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

• 批准号: 7756911
• 负责人: HARI Om GOYAL
• 金额: $ 18.18万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7756911
• 关键词: Accounting; Actins; Adipocytes; Advisory Committees; Affect; Aging; Agonist; Alligators; Ally; Androgen Antagonists; Androgen Receptor; Androgens; Area; Arts; 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; Minority; Modeling; Molecular; Neonatal; Neoplasms; Organ; Outcome; Paper; Participant; Pathway interactions; Peer Review; Perinatal Exposure; Peroxidases; Phenotype; Postdoctoral Fellow; Principal Investigator; Prostate; Protein C; Proteins; Publications; Publishing; Qualifying; Rattus; 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

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. PUBLIC HEALTH RELEVANCE: Exposure to environmental estrogens (endocrine disruptors) has been linked with increasing frequency of reproductive disorders, underscoring their global risks in human and wildlife health. The objective of this application is to determine molecular and cellular mechanisms whereby neonatal estrogen exposure results in permanent loss of fertility and mal-developed penis characterized by accumulation of fat cells and loss of smooth muscle cells and blood vessels in the body of the penis.

描述（由申请人提供）：男性生殖障碍占全球人类不孕症病例的40%。虽然不孕不育的原因是多因素的，但在发育过程中接触雌激素与生殖疾病的发病率增加有关。e诱导疾病的机制尚不清楚。本研究的目的是确定新生儿E暴露导致不育和阴茎发育不良的分子和细胞机制，其特征是阴茎体中脂肪细胞的异常积累和平滑肌和血管的丧失。核心假设是，E暴露通过雌激素受体（ER）途径或雄激素受体（AR）途径或两者同时发生，改变了阴茎基质细胞中ER1的表达（高E，高ER1；低雄激素，高ER1），然后重新编程，使脂肪细胞分化的关键基因（PPAR3, C/EBP1）不受欢迎地上调，而平滑肌细胞（1肌动蛋白）和内皮细胞（CD-31）的关键基因下调。特异性目的1将检验以下假设：1)E暴露以剂量依赖的方式上调ER1表达并下调新生儿睾酮激增；2)ER1上调是时间依赖的，发生在发育的关键时期；III) ER1上调可通过内质网拮抗剂ICI 182780 （ER通路）和AR激动剂DHT （AR通路）减轻。具体目标2将检验假设1)E暴露上调PPAR3和C/EBP1表达，下调1肌动蛋白和CD-31表达（因果关系）；II) ICI和DHT减轻了这些变化。特异性目的3将验证抗雄激素（gnrh拮抗剂和氟他胺）暴露由于雄激素作用降低而上调ER1表达的假设，但可能不会因为缺乏外源性E暴露而改变PPAR3， C/EBP1, 1肌动蛋白和CD-31的表达。特异性目的4将验证雌激素受体拮抗剂和AR受体激动剂干预可防止雌激素诱导的生育能力丧失的假设。实时荧光定量PCR将用于定量mrna，免疫组织化学将用于定位和定量蛋白质。总的来说，结果将揭示内质网途径或AR途径或两者的信号改变导致阴茎发育不良和阴茎功能障碍的机制。这项工作的结果将对人类和野生动物的健康产生重大影响，因为它们将导致更好的战略来预防e引起的生殖障碍。