Genes, environmental exposures, and hypospadias

描述(申请人提供)：尿道下裂是一种先天性畸形，其尿道口位于阴茎腹侧，是最常见的先天性畸形之一。环境和遗传因素被认为是影响母体、胎儿或胎盘雄激素和雌激素代谢的主要机制。然而，这些因素对尿道下裂风险的贡献要么没有被评估，要么在很大程度上已经通过流行病学研究进行了调查，这些研究具有许多局限性。我们建议通过对杀虫剂和候选基因进行基于人群的嵌套病例对照研究来解决这些缺点。本研究将验证农药和干扰母体、胎儿或胎盘性激素代谢的候选基因通过以下特定目的影响下裂风险的假说：目的1-农药和尿下裂。我们将确定产妇在尿路发育期间居住在靠近使用农用杀虫剂的地方是否会增加尿路下裂的风险。我们将研究单个杀虫剂以及具有共同物理化学或功能特性的杀虫剂分组。目的2-候选基因与尿道下裂的关系。我们将从以下机制途径破译尿道下裂风险与47个基因变异之间的关系：胎儿和胎盘的生物合成和生物转化，性类固醇激素的生物合成和作用的调节性类固醇激素的生物合成和作用，以及生殖器结节的生长和分化的调节。这些目标将通过将现有信息的几个来源联系起来实现：1)作为以人口为基础的积极确定的出生缺陷登记的一部分收集的详细表型数据；2)加州农药使用报告的数据；3)作为新生儿常规筛查的一部分收集的新生儿血斑；以及4)从生命统计中收集的孕产妇和新生儿的描述特征。因此，这项建议的一个关键优点是，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高度详细的数据。这项拟议的研究是探索遗传和环境暴露与尿道下裂风险的第一项大规模流行病学研究。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的高度讨论但研究最少的知识的一个重要空白。最终，这项研究将提供有关尿道下裂病因的有价值的信息，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。它的发现将有助于制定有效的干预措施或预防信息，以便预防尿道下裂。虽然这种畸形可以通过手术治疗，但它对个人和整个公众的健康都有重大影响，造成长期后果，如性功能受损以及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.