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: 8320929
• 负责人: Sheela Sathyanarayana
• 金额: $ 29.2万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8320929
• 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.

描述（由申请人提供）：在工业化国家的特定领域，从1950年至2000年开始的催生和加密智主义的发生率上升，与某些邻苯二甲酸酯的生产和使用相似，使用了作为塑料的抗雄激素合成化学物质，这些化学物质用作塑料化学物质，这些化学物质已在美国美国一般人群中90％以上的尿液中发现。遗传和环境因素在男性生殖结果异常发展中起作用。包括AR，SRD5A2，INSL3/LGR8，ESR1，ESR2，ATF3，CTGF和CYR61在内的多种基因中的多态性与不良男性生殖发育有关。在动物研究中，产前暴露于邻苯二甲酸盐会导致降低，密码术，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，与激素介导的男性生殖器发育有关的基因中的单核苷酸和重复多态性与缩短的AGD和肛门近距离距离（ASD：与动物中AGD相似的措施）和较小的PW有关。这种关系是通过邻苯二甲酸盐暴露来改变的。为了解决这一假设，提出的齿轮（遗传学和与男性生殖有关的环境）研究将基因型候选基因和重复的多态性重复招募到一项前瞻性NIEHS资助的队列研究中，潮汐（婴儿发育和环境研究），以及在ASD，ASD和PW和PW和Mational pernaltal phthanal phthanal phthanal perthal perthal perthal perthal perthal中。在潮汐中已经安排的出生检查期间，我们将从婴儿中获得和基因型颊拭子/FTA卡DNA样品。我们将首先检查AR，ESR1，ESR2，SRD5A2，ATF3，INSL3/LGR8，CTGF，CTGF，CYR61与AGD和ASD缩短的AR，ATF3，INSL3/LGR8，以及较小的PW之间的关联；然后继续测试该关联是否通过邻苯二甲酸盐暴露对这种关联进行修饰。通过利用前瞻性父母研究设计，通过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，齿轮是具有成本效益和新颖的。如果与男性生殖异常相关的遗传多态性存在关系，邻苯二甲酸盐暴露和新颖的临床表型AGD，ASD和PW之间的关系，这些发现将：1）增强对早期男性发展的基因型和新型临床表型之间的理解，以及第一次研究基因的贡献，以及3）研究，以及3个研究基因的贡献，以及3个研究的贡献，是针对基因的贡献。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。