Fetal Origin of Male Reproductive Disorders

男性生殖疾病的胎儿起源

基本信息

批准号：
7515046
负责人：
Vassilios Papadopoulos
金额：
$ 23.1万
依托单位：
MCGILL UNIVERSITY HEALTH CTR RES INST
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7515046
关键词：
Address Adult Affect Anabolism Androgen Antagonists Androgens Areola Aromatase Atherosclerosis Bioinformatics Birth Blood Cell physiology Cells Chemical Agents Chest Complement Cosmetics Coupled Cryptorchidism Data Defect Development Diethylhexyl Phthalate Disease Disruption Dose Embryo Endocrine Endocrine disruption Environmental Risk Factor Epididymis Estradiol Estrogens Event Exposure to Fetus Fibrinogen Functional disorder Genes Genomics Goals Growth Factor Hormones Human Hyperplasia Hypospadias In Vitro Individual Industry Infertility Insulin Insulin Signaling Pathway Kinetics Laboratories Lead Lesion Life Link MAPK Signaling Pathway Pathway Malignant neoplasm of testis Maternal Exposure Mediating Mesenchymal Molecular Molecular Target Mono-S National Research Council Nipples Numbers Organ Culture Techniques Osteoporosis Oxidoreductase Pathology Pathway interactions Patient currently pregnant Perinatal Exposure Phenotype Plastics Play Population Postpartum Period Predisposition Pregnancy Production Prostate Protein Tyrosine Kinase Proteomics Public Health Rattus Receptor Protein-Tyrosine Kinases Recording of previous events Research Personnel Risk Factors Role Seminal fluid Serum Signal Pathway Staging Steroid biosynthesis Steroids Suspension substance Suspensions Testing Testis Testosterone Urine Vas deferens structure Work adenoma base cellular targeting fetal fetus cell in vivo laser capture microdissection leydig interstitial cell male member men phthalate phthalates postnatal precursor cell progenitor programs reproductive reproductive function research study response

项目摘要

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。初步数据表明，Leydig 细胞在体内暴露于低且环境相关浓度的邻苯二甲酸二（2-乙基己基）（DEHP）和体外邻苯二甲酸单乙基己基（MEHP）会以某种方式改变细胞的基因组和蛋白质组谱。这与激素依赖性类固醇形成的抑制和间质细胞增生的诱导是平行的。该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随后成人睾酮和雌二醇产生的机制，更好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 会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，从而抑制成人的出生后发育和功能间质细胞群。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 在胎儿睾丸中的细胞和分子靶点； (2) 确定妊娠期接触 DEHP 导致胎儿睾丸产生睾酮减少的机制； (3) 确定胎儿接触 DEHP 对成年 Leydig 细胞群的形成和功能的影响及其对未成熟和成年睾丸中睾丸功能的影响。我们相信，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盐导致成人睾丸发育不全的增生和抗雄激素作用中的作用。总之，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。