Genetics and the Environment Associated with Male Reproduction (GEAR)

描述(申请人提供)：在工业化国家的特定地区，1950-2000年间尿下裂和隐睾症的发病率上升与一些邻苯二甲酸酯的生产和使用同步，邻苯二甲酸酯是用作增塑剂的抗雄激素合成化学品，在美国90%以上的总人口的尿液中发现了这种化合物。遗传和环境因素在男性生殖结局异常发育中发挥作用。AR、SRD5A2、INSL3/LGR8、ESR1、ESR2、ATF3、CTGF和CYR61等基因的多态性与男性生殖发育不良有关。在动物研究中，产前暴露于邻苯二甲酸盐会导致尿道下裂、隐睾症、肛门生殖器距离缩短(AGD)和阴茎宽度变小(PW)。我们的假设是，激素介导的男性生殖器发育相关基因的单核苷酸和重复多态与AGD和无阴囊距离(ASD：与动物的AGD相似)和较小的PW相关；这种关系可以通过产前邻苯二甲酸酯暴露而改变。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NIEHS资助的前瞻性队列研究DEDS(婴儿发育和环境研究)招募的400名男性婴儿中对候选基因进行分型并重复多态长度，并在这些婴儿中测量AGD、ASD、PW和孕妇尿邻苯二甲酸盐浓度。我们将在潮汐已经预定的出生检查期间从婴儿的口腔拭子/FTA卡DNA样本中获取DNA样本并进行基因分型。我们将首先研究AR、ESR1、ESR2、SRD5A2、ATF3、INSL3/LGR8、CTGF、CYR61基因变异与AGD和ASD缩短以及较小PW之间的关联；然后继续测试这种关联是否会被妊娠早期的邻苯二甲酸盐暴露所改变。通过利用预期的亲本研究设计，GEAR具有成本效益和新颖性，因为它允许评估男性生殖发育中的遗传变异和邻苯二甲酸盐暴露。如果与男性生殖异常、邻苯二甲酸酯暴露和新的临床表型AGD、ASD和PW相关的遗传多态之间存在关系，这些发现将：1)加强对早期男性生殖器发育的基因和新的临床表型之间的关系的理解；2)成为第一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)有助于未来利用基因、环境暴露和表型来预测未来男性生殖健康的研究。 公共卫生相关性：男性生殖道异常在新生儿中很常见，可能与遗传和环境对发育的影响有关。我们将测量肛门生殖器距离(AGD)、阴囊肛门距离(ASD)和阴茎宽度(PW)，并从400名新生男性的脸颊获取DNA样本，以评估遗传因素如何影响男性发育。我们将研究与生殖器测量有关的遗传差异，以及怀孕前三个月环境化学物质暴露如何影响这种关系。这些信息将加强我们对男性生殖系统如何发育的了解。

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. PUBLIC HEALTH RELEVANCE: Male reproductive tract abnormalities are common in newborn infants and may be related to genetic and environmental influences on development. We will measure anogenital distance (AGD), ano-scrotal distance (ASD), and penile width (PW) and obtain DNA samples from the cheeks of 400 newborn males to assess how genetic factors affect male development. We will examine genetic differences in relation to genital measurements and how environmental chemical exposures in the first trimester of pregnancy can impact this relationship. This information will enhance our understanding of how the male reproductive system develops.