Genetics and the Environment Associated with Male Reproduction (GEAR)

描述（由申请人提供）：在工业化国家的特定地区，1950- 2000年尿道下裂和隐睾症的发病率上升与一些邻苯二甲酸酯（用作增塑剂的抗雄激素合成化学品）的生产和使用相平行，在美国超过90%的普通人群的尿液中发现了邻苯二甲酸酯。遗传和环境因素在男性生殖结局的异常发育中起作用。包括AR、SRD 5A 2、INSL 3/LGR 8、ESR 1、ESR 2、ATF 3、CTGF和CYR 61在内的多个基因的多态性与不良男性生殖发育相关。在动物研究中，产前暴露于邻苯二甲酸酯可导致尿道下裂、隐睾、肛门与生殖器距离（AGD）缩短和阴茎宽度（PW）减小。我们的假设是，参与激素介导的男性生殖器发育的基因中的单核苷酸和重复多态性与缩短AGD和肛门阴囊距离（ASD：与动物中的AGD相似的测量）和较小的PW相关;并且这种关系被产前邻苯二甲酸酯暴露修改。为了解决这一假设，拟议的GEAR（遗传学和与男性生殖相关的环境）研究将在400名男性婴儿中对候选基因和重复多态性长度进行基因分型，这些男性婴儿被招募到一项前瞻性NIEHS资助的队列研究TIDES（婴儿发育和环境研究）中，并在其中测量AGD，ASD和PW以及孕产妇妊娠尿邻苯二甲酸酯浓度。我们将在TIDES计划的出生检查期间从婴儿中获取口腔拭子/FTA卡DNA样本并进行基因分型。我们将首先检查AR、ESR 1、ESR 2、SRD 5A 2、ATF 3、INSL 3/LGR 8、CTGF、CYR 61和缩短AGD和ASD以及较小PW的遗传变异之间的关联;然后继续测试这种关联是否被孕早期尿邻苯二甲酸酯暴露所改变。通过利用前瞻性母体研究设计，GEAR具有成本效益和新颖性，允许评估男性生殖发育中的遗传变异和邻苯二甲酸酯暴露。如果与男性生殖异常、邻苯二甲酸酯暴露和新型临床表型AGD、ASD和PW相关的遗传多态性之间存在关系，则这些结果将：1）加强对早期男性生殖发育的基因型和新临床表型之间关系的理解，2）成为首批研究男性生殖发育中基因/邻苯二甲酸酯相互作用的研究之一，3）有助于未来的研究，利用基因型，环境暴露和表型来预测未来的男性生殖健康。

DESCRIPTION (provided by applicant): In specific areas of industrialized nations, the rising incidence of hypospadias and cryptorchidism from 1950- 2000 parallels the production and use of some phthalates, anti-androgenic synthetic chemicals used as plasticizers, that have been found in the urine of over 90% of the general population in the United States. Genetic and environmental factors play a role in the development of abnormal development of male reproductive outcomes. Polymorphisms in several genes including AR, SRD5A2, INSL3/LGR8, ESR1, ESR2, ATF3, CTGF, and CYR61 are associated with adverse male reproductive development. Prenatal exposure to phthalates leads to hypospadias, cryptorchidism, and shortened anogenital distance (AGD) and smaller penile width (PW) in animal studies. Our hypothesis is that single nucleotide and repeat polymorphisms in genes involved in hormone mediated male genital development are associated with shortened AGD and ano-scrotal distance (ASD: a similar measure to AGD in animals) and smaller PW; and this relationship is modified by prenatal phthalate exposure. To address this hypothesis, the proposed GEAR (Genetics and the Environment Associated with Male Reproduction) study will genotype candidate genes and repeat polymorphism length in 400 male infants recruited into a prospective NIEHS-funded cohort study, TIDES (The Infant Development and Environment Study), and in whom AGD, ASD, and PW and maternal pregnancy urinary phthalate concentrations are being measured. We will obtain and genotype buccal swab/FTA card DNA samples from infants during already scheduled birth exams in TIDES. We will first examine the association between genetic variation in AR, ESR1, ESR2, SRD5A2, ATF3, INSL3/LGR8, CTGF, CYR61 and shortened AGD and ASD, and smaller PW; then proceed to test whether this association is modified by first trimester urine phthalate exposures. By taking advantage of a prospective parent study design, GEAR is cost effective and novel by allowing for assessment of genetic variation and phthalate exposures in male reproductive development. If a relationship exists between genetic polymorphisms associated with male reproductive abnormalities, phthalate exposure, and novel clinical phenotypes AGD, ASD, and PW, these findings would: 1) enhance understanding of the relationship between genotype and novel clinical phenotypes of early male genital development, and 2) be among the first studies to examine gene/phthalate interactions in male reproductive development, and 3) contribute to future research that uses genotype, environmental exposure, and phenotype to predict future male reproductive health.