Prins Gail S, Birch Lynn, Tang Wan-Yee, Ho Shuk-Mei
Department of Urology, University of Illinois at Chicago, 820 South Wood Street, MC 955, Chicago, IL 60612, United States.
Reprod Toxicol. 2007 Apr-May;23(3):374-82. doi: 10.1016/j.reprotox.2006.10.001. Epub 2006 Oct 24.
Prostate morphogenesis occurs in utero in humans and during the perinatal period in rodents. While largely driven by androgens, there is compelling evidence for a permanent influence of estrogens on prostatic development. If estrogenic exposures are abnormally high during the critical developmental period, permanent alterations in prostate morphology and function are observed, a process referred to as developmental estrogenization. Using the neonatal rodent as an animal model, it has been shown that early exposure to high doses of estradiol results in an increased incidence of prostatic lesions with aging which include hyperplasia, inflammatory cell infiltration and prostatic intraepithelial neoplasia or PIN, believed to be the precursor lesion for prostatic adenocarcinoma. The present review summarizes research performed in our laboratory to characterize developmental estrogenization and identify the molecular pathways involved in mediating this response. Furthermore, recent studies performed with low-dose estradiol exposures during development as well as exposures to environmentally relevant doses of the endocrine disruptor bisphenol A show increased susceptibility to PIN lesions with aging following additional adult exposure to estradiol. Gene methylation analysis revealed a potential epigenetic basis for the estrogen imprinting of the prostate gland. Taken together, our results suggest that a full range of estrogenic exposures during the postnatal critical period - from environmentally relevant bisphenol A exposure to low-dose and pharmacologic estradiol exposures - results in an increased incidence and susceptibility to neoplastic transformation of the prostate gland in the aging male which may provide a fetal basis for this adult disease.
前列腺形态发生在人类子宫内及啮齿动物围产期进行。虽然主要由雄激素驱动，但有令人信服的证据表明雌激素对前列腺发育有永久性影响。如果在关键发育时期雌激素暴露异常高，就会观察到前列腺形态和功能的永久性改变，这一过程称为发育性雌激素化。以新生啮齿动物作为动物模型，研究表明，早期高剂量暴露于雌二醇会导致随着年龄增长前列腺病变发生率增加，这些病变包括增生、炎症细胞浸润以及前列腺上皮内瘤变（PIN），而PIN被认为是前列腺腺癌的前体病变。本综述总结了我们实验室进行的研究，以表征发育性雌激素化并确定介导这种反应的分子途径。此外，近期关于发育期间低剂量雌二醇暴露以及环境相关剂量内分泌干扰物双酚A暴露的研究表明，成年后额外暴露于雌二醇会使随着年龄增长对PIN病变的易感性增加。基因甲基化分析揭示了前列腺雌激素印记的潜在表观遗传基础。综上所述，我们的结果表明，出生后关键时期内各种雌激素暴露——从环境相关的双酚A暴露到低剂量和药理剂量的雌二醇暴露——都会导致老年男性前列腺肿瘤转化的发生率和易感性增加，这可能为这种成年疾病提供胎儿期基础。
