Beckman W C, Newbold R R, Teng C T, McLachlan J A
Developmental Endocrinology and Pharmacology Section, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
J Urol. 1994 May;151(5):1370-8. doi: 10.1016/s0022-5347(17)35263-1.
Exposure to estrogens during critical stages of development has been reported to cause irreversible changes in estrogen target tissues such as the reproductive tract. In fact, recent studies using mice describe prenatal estrogen exposure resulting in the expression of the major estrogen-inducible uterine secretory protein, lactoferrin (LF), by the seminal vesicles of the male offspring. Thus, we have studied the role of estrogens in abnormal and normal gene expression in the developing male reproductive tract using LF and seminal vesicle secretory protein IV (SVS IV), an androgen-regulated murine seminal vesicle secretory protein, as markers. Lactoferrin and SVS IV protein and mRNA expression were studied in histological samples by using the techniques of in situ hybridization (ISH) and immunohistochemistry (IHC). Seminal vesicle secretory protein IV was expressed in all (100%) epithelial cells of the control seminal vesicle, but this protein was decreased by castration. However, LF expression was undetectable by ISH or IHC in control seminal vesicle epithelium. Lactoferrin was inducible in 2% of the seminal vesicle epithelial cells from adult castrated mice treated with estradiol 17 beta (E2; 20 micrograms/kg/day for 3 days), indicating that a small percentage of the seminal vesicle cells could be induced to secrete LF after modification of the endocrine environment. Prenatal DES treatment (100 micrograms./kg. maternal body weight on days 9 through 16 of gestation) resulted in the male offspring exhibiting constitutive expression of LF in 5% of the seminal vesicle epithelial cells, while expression of the androgen-regulated protein SVS IV was slightly decreased. The maximal contrast between LF and SVS IV expression was observed in prenatally DES-treated mice that were subsequently castrated as adults and further treated with E2; LF was detected in 40% of the epithelial cells in these mice. Double immunostaining techniques revealed that epithelial cells which were making LF had ceased production of SVS IV. Since a large percentage of the epithelial cells in the intact prenatal DES exposed male was capable of expressing the normal gene product, SVS IV, it was concluded that DES treatment during prenatal development appears to imprint or induce estrogenic sensitivity in the adult seminal vesicle, causing increased production of LF. The results suggest that this altered protein response may be an example of atypical gene expression in male reproductive tract tissues following hormonal manipulation early in development.
据报道，在发育的关键阶段接触雌激素会导致雌激素靶组织如生殖道发生不可逆变化。事实上，最近使用小鼠的研究表明，产前接触雌激素会导致雄性后代的精囊表达主要的雌激素诱导性子宫分泌蛋白乳铁蛋白（LF）。因此，我们以LF和精囊分泌蛋白IV（SVS IV，一种雄激素调节的小鼠精囊分泌蛋白）为标志物，研究了雌激素在发育中的雄性生殖道异常和正常基因表达中的作用。通过原位杂交（ISH）和免疫组织化学（IHC）技术研究了组织学样本中乳铁蛋白和SVS IV蛋白及mRNA的表达。精囊分泌蛋白IV在对照精囊的所有（100%）上皮细胞中表达，但这种蛋白在去势后减少。然而，在对照精囊上皮中，ISH或IHC检测不到LF的表达。用17β-雌二醇（E2；20微克/千克/天，共3天）处理成年去势小鼠，2%的精囊上皮细胞中可诱导LF表达，这表明在内分泌环境改变后，一小部分精囊细胞可被诱导分泌LF。产前己烯雌酚处理（妊娠第9至16天母体体重100微克/千克）导致雄性后代5%的精囊上皮细胞中出现LF的组成性表达，而雄激素调节蛋白SVS IV的表达略有下降。在产前经己烯雌酚处理、随后成年去势并进一步用E2处理的小鼠中，观察到LF和SVS IV表达之间的最大差异；在这些小鼠中，40%的上皮细胞中检测到LF。双重免疫染色技术显示，产生LF的上皮细胞已停止产生SVS IV。由于完整的产前暴露于己烯雌酚的雄性小鼠中很大比例的上皮细胞能够表达正常基因产物SVS IV，因此得出结论，产前发育期间的己烯雌酚处理似乎在成年精囊中印记或诱导了雌激素敏感性，导致LF产生增加。结果表明，这种改变的蛋白质反应可能是发育早期激素操纵后雄性生殖道组织中非典型基因表达的一个例子。
