Genes, environmental exposures, and hypospadias

描述（由申请人提供）：尿道下裂是一种先天性畸形，尿道开口位于阴茎的腹侧，是最常见的先天性畸形之一。尿道下裂的主要机制被认为是环境和遗传因素损害母体、胎儿或胎盘的雄激素和雌激素代谢。然而，这些因素对尿道下裂风险的贡献要么没有被评估，要么在很大程度上通过流行病学研究进行了调查，这些研究有许多局限性。我们建议通过基于种群的农药和候选基因的巢式病例对照研究来解决这些缺点。本研究将通过以下具体目的来验证农药和干扰母体、胎儿或胎盘性类固醇代谢的候选基因影响尿道下裂风险的假设：目的1 -农药和尿道下裂。我们将确定在尿道发育期间，产妇居住地附近是否与尿道下裂风险增加有关。我们将研究单个农药以及具有共同物理化学或功能特性的农药分组。目的2 -候选基因与尿道下裂。我们将从以下对尿道发育重要的机制途径解读尿道下裂风险与47个基因变异之间的关系：胎儿和胎盘性类固醇激素的生物合成和生物转化，性类固醇激素生物合成和作用的调节，以及生殖器结节生长和分化的调节。这些目标将通过连接几个现有信息来源来实现：1)作为基于人群的、积极确定的出生缺陷登记处的一部分收集的详细表型数据；2)加州农药使用报告数据；3)采集新生儿血斑作为新生儿常规筛查的一部分；4)孕产妇和新生儿生命统计的描述性特征。因此，该建议的一个关键优势是，它将利用使用严格的病例确定和分类标准收集的流行病学数据以及关于暴露和协变量的非常详细的数据。这项研究是第一次大规模的流行病学研究，旨在探索遗传和环境暴露与尿道下裂风险之间的关系。这项工作将填补我们关于内分泌相关暴露与尿道下裂风险之间的高度讨论但很少研究的知识的重要空白。最终，本研究将提供有关尿道下裂原因的宝贵信息，并为预防这种常见的先天性畸形提供途径。公共卫生相关性：拟议的研究将提高我们对尿道下裂原因的理解。其研究结果将有助于制定有效的干预措施或预防信息，从而预防尿道下裂。虽然这种畸形可以通过手术治疗，但它对个人和整体公众的健康都有重大影响，并带来长期后果，如性功能受损和与性和性活动有关的心理社会困难。

DESCRIPTION (provided by applicant): Hypospadias, a congenital malformation in which the urethral opening is on the ventral side of the penis, is one of the most common congenital malformations. The main mechanisms believed to underlie hypospadias are environmental and genetic factors that impair maternal, fetal, or placental androgen and estrogen metabolism. However, the contribution of such factors to hypospadias risk has either not been evaluated or has largely been investigated with epidemiologic studies that have numerous limitations. We propose to address these shortcomings with a population-based nested case-control study of pesticides and candidate genes. This study will test the hypothesis that pesticides and candidate genes which interfere with maternal, fetal, or placental sex steroid metabolism affect hypospadias risk through the following specific aims: Aim 1 - Pesticides and hypospadias. We will determine whether maternal residential proximity to applications of agricultural pesticides around the time of urethral development is associated with increased hypospadias risk. We will examine individual pesticides as well as groupings of pesticides that have common physicochemical or functional properties. Aim 2 - Candidate genes and hypospadias. We will decipher the association between hypospadias risk and variants in 47 genes from the following mechanistic pathways important to urethral development: fetal and placental biosynthesis and biotransformation of sex steroid hormones, regulation of sex steroid hormone biosynthesis and action, and regulation of genital tubercle outgrowth and differentiation. These aims will be achieved by linking several sources of existing information: 1) detailed phenotypic data collected as part of a population-based, actively ascertained birth defects registry; 2) data from California pesticide-use reports; 3) newborn bloodspots collected as part of routine newborn screening; and 4) maternal and newborn descriptive characteristics from vital statistics. Thus, a critical strength of this proposal is that it will utilize epidemiologic data that were collected using rigorous case ascertainment and classification criteria and highly detailed data on exposures and covariates. The proposed research represents the first large-scale epidemiologic study to explore genetic and environmental exposures and hypospadias risk. This work will fill an important gap in our knowledge regarding the highly discussed but minimally studied association of endocrine-related exposures with hypospadias risk. Ultimately this research will provide valuable information about the causes of hypospadias and give avenues for preventive measures against this common congenital malformation. PUBLIC HEALTH RELEVANCE: The proposed research will improve our understanding of the causes of hypospadias. Its findings will contribute to the development of effective interventions or prevention messages, so that hypospadias can be prevented. While this malformation can be treated with surgery, it has a significant impact both on an individual's-and the overall public's-health, with long-term consequences such as impaired sexual function and psychosocial difficulties related to sexuality and sexual activity.