Fetal Origin of Male Reproductive Disorders

男性生殖疾病的胎儿起源

• 批准号: 6966407
• 负责人: Vassilios Papadopoulos
• 金额: $ 32.64万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966407
• 关键词: Leydig cells; androgen inhibitor; aromatase; bioinformatics; diethylhexylphthalate; embryo /fetus tissue /cell culture; embryo /fetus toxicology; environmental exposure; estradiol; hormone regulation /control mechanism; insulinlike growth factor; laboratory rat; laser capture microdissection; male; male reproductive system disorder; organ culture; protein tyrosine kinase; reproductive development; steroid hormone biosynthesis; testis; testosterone

DESCRIPTION (provided by applicant): Epidemiological and experimental studies suggest that disruption of embryonic programming and gonadal development during human fetal life can result in testicular dysgenesis, manifested as undescended testis, hypospadias, poor semen quality, and testicular cancer. Preliminary data indicates that exposure of Leydig cells to low and environmentally relevant concentrations of di-(2-ethylhexyl) phthalate (DEHP) in vivo and mono-ethylhexyl phthalate (MEHP) in vitro altered the genomic and proteomic profile of the cells in a manner that parallels the inhibition of hormone-dependent steroid formation and the induction of Leydig cell hyperplasia. The central objective of this proposal is to gain greater understanding of the fetal basis of male reproductive disorders by elucidating the mechanisms by which exposure of the fetus to the environmental antiandrogen DEHP suppresses fetal testosterone production and later, testosterone and estradiol production by the adult. Our major goals are to identify the cellular targets and the molecular mechanisms underlying the responses of the fetus to DEHP, and to reveal the mechanisms by which effects on the fetus lead to pathologies of the male reproductive tract in the adult. The overarching hypothesis is that in utero exposures to DEHP suppress fetal testosterone production by direct effects on fetal Leydig cells and/or on the mesenchymal cells that are the precursors of adult Leydig cells, and by doing so, suppresses postnatal development and function of the adult Leydig cell population. We will test this hypothesis with the following specific aims: (1) identify the cellular and molecular targets of gestational DEHP in the fetal testis; (2) identify the mechanism(s) by which gestational exposure to DEHP results in reduced testosterone production by the fetal testis; and (3) determine the effects of fetal exposure to DEHP on the formation and function of the adult population of Leydig cells and its impact on testicular function in the immature and adult testis. We believe that these Aims will identify the molecular signaling pathways and characterize their role in mediating the hyperplasic and antiandrogenic effect of phthalates leading to testicular dysgenesis in the adult. Taken together the proposed studies will unveil the endocrine disruptor-sensitive steps in the steroidogenic pathway that are affected by this antiandrogen, and the mechanisms and consequences of endocrine disruption on the endocrine milieu of the adult.

描述（由申请人提供）：流行病学和实验研究表明，人类胎儿生命期间胚胎编程和性腺发育的破坏会导致睾丸发作性疾病，表现为未延伸的睾丸，降低，精液质量差，精液质量和睾丸癌。初步数据表明，在体内和邻苯二甲酸二（2-乙基己基）邻苯二甲酸酯（DEHP）中暴露于体内和单乙基苯二甲酸酯（MEHP）体外，在体外和单乙二醇中的基因组和蛋白质谱图中的基因组和蛋白质谱系的体积依赖于Hyors的基因组谱系的体外，增生。该提议的核心目的是通过阐明胎儿暴露于环境抗雄激素DEHP抑制胎儿睾丸激素的产生以及后来，成年人的睾丸激素和雌二醇产生的机制，以更深入地了解男性生殖疾病的胎儿基础。我们的主要目标是确定胎儿对DEHP反应的基础的细胞靶标和分子机制，并揭示对胎儿影响的机制导致成人男性生殖道的病理。总体假设是，在子宫内暴露于DEHP抑制胎儿睾丸激素，通过直接影响胎儿leydig细胞和/或对成年leydig细胞的前体的胎儿leydig细胞和/或抑制胎儿睾丸激素的产生，并通过抑制成年的Leydig细胞群体的产后发育和功能来抑制胎儿睾丸激素。我们将以以下特定目的检验该假设：（1）确定胎儿睾丸中妊娠DEHP的细胞和分子靶标； （2）确定妊娠暴露于DEHP的机制导致胎儿睾丸产生睾丸激素的降低； （3）确定胎儿暴露于DEHP对Leydig细胞成年群体的形成和功能的影响及其对未成熟和成人睾丸中睾丸功能的影响。我们认为，这些目标将确定分子信号传导途径，并表征它们在介导邻苯二甲酸酯的增生和抗原作用中的作用，从而导致成年人的睾丸发病障碍。总而言之，拟议的研究将在类固醇生成途径的内分泌破坏者敏感的步骤中揭示受该抗雄激素影响的类固醇生成途径，以及内分泌干扰对成人内分泌环境的机制和后果。