Whitten Patricia L, Patisaul Heather B, Young Larry J
Center for Behavioral Neuroscience, Emory University, Atlanta, GA 30329, USA.
Neurotoxicol Teratol. 2002 Jan-Feb;24(1):47-54. doi: 10.1016/s0892-0362(01)00192-1.
Isoflavonoids are plant estrogens that are increasingly advocated as a natural alternative to estrogen replacement therapy (ERT) and are available as dietary supplements. As weak estrogen agonists/antagonists with a range of other enzymatic activities, the isoflavonoids provide a useful model for the actions of endocrine disruptors. This paper reviews the responses of rodents to diets containing coumestrol or an isoflavone supplement in comparison to animals fed the phytoestrogen-free AIN76A diet. Neural mechanisms were investigated by examining isoflavonoid effects on ER(alpha)-dependent (regulation of oxytocin receptor [OTR] binding in the ventromedial nucleus of the hypothalamus [VMN]) and ERbeta-dependent (regulation of ERbeta mRNA in the paraventricular nucleus [PVN]) endpoints. Activational as well as organizational effects on sexual behavior and gonadotropin secretion were observed for coumestrol. Treatment of rat dams with a 100-ppm coumestrol diet from birth to postnatal day (PND) 21 induced premature anovulation in female offspring, and treatment from birth to PND 10 suppressed sexual behavior in male offspring. One-week treatment of ovariectomized (OVX) female rats with the same coumestrol diet increased ERbeta mRNA expression in the PVN, an effect opposite to that of estradiol. Ten days of treatment with a 200-ppm coumestrol diet increased LH secretion in OVX wild-type mice, an effect opposite to the normal negative feedback effects of estradiol. No effects were observed in ER(alpha) knockout (ER(alpha)KO)-OVX females, indicating that coumestrol's action on LH was mediated through ER(alpha). Similar activational effects were observed for the isoflavone diet. The lordotic response to estrogen was significantly reduced by 2 days of treatment of OVX adult females with an isoflavone diet providing 13 ppm genistein and 33 ppm daidzein. One week of treatment with the same isoflavone diet produced an effect opposite to that of estradiol in the PVN, increasing ERbeta mRNA expression above control levels. These investigations show that, in spite of their preferential affinity for ERbeta, isoflavonoids act through both ER(alpha) and ERbeta. Moreover, their neurobehavioral actions were antiestrogenic, either antagonizing or producing an action in opposition to that of estradiol. This work demonstrates that even small, physiologically relevant exposure levels can alter estrogen-dependent gene expression in the brain and complex behavior.
异黄酮是植物雌激素，越来越多地被提倡作为雌激素替代疗法（ERT）的天然替代品，并可作为膳食补充剂获得。作为具有一系列其他酶活性的弱雌激素激动剂/拮抗剂，异黄酮为内分泌干扰物的作用提供了一个有用的模型。本文综述了与喂食不含植物雌激素的AIN76A饮食的动物相比，啮齿动物对含有香豆雌酚或异黄酮补充剂的饮食的反应。通过检查异黄酮对雌激素受体α（ERα）依赖性（下丘脑腹内侧核[VMN]中催产素受体[OTR]结合的调节）和雌激素受体β（ERβ）依赖性（室旁核[PVN]中ERβ mRNA的调节）终点的影响来研究神经机制。观察到香豆雌酚对性行为和促性腺激素分泌有激活和组织作用。从出生到出生后第21天（PND）用100 ppm香豆雌酚饮食处理大鼠母鼠会诱导雌性后代过早排卵，从出生到PND 10处理会抑制雄性后代的性行为。用相同的香豆雌酚饮食对去卵巢（OVX）雌性大鼠进行一周的处理会增加PVN中ERβ mRNA的表达，这与雌二醇的作用相反。用200 ppm香豆雌酚饮食处理10天会增加OVX野生型小鼠的促黄体生成素（LH）分泌，这与雌二醇正常的负反馈作用相反。在雌激素受体α基因敲除（ERαKO）-OVX雌性小鼠中未观察到影响，表明香豆雌酚对LH的作用是通过ERα介导的。对异黄酮饮食也观察到了类似的激活作用。用提供13 ppm染料木黄酮和33 ppm大豆苷元的异黄酮饮食对OVX成年雌性小鼠进行2天处理后，对雌激素的脊柱前凸反应显著降低。用相同的异黄酮饮食处理一周在PVN中产生了与雌二醇相反的作用，使ERβ mRNA表达增加到对照水平以上。这些研究表明，尽管异黄酮对ERβ具有优先亲和力，但它们通过ERα和ERβ发挥作用。此外，它们的神经行为作用是抗雌激素的，要么拮抗雌二醇的作用，要么产生与雌二醇相反的作用。这项工作表明，即使是小的、生理相关的暴露水平也可以改变大脑中雌激素依赖性基因的表达和复杂行为。
