Targets of Endocrine Disruptors in External Genitalia

外生殖器内分泌干扰物的目标

• 批准号: 8232159
• 负责人: MARTIN J COHN
• 金额: $ 38.11万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232159
• 关键词: Accounting; Affect; Androgens; Anogenital region; Biological Models; Birth; Candidate Disease Gene; Cell Differentiation process; Cell Lineage; Cells; Chemicals; Child; Clitoris; Congenital Abnormality; Defect; Development; Developmental Gene; Ectoderm; Embryo; Endocrine Disruptors; Environment; Epithelium; Estrogens; Event; Exposure to; Failure; Family; Feminization; Fertility; Flutamide; Foundations; Frequencies; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Programming; Genetic Screening; Genital system; Genitalia; Genitourinary system; Genome; Genomics; Growth; Growth Factor; Health; Human; Hypospadias; Incidence; Knock-in Mouse; Knock-out; Laboratory Animals; Life; Link; Male Genital Organs; Malignant Neoplasms; Maps; Mesenchyme; Modeling; Molecular; Morphology; Movement; Mus; Mutation; Obesity; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Patients; Pattern; Perinatal Exposure; Physiological; Play; Pregnancy; Procedures; Production; Rattus; Research; Resources; Role; Scrotum; Side; Signal Transduction; Staging; Stem cells; Supplementation; Swelling; Testing; Tissues; Transcriptional Regulation; Translating; Tube; Urethra; Urothelial Cell; base; cell behavior; developmental genetics; embryonic stem cell; external genitalia; gene function; gene repression; male; malformation; mouse model; penis; penis foreskin; prepuce; psychological outcomes; psychosocial; public health relevance; reproductive; sex; stem cell technology; steroid hormone; transcription factor; vinclozolin

DESCRIPTION (provided by applicant): Exposure of the developing embryo to endocrine disrupting chemicals (EDCs) has been proposed to underlie a number of human health problems, including birth defects of genitourinary organs, obesity, decreased fertility and cancer. The most common anomaly of the genitourinary system is hypospadias, a malformation of the external genitalia that is characterized by failure of urethral tube closure and incomplete formation of the prepuce (foreskin) and ventral penis. Affected children can have oversized or multiple urethral openings, and children with severe hypospadias are born with ambiguous genitalia. In the industrialized world, the incidence of hypospadias has risen steadily over the past thirty years and now affects approximately 1 in 125 live male births. Genetic screens of patients with hypospadias have, thus far, failed to identify mutations in candidate genes that can account for this condition, and it has been hypothesized that the high incidence of hypospadias may be due to exposure of the embryo to EDCs in the environment. A number of environmental EDCs have been shown to induce hypospadias in rats (and related defects in wildlife) but little is known about how these factors influence the genetic pathways that operate during development of the external genitalia. Our preliminary studies in mice show that EDCs can induce transient down-regulation of genes that control urethral tube formation, suggesting a mutation-independent mechanism by which these factors can disrupt the genetic program that directs genital development. In this project we propose to integrate mouse developmental genetics and ecotoxicology in order to identify how the gene networks that function during penile development are affected by EDCs. The overarching aim of this proposal is to identify the molecular and cellular events that translate embryonic exposure to an EDC into a structural defect of the genitalia. Identifying the genetic targets of EDCs and determining their functions in the genital tubercle (the embryonic anlagen of the penis and clitoris) is critical if we are to (a) understand the mechanisms by which EDCs perturb normal development, (b) understand why developing genitalia are sensitive to EDCs at specific stages of pregnancy, (c) develop new model systems to test EDC effects on genitourinary cells and tissues, and (d) develop preventative treatments such as supplementation to augment EDC-sensitive pathways. PUBLIC HEALTH RELEVANCE: Malformation of the external genitalia is the second most common birth defect in humans, and there is increasing evidence that fetal exposure to endocrine disrupting chemicals (EDCs) plays a role in the rising frequency of occurrence in the industrialized world. This project aims to identify how EDCs alter developmental gene networks and cell behavior to produce hypospadias. The results will identify the mechanisms by which EDCs perturb normal genital development, determine why genitalia are sensitive to EDCs at particular stages of pregnancy, produce new model systems to screen for EDC effects in genitalia, and provide a foundation for development of preventative treatments.

描述（由申请人提供）：发育中的胚胎暴露于内分泌干扰化学物质（EDCs）已被提出是许多人类健康问题的基础，包括生殖泌尿器官的出生缺陷、肥胖、生育能力下降和癌症。泌尿生殖系统最常见的异常是尿道下裂，这是一种外生殖器畸形，其特征是尿道管关闭失败，包皮（包皮）和阴茎腹侧不完整。受影响的儿童可能有过大或多个尿道开口，严重尿道下裂的儿童出生时生殖器模糊。在工业化国家，尿道下裂的发病率在过去的30年里稳步上升，现在大约每125个活产男婴中就有1个患有尿道下裂。到目前为止，尿道下裂患者的基因筛查未能发现可能导致这种情况的候选基因突变，并且有一种假设认为，尿道下裂的高发病率可能是由于胚胎暴露于环境中的EDCs。许多环境中的EDCs已被证明会诱发大鼠尿道下裂（以及野生动物的相关缺陷），但对于这些因素如何影响外生殖器发育过程中的遗传途径，人们知之甚少。我们在小鼠中的初步研究表明，EDCs可以诱导控制尿道管形成的基因的短暂下调，这表明这些因素可以通过一种不依赖突变的机制破坏指导生殖器发育的遗传程序。在这个项目中，我们建议将小鼠发育遗传学和生态毒理学结合起来，以确定EDCs如何影响阴茎发育过程中的基因网络。本提案的总体目标是确定将胚胎暴露于EDC转化为生殖器结构缺陷的分子和细胞事件。如果我们要(a)了解EDC干扰正常发育的机制，(b)了解为什么发育中的生殖器在怀孕的特定阶段对EDC敏感，(c)开发新的模型系统来测试EDC对泌尿生殖系统细胞和组织的影响，确定EDC的遗传靶点并确定其在生殖器结节（阴茎和阴蒂的胚胎原）中的功能是至关重要的。(d)开发预防性治疗方法，如补充edc敏感通路。