Fetal Origin of Male Reproductive Disorders

描述（由申请人提供）：流行病学和实验研究表明，人类胎儿期胚胎编程和性腺发育的中断可导致睾丸发育不良，表现为睾丸隐睾、尿道下裂、精液质量差和睾丸癌。初步数据表明，体内暴露于低浓度和环境相关浓度的邻苯二甲酸二（2-乙基己基）酯（DEHP）和体外暴露于邻苯二甲酸单乙基己基（MEHP）的间质细胞改变了细胞的基因组和蛋白质组学特征，其方式与抑制激素依赖性类固醇形成和诱导间质细胞增生相似。本提案的中心目标是通过阐明胎儿暴露于环境抗雄激素DEHP抑制胎儿睾酮产生以及后来成人睾酮和雌二醇产生的机制，从而更好地了解男性生殖障碍的胎儿基础。我们的主要目标是确定胎儿对DEHP反应的细胞靶点和分子机制，并揭示对胎儿的影响导致成人男性生殖道病变的机制。最重要的假设是，子宫内暴露于DEHP通过直接影响胎儿间质细胞和/或间充质细胞（成年间质细胞的前体）来抑制胎儿睾酮的产生，从而抑制成年间质细胞群的出生后发育和功能。我们将通过以下具体目的来验证这一假设：(1)确定妊娠DEHP在胎儿睾丸中的细胞和分子靶点；(2)确定妊娠期暴露于DEHP导致胎儿睾丸激素分泌减少的机制；(3)确定胎儿暴露于DEHP对成年睾丸间质细胞群形成和功能的影响及其对未成熟和成年睾丸功能的影响。我们相信这些目的将确定分子信号通路，并描述它们在介导邻苯二甲酸盐导致成人睾丸发育不良的增生和抗雄激素作用中的作用。综上所述，拟议的研究将揭示类固醇生成途径中受这种抗雄激素影响的内分泌干扰物敏感步骤，以及内分泌干扰对成人内分泌环境的机制和后果。

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.