Gray K, Bullock B, Dickson R, Raszmann K, Walmer D, McLachlan J, Merlino G
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Mol Carcinog. 1996 Nov;17(3):163-73. doi: 10.1002/(SICI)1098-2744(199611)17:3<163::AID-MC9>3.0.CO;2-G.
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.
新生儿期接触雌激素会导致女性生殖道出现众多异常，包括致癌作用。新生儿期雌激素引发致畸和致癌效应的一种机制是表观遗传机制，涉及对许多雌激素调节基因的调控，包括表皮生长因子（EGF）。鉴于有证据表明EGF家族、雌激素作用与生殖道生长和分化调节之间存在内在联系，我们利用转化生长因子-α（TGFα）转基因小鼠来研究组成型TGFα表达与强效雌激素己烯雌酚（DES）在诱导生殖道改变方面的相互作用。我们的研究旨在确定TGFα表达是否能调节DES诱导的雌性小鼠生殖道致癌作用。实验动物为来自MT42品系的纯合TGFα转基因雌性小鼠和作为亲本的远交系CD-1小鼠。TGFα转基因的存在显著增加了DES诱导的阴道腺病、子宫内膜增生、子宫息肉、尿道下裂、良性卵巢囊肿和垂体腺瘤的发生率。然而，组成型TGFα表达并未促进生殖道肿瘤形成。这项研究表明，TGFα参与了苗勒管和泌尿生殖窦发育及形态发生事件的调节，提示TGFα在生殖道疾病发病机制中发挥作用。此外，我们发现，虽然TGFα转基因的组成型表达确实对生殖道有影响，但单独的TGFα过表达不能替代DES作为生殖道致癌物或子宫肿瘤的促进剂，这表明DES诱导的致癌作用除了这种单一肽生长因子的过表达外，还需要其他事件。
