MECHANISTIC BIOMARKERS OF ENDOCRINE DISRUPTION

内分泌干​​扰的机制生物标志物

• 批准号: 8360762
• 负责人: KAMIN J JOHNSON
• 金额: $ 21.82万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360762
• 关键词: Algorithms; Animal Model; Biological Markers; Characteristics; Congenital Abnormality; Cryptorchidism; Data; Dibutyl Phthalate; Endocrine Disruptors; Endocrine disruption; Environment; Epidemiologic Studies; Funding; Future; Genes; Genome; Genomics; Goals; Gonadotropin-Releasing Hormone Receptor; Grant; Hormones; Human; Hypospadias; Lead; Machine Learning; Molecular; Molecular Profiling; Mus; National Center for Research Resources; Pediatric Research; Perinatal Exposure; Phenotype; Placenta; Predisposition; Prevalence; Principal Investigator; Production; Rattus; Receptor Signaling; Research; Research Infrastructure; Resistance; Resources; Rodent; Role; Signaling Molecule; Source; Testicular Hormones; Testing; Testis; Tissues; United States; United States National Institutes of Health; cost; exposed human population; fetal; genetic profiling; human male; in vivo; leydig interstitial cell; male; malformation; mouse model; novel; penis; phthalates; reproductive; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In the United States, malformations of the reproductive tract are the most common male birth defect. Several pieces of evidence suggest the human environment is partially responsible for these birth defects, including the increasing prevalence of malformations and the ubiquitous exposure of humans to endocrine disrupting chemicals that, in animal models of exposure, recapitulate the suite of human malformations. One of these endocrine disrupting chemical classes is the phthalates. Exposure of fetal rats to dibutyl phthalate (DBP) reduces testicular Leydig cell hormone production leading to common human malformations: hypospadias (malformed penis) and cryptorchidism (undescended testis). The mouse is resistant to phthalate-induced endocrine disruption. This species-dependent sensitivity raises the question of whether or not the ubiquitous human phthalate exposure contributes to human male reproductive malformations, and answering this question is the long-term goal of this project. The scientific bottleneck to determining if phthalate exposure contributes to human male reproductive is the lack of validated molecular biomarkers of phthalate exposure and endocrine disruption that can be used in human epidemiological studies. Appropriate biomarkers have two characteristics. Biomarkers should be from a source readily available from humans and be associated with the mechanism of phthalate endocrine disruption. Here, mechanistically relevant, surrogate tissue phthalate endocrine disruption biomarkers will be developed from profiling expression of the placental genome in exposed rodents and exploration of the molecular mechanism of testicular phthalate endocrine disruption. Three main pieces of information have led to our hypothesis that placental biomarkers of phthalate exposure predict fetal testis endocrine disruption that requires testicular gonadotropin releasing hormone receptor (Gnrhr) signaling: 1) DBP exposure alters the genetic profile of rat placenta; 2) Gnrhr signaling in testis disrupts testicular hormone production in rats (phthalate sensitive species) but not mice (phthalate insensitive species); and 3) rat DBP exposure induces testicular expression of Gnrhr and potential Gnrhr signaling molecules in rat, but not mouse, testis. Three specific aims will test the hypothesis. In the first aim, a machine learning algorithm will be applied to placental genomic expression data to define a surrogate biomarker set of genes predictive of testicular endocrine disruption. Using the species-dependent phthalate susceptibility as a tool in aim two, the role of Gnrhr signaling in phthalate endocrine disruption will be explored by determining the endocrine disruption phenotype in rat Leydig cells with disrupted Gnrhr signaling and in mouse Leydig cells with activated Gnrhr signaling. In the final aim, a Leydig cell-specific Gnrhr knockin mouse model will be used to ascertain if forced Gnrhr signaling in vivo sensitizes the mouse the endocrine disruption. Successful completion of these aims will lead to novel biomarkers of endocrine disruption to be used in future studies examining the role of phthalate exposure in human male reproductive birth defects.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 在美国，生殖道的畸形是最常见的男性先天缺陷。 几个证据表明，人类环境对这些先天缺陷有部分原因，包括畸形的患病率的增加以及人类无处不在地暴露于内分泌中破坏化学物质，这些化学物质在暴露的动物模型中概述了人类畸形的套件。 这些内分泌干扰化学类别之一是邻苯二甲酸盐。 胎儿大鼠暴露于邻苯二甲酸二丁酯（DBP）会减少睾丸leydig细胞激素的产生，导致人类畸形的常见畸形：Hypospadias（畸形的阴茎）和隐齿术（未得出的睾丸）。 小鼠对邻苯二甲酸酯诱导的内分泌破坏具有抗性。 这种依赖物种的敏感性提出了一个问题，即无处不在的人类邻苯二甲酸盐暴露是否有助于人类男性生殖畸形，而回答这个问题是该项目的长期目标。 确定邻苯二甲酸盐暴露是否有助于人类繁殖的科学瓶颈是缺乏邻苯二甲酸盐暴露和内分泌干扰的经过验证的分子生物标志物，可用于人类流行病学研究。 适当的生物标志物具有两个特征。 生物标志物应来自人类容易获得的来源，并与邻苯二甲酸酯内分泌破坏的机理有关。 在这里，机械学相关的，替代组织邻苯二甲酸酯内分泌破坏生物标志物将从暴露啮齿动物中胎盘基因组的表达以及探索睾丸邻苯二甲酸睾丸内分泌干扰的分子机制的探索中发展。 三个主要信息导致了我们的假设，即邻苯二甲酸酯暴露的胎盘生物标志物可以预测胎儿睾丸内分泌干扰，这需要睾丸性腺激素释放激素受体（GNRHR）信号传导：1）DBP暴露会改变RAT胎盘遗传胎盘的遗传特征。 2）睾丸中的GnRHR信号传导破坏大鼠（邻苯二甲酸酯敏感的物种）的睾丸激素的产生，但不破坏小鼠（邻苯二甲酸酯不敏感的物种）； 3）大鼠DBP暴露诱导大鼠（但不是小鼠）睾丸中GnRHR的睾丸表达和潜在的GNRHR信号分子。 三个具体目标将检验该假设。 在第一个目标中，机器学习算法将应用于胎盘基因组表达数据，以定义一个可预测睾丸内分泌破坏的基因替代生物标志物。 将依赖物种依赖性的邻苯二甲酸酯易感性作为目标二的工具，将通过确定gnRHR leydig细胞中的内分泌干扰表型在邻苯二甲酸邻苯二甲酸酯内分泌破坏中的作用，并具有破坏的GNRHR gnRHR和带有活化GNRHR的小鼠Leydig细胞中的内分泌破坏表型。 在最终目标中，将使用Leydig细胞特异性GNRHR敲蛋白小鼠模型来确定体内强制GNRHR信号是否会使小鼠的内分泌破坏敏感。 这些目标的成功完成将导致内分泌干扰的新生物标志物在未来的研究中使用，以研究邻苯二甲酸盐暴露在人类男性生殖先天缺陷中的作用。