Mechanism of Estrogen-Induced Penile Dysfunction and Loss of Fertility

雌激素引起的阴茎功能障碍和生育能力丧失的机制

基本信息

批准号：
8435455
负责人：
HARI Om GOYAL
金额：
$ 17.83万
依托单位：
TUSKEGEE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8435455
关键词：
Accounting Actins Adipocytes Advisory Committees Affect Aging Agonist Alligators Ally Androgen Antagonists Androgen Receptor Androgens Area Binding Blood Vessels CCAAT-Enhancer-Binding Proteins Cell Differentiation process Data Development Discipline of Nursing Disease Doctor of Philosophy Dose Educational workshop Endocrine Disruptors Endothelial Cells Environmental Estrogen Equipment Estrogen Receptors Estrogens Exposure to Extramural Activities Faculty Fertility Flutamide Frequencies Functional disorder Funding Gene Expression Genes Goals Gonadotropin Releasing Hormone Inhibitor Grant Health Hormonal Human Human Resources Hypospadias Hypothalamic structure ICI 182780 Illinois Immunohistochemistry Incidence Infertility International Intervention Journals Lead Learning Length Link Malignant Neoplasms Measurable Mediating Mentors Messenger RNA Minority Modeling Molecular Neonatal Neoplasms Organ Outcome Paper Participant Pathway interactions Peer Review Perinatal Exposure Peroxidases Phenotype Postdoctoral Fellow Principal Investigator Prostate Proteins Publications Publishing Qualifying Rattus Receptor Up-Regulation Reporting Research Research Project Grants Risk Rodent Signal Transduction Smooth Muscle Smooth Muscle Myocytes Solid Spontaneous abortion Stanolone Stromal Cells Students Techniques Testing Testosterone Time Training Universities Up-Regulation Veterinary Medicine Visit Woman Work Writing adipocyte differentiation base bisphenol A career college critical developmental period critical period developmental disease innovation insight lectures male meetings member men neonatal exposure offspring penis penis body prevent professor programs public health relevance receptor receptor expression reproductive reproductive development

项目摘要

DESCRIPTION (provided by applicant): Male reproductive disorders account for 40% of infertility cases worldwide in humans. Although causes of infertility are multi-factorial, exposure to estrogens (E) during development has been linked with increasing incidence of reproductive disorders. Mechanisms underlying E-induced disorders remain unclear. The goal of this study is to determine molecular and cellular mechanisms whereby neonatal E exposure results in infertility and mal-developed penis characterized by abnormal accumulation of fat cells and loss of smooth muscle and blood vessels in the penis body. The central hypothesis is that E exposure, via estrogen receptor (ER) pathway or androgen receptor (AR) pathway or both, alters ER1 expression in penile stromal cells (higher E, higher ER1; lower androgen, higher ER1), which are then re-programmed so that key genes for differentiation of fat cells (PPAR3, C/EBP1) are undesirably up-regulated and those for smooth muscle cell (1 actin) and endothelial cell (CD-31) are down-regulated. Specific aim 1 will test the hypotheses that I) E exposure up-regulates ER1 expression and down-regulates neonatal testosterone surge in a dose- dependent manner, II) ER1 up-regulation is time-dependent and occurs during a critical developmental period; and III) ER1 up-regulation is mitigated by ER antagonist ICI 182,780 (ER pathway), as well as by AR agonist DHT (AR pathway). Specific aim 2 will test the hypotheses I) that E exposure up-regulates PPAR3 and C/EBP1 expression and down-regulates 1 actin and CD-31 expression (cause and effect relationships); and II) that ICI and DHT mitigate these alterations. Specific aim 3 will test the hypothesis that exposure to anti-androgens (GnRH-antagonist and flutamide) up-regulates ER1 expression because of lower androgenic action, but may not alter PPAR3, C/EBP1, 1 actin, and CD-31 expression because of lack of exogenous E exposure. Specific aim 4 will test the hypothesis that intervention with ER antagonist and AR agonist prevents E-induced loss of fertility. Real-time PCR will be used to quantify mRNAs and immunohistochemistry will be used to localize and quantify proteins. Collectively, results will unravel mechanisms whereby altered signaling in ER pathway or AR pathway or both results in mal-development of the penis and penile dysfunction. Outcomes of this work will have a significant impact on human and wildlife health because they will lead to better strategies to prevent E-induced reproductive disorders.

描述（由申请人提供）：全球人类不孕症病例中，40% 是由男性生殖障碍引起的。尽管不孕的原因是多因素的，但在发育过程中接触雌激素（E）与生殖疾病发病率的增加有关。电子诱发疾病的机制仍不清楚。本研究的目的是确定新生儿接触电子导致不育和阴茎发育不良的分子和细胞机制，其特征是脂肪细胞异常积累以及阴茎体平滑肌和血管丧失。中心假设是，E暴露通过雌激素受体（ER）途径或雄激素受体（AR）途径或两者，改变阴茎基质细胞中的ER1表达（E越高，ER1越高；雄激素越低，ER1越高），然后这些细胞被重新激活。 -经过编程，使脂肪细胞分化的关键基因（PPAR3、C/EBP1）以及平滑肌细胞（1 肌动蛋白）和内皮细胞的关键基因上调(CD-31) 下调。具体目标 1 将检验以下假设：I) E 暴露以剂量依赖性方式上调 ER1 表达并下调新生儿睾酮激增，II) ER1 上调具有时间依赖性并发生在关键发育时期； III) ER 拮抗剂 ICI 182,780（ER 途径）以及 AR 激动剂 DHT（AR 途径）可减轻 ER1 上调。具体目标 2 将检验假设 I) E 暴露上调 PPAR3 和 C/EBP1 表达并下调 1 肌动蛋白和 CD-31 表达（因果关系）； II) ICI 和 DHT 可以减轻这些改变。具体目标 3 将检验以下假设：由于雄激素作用较低，接触抗雄激素（GnRH 拮抗剂和氟他胺）会上调 ER1 表达，但可能不会改变 PPAR3、C/EBP1、1 肌动蛋白和 CD-31 表达，因为缺乏外源性 E 暴露。具体目标 4 将检验以下假设：使用 ER 拮抗剂和 AR 激动剂进行干预可预防 E 诱导的生育力丧失。实时 PCR 将用于量化 mRNA，免疫组织化学将用于定位和量化蛋白质。总的来说，结果将揭示 ER 通路或 AR 通路或两者中信号传导改变导致阴茎发育不良和阴茎功能障碍的机制。这项工作的成果将对人类和野生动物的健康产生重大影响，因为它们将带来更好的策略来预防电子引起的生殖障碍。