Hilakivi-Clarke L, Cho E, Onojafe I, Raygada M, Clarke R
Research Bldg., Lombardi Cancer Center, Georgetown University, NW, Washington, DC 20007-2197, USA.
Oncol Rep. 1999 Sep-Oct;6(5):1089-95. doi: 10.3892/or.6.5.1089.
A high estrogenic environment in utero may increase subsequent breast cancer risk. It was therefore determined whether a maternal exposure during pregnancy to the phytoestrogen genistein or zearalenone, both of which exhibit estrogenic activities in vitro and in vivo, alters breast cancer risk among female offspring. Pregnant rat dams were treated daily with subcutaneous injections of 20, 100 or 300 microgram genistein, 20 microgram zearalenone, or vehicle between days 15 and 20 of gestation. The offspring were given 7, 12-dimethylbenz(a)anthracene (DMBA) at the age of 2 months to induce mammary tumors. The results indicate that in utero exposure to genistein, but not to zearalenone, dose-dependently increased the incidence of DMBA-induced mammary tumors, when compared with the controls. Tumor growth characteristics were not altered. Prior to the carcinogen administration, the number of estrogen receptor (ER) binding sites, determined using a ligand binding assay, were significantly elevated in the mammary glands of genistein offspring. In contrast, the mammary protein kinase C (PKC) activity was significantly reduced in the genistein offspring. Our results suggest that a maternal exposure to subcutaneous administration of genistein can increase mammary tumorigenesis in the offspring, mimicking the effects of in utero estrogenic exposures. Further, increased ER protein levels and reduced PKC activity in the mammary gland may be involved in increasing susceptibility to carcinogen-induced mammary tumorigenesis in rats exposed to genistein in utero.
子宫内的高雌激素环境可能会增加后续患乳腺癌的风险。因此，研究人员确定孕期母体暴露于植物雌激素染料木黄酮或玉米赤霉烯酮（这两种物质在体外和体内均表现出雌激素活性）是否会改变雌性后代患乳腺癌的风险。在妊娠第15至20天期间，对怀孕的大鼠母鼠每天进行皮下注射，分别给予20、100或300微克的染料木黄酮、20微克的玉米赤霉烯酮或赋形剂。在后代2个月大时给予7,12-二甲基苯并(a)蒽（DMBA）以诱导乳腺肿瘤。结果表明，与对照组相比，子宫内暴露于染料木黄酮而非玉米赤霉烯酮会剂量依赖性地增加DMBA诱导的乳腺肿瘤的发生率。肿瘤生长特征未改变。在给予致癌物之前，使用配体结合测定法确定的雌激素受体（ER）结合位点数量在染料木黄酮处理组后代的乳腺中显著升高。相比之下，染料木黄酮处理组后代的乳腺蛋白激酶C（PKC）活性显著降低。我们的结果表明，母体皮下注射染料木黄酮会增加后代的乳腺肿瘤发生，模拟子宫内雌激素暴露的影响。此外，子宫内暴露于染料木黄酮的大鼠乳腺中ER蛋白水平升高和PKC活性降低可能与致癌物诱导的乳腺肿瘤发生易感性增加有关。
