Fetal Origin of Male Reproductive Disorders

描述（由申请方提供）：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全，表现为隐睾、尿道下裂、精液质量差和睾丸癌。本提案的中心目标是通过阐明胎儿暴露于两种不同的环境抗雄激素DEHP和阿特拉津抑制胎儿睾酮产生以及随后抑制成人睾酮产生的机制，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和阿特拉津反应的细胞靶点和分子机制，并揭示对胎儿的影响导致成年男性生殖道病变的机制。总体假设是，在子宫内暴露于DEHP或阿特拉津通过直接影响胎儿间质细胞和/或作为成人间质细胞前体的间充质细胞来抑制胎儿睾酮的产生，并通过这样做来抑制成人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检验这一假设：（1）确定胎儿睾丸中妊娠期DEHP和阿特拉津的细胞和分子靶点;（2）确定、比较和对比妊娠期暴露于DEHP或阿特拉津导致胎儿睾丸睾酮分泌减少的机制;和（3）确定胎儿暴露于DEHP或阿特拉津对成年Leydig细胞群的形成和功能的影响。总之，拟议的研究将揭示类固醇生成途径中受这些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。通过同时研究这两种抗雄激素化合物，我们期望获得对抗雄激素干扰睾丸雄激素产生的机制的广泛理解，以及这种干扰影响以后生活中的过程。

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. 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 two distinct environmental antiandrogens, DEHP and atrazine, suppress fetal testosterone production and later, testosterone 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 atrazine, 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 or atrazine 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, suppress 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 and atrazine in the fetal testis; (2) identify, compare and contrast the mechanism(s) by which gestational exposure to DEHP or atrazine results in reduced testosterone production by the fetal testis; and (3) determine the effects of fetal exposure to DEHP or atrazine on the formation and function of the adult population of Leydig cells. Taken together the proposed studies will unveil the endocrine disruptor-sensitive steps in the steroidogenic pathway that are affected by these antiandrogens, and the mechanisms and consequences of endocrine disruption on the endocrine milieu of the adult. By studying both antiandrogenic compounds at once, we expect to gain broad understanding of the mechanism or mechanisms by which antiandrogens disrupt androgen production by the testis, and by which this disruption affects processes later in life.