Hilakivi-Clarke L, Cho E, Clarke R
Lombardi Cancer Center, Research Bldg., Room W405, Georgetown University, 3970 Reservoir Road, NW, Washington, DC, 20007-2197, USA.
Oncol Rep. 1998 May-Jun;5(3):609-16. doi: 10.3892/or.5.3.609.
Human and animal data indicate that a high maternal estrogen exposure during pregnancy increases breast cancer risk among daughters. This may reflect an increase in the epithelial structures that are the sites for malignant transformation, i.e., terminal end buds (TEBs), and a reduction in epithelial differentiation in the mammary gland. Some phytoestrogens, such as genistein which is a major component in soy-based foods, and zearalenone, a mycotoxin found in agricultural products, have estrogenic effects on the reproductive system, breast and brain. The present study examined whether in utero exposure to genistein or zearalenone influences mammary gland development. Pregnant mice were injected daily with i) 20 ng estradiol (E2); ii) 20 microg genistein; iii) 2 microg zearalenone; iv) 2 microg tamoxifen (TAM), a partial estrogen receptor agonist; or v) oil-vehicle between days 15 and 20 of gestation. E2, genistein, zearalenone, and tamoxifen all increased the density of TEBs in the mammary glands. Genistein reduced, and zearalenone increased, epithelial differentiation. Zearalenone also increased epithelial density, when compared with the vehicle-controls. None of the treatments had permanent effects on circulating E2 levels. Maternal exposure to E2 accelerated body weight gain, physical maturation (eyelid opening), and puberty onset (vaginal opening) in the female offspring. Genistein and tamoxifen had similar effects on puberty onset than E2. Zearalenone caused persistent cornification of the estrus smears. These findings indicate that maternal exposure to physiological doses of genistein mimics the effects of E2 on the mammary gland and reproductive systems in the offspring. Thus, our results suggest that genistein acts as an estrogen in utero, and may increase the incidence of mammary tumors if given through a pregnant mother. The estrogenic effects of zearalenone on the mammary gland, in contrast, are probably counteracted by the permanent changes in estrus cycling.
人类和动物数据表明，孕期母亲雌激素暴露水平高会增加女儿患乳腺癌的风险。这可能反映出作为恶性转化部位的上皮结构（即终末芽，TEBs）增多，以及乳腺上皮分化减少。一些植物雌激素，如大豆类食品中的主要成分染料木黄酮，以及农产品中发现的霉菌毒素玉米赤霉烯酮，对生殖系统、乳腺和大脑具有雌激素样作用。本研究检测了子宫内暴露于染料木黄酮或玉米赤霉烯酮是否会影响乳腺发育。在妊娠第15至20天，每天给怀孕小鼠注射：i）20 ng雌二醇（E2）；ii）20 μg染料木黄酮；iii）2 μg玉米赤霉烯酮；iv）2 μg他莫昔芬（TAM），一种部分雌激素受体激动剂；或v）油剂载体。E2、染料木黄酮、玉米赤霉烯酮和他莫昔芬均增加了乳腺中终末芽的密度。染料木黄酮减少了上皮分化，而玉米赤霉烯酮增加了上皮分化。与载体对照组相比，玉米赤霉烯酮还增加了上皮密度。所有处理对循环E2水平均无永久性影响。母亲暴露于E2会加速雌性后代的体重增加、身体成熟（睁眼）和青春期开始（阴道开口）。染料木黄酮和他莫昔芬对青春期开始的影响与E2相似。玉米赤霉烯酮导致动情期涂片持续角化。这些发现表明，母亲暴露于生理剂量的染料木黄酮会模拟E2对后代乳腺和生殖系统的影响。因此，我们的结果表明，染料木黄酮在子宫内起到雌激素的作用，如果通过怀孕母亲给予，可能会增加乳腺肿瘤的发病率。相比之下，玉米赤霉烯酮对乳腺的雌激素样作用可能会被动情周期的永久性变化所抵消。
