Intrinsic function of the aryl hydrocarbon (Dioxin) receptor as a key factor in female reproduction
Intrinsic function of the aryl hydrocarbon (Dioxin) receptor as a key factor in female reproduction
复制标题
DOI：
10.1128/mcb.25.22.10040-10051.2005
复制
发表时间：
2005-11-01
影响因子：
5.3
通讯作者：
Fujii-Kuriyama, Y
中科院分区：
文献类型：
--
作者：
Baba, T;Mimura, J;Fujii-Kuriyama, Y
二恶英对生物体具有多种不良影响，包括致畸、免疫抑制、促进肿瘤和雌激素作用。使用芳香烃受体(AhR)缺陷小鼠的研究表明，这些毒性作用中的大部分是由AhR介导的。尽管这种受体介导的副作用，AhR基因在从无脊椎动物到脊椎动物的许多动物物种中都是保守的。这种高度的保守性强烈地表明AhR具有重要的生理功能，而且在AhR-Nuil雌性小鼠中观察到的生育力下降也支持这种关键功能。我们证明AhR通过调节卵巢P450芳香酶(Cyp19)的表达在雌性生殖中发挥关键作用，Cyp19是雌激素合成的关键酶。体外报告基因实验和体内染色质免疫沉淀实验表明，AhR与孤儿核受体Ad4BP/SF-1协同激活卵巢颗粒细胞Cyp19基因转录。给雌性小鼠注射AhR配体DMBA(9，10-二甲基-1，2-苯并茂)，可诱导卵巢Cyp19基因表达，而与发情周期的内在阶段无关。除了阐明AhR的生理功能外，我们的研究还提示了外源性AhR配体作为内分泌干扰物的毒性作用的可能机制。
Dioxins exert a variety of adverse effects on organisms, including teratogenesis, immunosuppression, tumor promotion, and estrogenic action. Studies using aryl hydrocarbon receptor (AhR)-deficient mice suggest that the majority of these toxic effects are mediated by the AhR. In spite of the adverse effects mediated by this receptor, the AhR gene is conserved among a number of animal species, ranging from invertebrates to vertebrates. This high degree of conservation strongly suggests that AhR possesses an important physiologic function, and a critical function is also supported by the reduced fertility observed with AhR-nuil female mice. We demonstrate that AhR plays a crucial role in female reproduction by regulating the expression of ovarian P450 aromatase (Cyp19), a key enzyme in estrogen synthesis. As revealed by in vitro reporter gene assay and in vivo chromatin immunoprecipitation assay, AhR cooperates with an orphan nuclear receptor, Ad4BP/SF-1, to activate Cyp19 gene transcription in ovarian granulosa cells. Administration to female mice of an AhR ligand, DMBA (9,10-dimethyl-1,2-benzanthracene), induced ovarian Cyp19 gene expression, irrespective of the intrinsic phase of the estrus cycle. In addition to elucidating a physiological function for AhR, our studies also suggest a possible mechanism for the toxic effects of exogenous AhR ligands as endocrine disruptors.