Action of an endocrine disruptor on the Leydig cell

描述（由申请人提供）：邻苯二甲酸酯，邻苯二甲酸二乙基己酯（DEHP）是许多塑料的组成化学品，赋予其柔韧性。在美国和大多数工业化国家，塑料被广泛使用，DEHP与塑料基质没有化学结合，随着时间的推移会浸出：因此人类接触很普遍。接触DEHP与男性性发育中断和生育能力下降有关。Earl Gray及其同事的研究表明，DEHP具有抗雄激素作用，其雄性生殖毒性机制并非通过直接干扰雄激素受体水平。私家侦探其他研究表明，大鼠睾丸间质细胞在体内暴露于DEHP后，雄激素分泌受到损害。这导致了为本申请提供总体主题的假设，即DEHP的内分泌干扰特性是由于对Leydig细胞发育的不良影响导致雄激素分泌减少。与这一假设相一致，最近的数据从P.L.的实验室证明了在年轻动物中存在一个敏感性受损的关键窗口。在本次更新申请所述的实验中，我们将分析DEHP暴露的可能性：I.抑制类固醇生成因子-I的表达水平，所述类固醇生成因子-I是调节间质细胞和垂体促性腺激素细胞分化的关键核转录因子，并且降低苗勒管抑制物质的作用，所述苗勒管抑制物质是限制间质细胞分裂的SF-1调节的生长因子; II.抑制Leydig祖细胞的增殖;和III.以延迟类固醇生成酶基因表达和类固醇生成能力的获得。出生后长期暴露于DEHP可诱导垂体促性腺激素分泌水平增加，血清睾酮和雌二醇水平升高，这与间质细胞增生（肿瘤发生的前体）相关。在DEHP处理的大鼠中通常观察到Leydig细胞瘤的形成。我们将描述DEHP诱导Leydig细胞增生的时间过程，并分析LH、睾酮和雌二醇在肿瘤发生发展中的作用。这些研究将首次确定间质细胞参与DEHP的内分泌干扰作用。我们的数据将有助于识别暴露于环境污染物的生物标志物，并为监管机构制定消费品中DEHP和邻苯二甲酸酯的使用限制提供信息

DESCRIPTION (provided by applicant): The phthalate ester, diethylhexylphthalate (DEHP), is a constituent chemical of many plastics, conferring their flexibility. Plastics are used ubiquitously in the United States and most industrialized countries and DEHP, which is not chemically bound to the plastic matrix, leaches out over time: human exposure is therefore widespread. Exposure to DEHP is associated with disruption of male sexual development and decreased fertility. Studies by Earl Gray and colleagues have shown that DEHP is anti-androgenic, and that its mechanism of male reproductive toxicity is not through direct interference at the level of the androgen receptor. The P.I. and others have shown that androgen secretion by rat Leydig cells is compromised after in vivo exposures to DEHP. This leads to the hypothesis providing the overall theme to the present application, that the endocrine disrupting properties of DEHP result from adverse effects on Leydig cell development with consequent decreases in androgen secretion. Consistent with this hypothesis, recent data from the P.l.'s lab demonstrate the existence of a critical window of sensitivity for impairment of Leydig cell steroidogenesis in younger animals. In the experiments described for this renewal application, we will analyze the potential for DEHP exposures: I. to suppress expression levels of steroidogenic factor-I, a key nuclear transcription factor that regulates differentiation of Leydig cells and pituitary gonadotropes, and decrease the action of Mullerian inhibiting substance, an SF-1 regulated growth factor that limits Leydig cell division; II. to inhibit proliferation of progenitor Leydig cells; and III. to delay acquisition of steroidogenic enzyme gene expression and steroidogenic capacity. Chronic postnatal exposures to DEHP induced increased levels of gonadotropic secretion by the pituitary and elevated serum testosterone and estradiol levels, which were associated with Leydig cell hyperplasia, a precursor to tumorigenesis. Formation of Leydig cell tumors is commonly observed in DEHP-treated rats. We will describe the time course of DEHP induced Leydig cell hyperplasia and analyze the role of LH, testosterone, and estradiol in the development of tumorigenesis. These studies will be the first to define the involvement of Leydig cells in the endocrine disrupting effects of DEHP. Our data will facilitate identification of biomarkers of exposure to environmental pollutants, and provide information to regulatory agencies in setting limits for the use of DEHP and phthalates in consumer products