MECHANISTIC BIOMARKERS OF ENDOCRINE DISRUPTION

内分泌干​​扰的机制生物标志物

• 批准号: 8168447
• 负责人: KAMIN J JOHNSON
• 金额: $ 4.05万
• 依托单位: ALFRED I. DU PONT HOSP FOR CHILDREN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168447
• 关键词: Address; Adverse effects; Affect; Androgen Receptor; Androgens; Animal Model; Biological Assay; Biological Markers; Cell physiology; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Congenital Abnormality; Cryptorchidism; Data; Developed Countries; Development; Disease; Dose; Educational workshop; Endocrine; Endocrine Disruptors; Endocrine disruption; Environmental Risk Factor; Estrogens; Etiology; Exposure to; Funding; Gene Expression; Gene Expression Profiling; Genes; Genomics; Glans penis; Grant; Hormones; Human; Hypospadias; In Vitro; Incidence; Institution; Knowledge; Laboratories; Link; Molecular; Newborn Infant; Participant; Pathway interactions; Perinatal; Perinatal Exposure; Placenta; Plasticizers; Prevalence; Puberty; Rattus; Reporting; Research; Research Personnel; Resources; Role; Source; Testis; Tissues; Translating; United States; United States National Institutes of Health; Weight; base; cell type; endocrine disruptor exposure; environmental chemical; environmental chemical exposure; epidemiology study; exposed human population; fetal; human data; human male; lipid metabolism; male; malformation; penis foreskin; phthalates; reproductive; research study; Address; Adverse effects; Affect; Androgen Receptor; Androgens; Animal Model; Biological Assay; Biological Markers; Cell physiology; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Congenital Abnormality; Cryptorchidism; Data; Developed Countries; Development; Disease; Dose; Educational workshop; Endocrine; Endocrine Disruptors; Endocrine disruption; Environmental Risk Factor; Estrogens; Etiology; Exposure to; Funding; Gene Expression; Gene Expression Profiling; Genes; Genomics; Glans penis; Grant; Hormones; Human; Hypospadias; In Vitro; Incidence; Institution; Knowledge; Laboratories; Link; Molecular; Newborn Infant; Participant; Pathway interactions; Perinatal; Perinatal Exposure; Placenta; Plasticizers; Prevalence; Puberty; Rattus; Reporting; Research; Research Personnel; Resources; Role; Source; Testis; Tissues; Translating; United States; United States National Institutes of Health; Weight; base; cell type; endocrine disruptor exposure; environmental chemical; environmental chemical exposure; epidemiology study; exposed human population; fetal; human data; human male; lipid metabolism; male; malformation; penis foreskin; phthalates; reproductive; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Reproductive tract malformations are the most common male congenital defects in developed countries, and data suggest a rising incidence in recent decades. In the United States and other industrialized countries, cryptorchidism (undescended testis) affects 2 to 3% of male newborns, while hypospadias (abnormal penile development) presents in 1 out of 125 male newborns. In most cases, the etiology of reproductive tract disorders is unknown, but the reported rise in prevalence suggests environmental factors are major contributors. Indeed, in utero exposure of animal models to environmental chemicals called "endocrine disruptors" recapitulates the suite of reproductive malformations observed in humans. These laboratory experiments have