Targets of Endocrine Disruptors in External Genitalia

外生殖器内分泌干扰物的目标

• 批准号: 8009852
• 负责人: MARTIN J COHN
• 金额: $ 44.59万
• 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/8009852
• 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 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; 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）：已经提出，发育中的胚胎暴露于内分泌干扰化学物质（EDC）是为了构成许多人类健康问题的基础，包括泌尿生殖器官的先天缺陷，肥胖，肥胖和癌症。泌尿生殖系统最常见的异常是Hypospadias，这是外生殖器的畸形，其特征是尿道管闭合的失败以及皮克皮（包皮）和腹阴茎的不完全形成。受影响的儿童可以有超大或多个尿道开口，患有严重催化性的儿童出生于模棱两可的生殖器。在工业化的世界中，在过去的三十年中，催生症的发生率稳步上升，现在影响了125名活着的男性出生中的大约1个。到目前为止，催生症患者的遗传筛查未能鉴定出可以解释这种情况的候选基因突变，并且已经假设催化性高孢子虫的发生率可能是由于环境中EDC的暴露于EDC。已经显示出许多环境EDC会诱导大鼠（以及野生动植物中的相关缺陷）诱导降低，但对于这些因素如何影响在外生殖器发育过程中运作的遗传途径如何了解。我们在小鼠中的初步研究表明，EDC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整合，以确定在阴茎发育过程中发挥作用的基因网络如何受EDC的影响。该建议的总体目的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。识别EDC的遗传靶标并确定其在生殖结节（阴茎和阴蒂的胚胎Anlagen）中的功能至关重要预防性处理，例如补充EDC敏感途径。 公共卫生相关性：外部生殖器的畸形是人类第二常见的先天缺陷，并且有越来越多的证据表明，胎儿暴露于内分泌中的化学物质（EDC）在工业化世界中发生的频率上升中起作用。该项目旨在确定EDC如何改变发育基因网络和细胞行为以产生催生。结果将确定EDC扰动正常生殖器发育的机制，确定为什么生殖器在特定妊娠阶段对EDC敏感，生成新的模型系统来筛选生殖器的EDC效应，并为预防治疗的发展提供基础。