubes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005833:Genital Neoplasms, Female / Q000139:chemically induced* / Q000235:genetics*; D005836:Genitalia, Female / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010053:Ovary / Q000187:drug effects / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019076:Transgenes; D014599:Uterus / Q000187:drug effects / Q000378:metabolism; D014621:Vagina / Q000187:drug effects / Q000378:metabolism
D002273:Carcinogens; D016211:Transforming Growth Factor alpha; D004054:Diethylstilbestrol