Targets of Endocrine Disruptors in External Genitalia

描述(由申请人提供)：发育中的胚胎暴露在内分泌干扰物(EDCs)中被认为是许多人类健康问题的基础，包括生殖泌尿器官出生缺陷、肥胖、生育力下降和癌症。最常见的泌尿生殖系统异常是尿道下裂，这是一种外生殖器畸形，其特征是尿管关闭失败，包皮(包皮)和腹侧阴茎形成不完全。受影响的儿童可能有超大或多个尿道口，患有严重尿道下裂的儿童出生时生殖器不明确。在工业化世界，尿道下裂的发病率在过去30年里稳步上升，现在大约每125名活产男婴中就有1名受到影响。到目前为止，对尿道下裂患者的基因筛查未能发现可以解释这种情况的候选基因的突变，有人推测，尿道下裂的高发病率可能是由于胚胎暴露在环境中的内分泌细胞所致。许多环境中的内分泌细胞已经被证明可以诱导大鼠的尿道下裂(以及野生动物中的相关缺陷)，但关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。我们在小鼠身上的初步研究表明，EDCs可以诱导控制尿道管形成的基因瞬时下调，这表明了一种突变无关的机制，通过这种机制，这些因素可以扰乱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，以确定在阴茎发育过程中发挥作用的基因网络是如何受到EDCs的影响的。这项建议的首要目标是确定将胚胎暴露在EDC中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EDCs扰乱正常发育的机制，(B)了解为什么发育中的生殖器在怀孕的特定阶段对EDCs敏感，(C)开发新的模型系统来测试EDC对生殖道细胞和组织的影响，以及(D)开发预防性治疗方法，例如补充EDC敏感的途径，识别EDCs的遗传靶点并确定其在生殖器结节(阴茎和阴蒂的胚胎期)中的功能是至关重要的。 公共卫生相关性：外生殖器畸形是人类第二常见的出生缺陷，越来越多的证据表明，在工业化世界，胎儿接触内分泌干扰物(EDCs)在发病率上升中起到了作用。该项目旨在确定内分泌细胞如何改变发育基因网络和细胞行为以产生尿道下裂。这些结果将确定EDCs扰乱正常生殖器发育的机制，确定为什么生殖器在怀孕的特定阶段对EDCs敏感，产生新的模型系统来筛选EDC对生殖器的影响，并为开发预防性治疗提供基础。

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.