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，人类胎儿生命期间胚胎编程和性腺发育的破坏可能导致睾丸发育不全，表现为睾丸未降、尿道下裂、精液质量差和睾丸癌。该提案的核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 和莠去津）抑制胎儿睾酮生成以及随后抑制成人睾酮生成的机制，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 和莠去津反应的细胞靶标和分子机制，并揭示对胎儿的影响导致成人男性生殖道病变的机制。总体假设是，在子宫内暴露于 DEHP 或莠去津会通过直接影响胎儿间质细胞和/或成年间质细胞的前体间充质细胞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标来检验这一假设：（1）确定妊娠期 DEHP 和莠去津在胎儿睾丸中的细胞和分子靶点； (2) 识别、比较和对比妊娠期暴露于 DEHP 或莠去津导致胎儿睾丸产生睾酮减少的机制； (3) 确定胎儿接触 DEHP 或莠去津对成年 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，我们希望能够广泛了解抗雄激素药物破坏睾丸雄激素产生的机制，以及这种破坏影响以后生命过程的机制。

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.