Genetics and the Environment Associated with Male Reproduction (GEAR)

与男性生殖相关的遗传学和环境（GEAR）

• 批准号: 8190749
• 负责人: Sheela Sathyanarayana
• 金额: $ 17.65万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190749
• 关键词: Address; Adult; Affect; Androgens; Animal Model; Animals; Area; Birth; Candidate Disease Gene; Charge; Cheek structure; Chemicals; Cohort Studies; Cryptorchidism; DNA; Data; Defect; Developed Countries; Development; Disease; ESR1 gene; ESR2 gene; Environment; Environmental Exposure; Environmental Risk Factor; Exposure to; First Pregnancy Trimester; Foundations; Funding; Future; Gene Targeting; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genital system; Genotype; Grant; Health; Hormones; Human; Human Genetics; Hypospadias; Incidence; Infant; Infant Development; Left; Length; Life; Male Genital Organs; Malignant neoplasm of testis; Measurement; Measures; Mediating; Metabolism; Modeling; Molecular; National Institute of Environmental Health Sciences; Newborn Infant; Nucleotides; Outcome; Parents; Phenotype; Plasticizers; Plastics; Play; Pregnancy; Production; Recruitment Activity; Reproduction; Reproductive Health; Research Design; Risk; Role; SRD5A2 gene; Sampling; Schedule; Single Nucleotide Polymorphism; Swab; Testicular Dysgenesis Syndrome; Testing; Testosterone; Tissue Differentiation; Toxic effect; United States; Urine; Variant; Vulnerable Populations; Width; clinical phenotype; clinical practice; cohort; connective tissue growth factor; cost; cost effective; environmental chemical exposure; fetal; human male; in utero; longitudinal design; male; novel; phthalates; prenatal; prenatal exposure; programs; prospective; reproductive; reproductive development; urinary

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.

描述（由申请人提供）：在工业化国家的特定地区，从1950年到2000年，尿道下裂和隐睾的发病率上升与一些邻苯二甲酸盐的生产和使用相似，邻苯二甲酸盐是一种抗雄激素合成化学品，用作增塑剂，在美国超过90%的普通人群的尿液中发现。遗传和环境因素在男性生殖结果发育异常的发展中起作用。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、缩短肛门生殖器距离（AGD）和较小的阴茎宽度（PW）。我们的假设是，参与激素介导的男性生殖器发育的基因的单核苷酸和重复多态性与AGD缩短和无阴囊距离（ASD：与动物的AGD相似）和较小的PW有关；这种关系被产前邻苯二甲酸盐暴露所改变。为了验证这一假设，GEAR（遗传与环境与男性生殖相关）研究将招募400名男婴进行候选基因分型和重复多态性长度，这些男婴被纳入niehs资助的前瞻性队列研究TIDES（婴儿发育与环境研究），并在其中测量AGD， ASD， PW和产妇妊娠尿邻苯二甲酸盐浓度。我们将在TIDES中已安排的出生检查中从婴儿获得口腔拭子/FTA卡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PW减小之间的关系；然后继续测试这种关联是否被妊娠早期尿邻苯二甲酸盐暴露所改变。通过利用前瞻性亲本研究设计，GEAR具有成本效益和创新性，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、邻苯二甲酸盐暴露相关的遗传多态性与新的临床表型AGD、ASD和PW之间存在关系，这些发现将：1)加强对基因型与早期男性生殖发育新临床表型之间关系的理解；2)成为首批研究基因/邻苯二甲酸盐在男性生殖发育中的相互作用的研究之一；3)为未来使用基因型、环境暴露和表型来预测未来男性生殖健康的研究做出贡献。