led researchers to propose a causative role of endocrine disrupting chemicals in human male reproductive abnormalities. However, there is little if any human data linking environmental chemical exposure with human male reproductive tract malformations. While human exposure to endocrine disruptors and the effects of endocrine disruptors in animal models are two relatively easy approaches to assay, linking human endocrine disruptor exposure to human reproductive malformations has proven difficult. Participants at a recent National Institutes of Health-sponsored workshop addressing this knowledge gap concluded that the field is constrained by a lack of validated molecular biomarkers of endocrine disruptor exposure and adverse effect that can be translated to human epidemiology studies. This is the important knowledge gap we propose to close. Chemical plasticizers termed phthalates are one class of endocrine disruptors producing cryptorchidism and hypospadias in animal models, and human phthalate exposure is daily and ubiquitous. During rat in utero exposure, phthalates disrupt fetal testis expression of lipid metabolism genes responsible for producing hormones leading to maldevelopment of hormone-dependent reproductive tissues. However, phthalates alter gene expression in several testis cell types as well as other tissues. We will use this promiscuity to develop biomarkers of phthalate exposure and, more importantly, adverse effect in perinatal reproductive tissues that can be readily obtained from humans (placenta and foreskin). These tissues are excellent choices for biomarker development because 1) placenta expresses steroidogenic genes, altered placental function or weight is linked to male reproductive malformations, and in vitro phthalate exposure perturbs placental cell function, and 2) foreskin expresses androgen receptor and its separation from the glans penis at puberty is androgen-dependent and delayed by endocrine disruptor (phthalate and estrogen) exposure. In preliminary gene expression profiling of the rat placenta after phthalate exposure, we have observed changes in several hundred genes; similar to testis, the lipid metabolism pathway was significantly altered in placenta. Based upon these data, we hypothesize that candidate genomic biomarkers of low dose level phthalate exposure and adverse effect can be derived from gene profiling rat placenta and foreskin.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 生殖道畸形是发达国家最常见的男性先天性缺陷，数据表明，近几十年来的发病率上升。 在美国和其他工业化国家中，隐齿术（未降低的睾丸）影响了2至3％的男性新生儿，而在125名男性新生儿中，有1个hypospadias（阴茎发展异常）提出。 在大多数情况下，生殖道疾病的病因尚不清楚，但报道的患病率上升表明环境因素是主要因素。 确实，在子宫内动物模型暴露于称为“内分泌破坏者”的环境化学物质中，概括了人类观察到的生殖畸形套件。 这些实验室实验使研究人员提出了内分泌破坏化学物质在人类男性生殖异常中的作用。 但是，几乎没有任何人类数据将环境化学暴露与人类男性生殖道畸形联系起来。 尽管人类对内分泌破坏者的接触以及动物模型中内分泌破坏者的影响是两种相对容易的测定方法，但事实证明，人类内分泌干扰物与人类生殖畸形的暴露与人类内分泌破坏者相关联已被证明很困难。 最近，美国国立卫生资助研讨会的一家美国国家研究所的参与者解决了这一知识差距，得出的结论是，该领域受到内分泌干扰物暴露和不利影响的缺乏验证的分子生物标志物的限制，这些分子生物标志物可以将其转化为人类流行病学研究。 这是我们建议填补的重要知识差距。 称为邻苯二甲酸盐的化学塑料是一类内分泌干扰物，在动物模型中产生隐齿术和降压剂，人类邻苯二甲酸盐暴露是每天且无处不在的。 在子宫暴露中大鼠期间，邻苯二甲酸酯会破坏胎儿睾丸表达脂质代谢基因，导致激素导致激素依赖性生殖组织的促成。 然而，邻苯二甲酸改变了几种睾丸细胞类型以及其他组织中的基因表达。 我们将使用这种滥交来发展邻苯二甲酸酯暴露的生物标志物，更重要的是，在围产期生殖组织中，可以很容易地从人类（胎盘和包皮）那里获得。 这些组织是生物标志物发育的绝佳选择，因为1）胎盘表达类固醇基因，胎盘功能改变或体重改变与男性生殖畸形以及体外邻苯二甲酸酯暴露有关胎盘胎盘细胞功能，以及2）或2）。雌激素）暴露。 在邻苯二甲酸酯暴露后大鼠胎盘的初步基因表达分析中，我们观察到数百个基因的变化。与睾丸类似，脂质代谢途径在胎盘中显着改变。 基于这些数据，我们假设低剂量水平邻苯二甲酸盐暴露和不良影响的候选基因组生物标志物可以从基因分析大鼠胎盘和包皮中得出。