Phthalate Exposure, Sperm DNA Methylation and Early-life Development

邻苯二甲酸盐暴露、精子 DNA 甲基化和早期生命发育

• 批准号: 8856245
• 负责人: J. Richard Pilsner
• 金额: $ 14.63万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856245
• 关键词: Area; Biological; Biology; Birth; Cohort Studies; Computational Biology; Couples; DNA; DNA Methylation; Data; Development; Disease; Embryo; Embryonic Development; Endocrine Disruptors; Ensure; Environmental Exposure; Environmental Health; Environmental Pollution; Epidemiologist; Epidemiology; Epigenetic Process; Exposure to; Fertilization; Fertilization in Vitro; Fostering; Gene Targeting; Genes; Germ Cells; Goals; Grant; H19 gene; Health; Human; IGF2 gene; In Vitro; Informatics; Intervention; K-Series Research Career Programs; K22 Award; Laboratories; Leukocytes; Life; Link; Mediation; Mentors; Methylation; Molecular; Outcome; Participant; Paternal Exposure; Pathway interactions; Pattern; Plastics; Play; Predisposition; Prevention; Process; Reproductive Health; Research; Research Personnel; Resources; Role; Secure; Self Care; Sperm Maturation; Testing; Time; Translational Research; animal data; biobank; career; career development; cell type; cohort; epigenome; epigenomics; exposed human population; human data; imprint; innovation; male; methylation biomarker; neurodevelopment; novel; novel strategies; offspring; phthalates; population based; professor; prospective; public health relevance; reproductive; reproductive success; research and development; sperm cell; sperm quality; success; transmission process; urinary

DESCRIPTION (provided by applicant): The purpose of this K22 Career Development Award is to foster the career development of Dr. J. Richard Pilsner, an interdisciplinary molecular epidemiologist. A long-term research goal is to delineate the role of epigenetics as an intermediate step in the mechanistic pathway linking maternal and paternal environmental exposures to reproductive success and subsequent offspring health and development. As a newly appointed Assistant Professor, I have been provided the necessary facilities and resources to establish a robust high- throughput laboratory for epigenetic analyses tailored for large population-based studies. The objective of this K22 application is to establish a cohort study of 250 subfertile couples seeking in vitro fertilizationto examine the association between paternal phthalate exposure, sperm epigenetics, and reproductive health. To this end, I have identified specific areas where additional development will enhance my success as an independent researcher. These include: 1) endocrine disruptor compounds (EDCs); 2) sperm biology and male reproductive health; 3) cohort and biorepository implementation and 4) epigenetic informatics and computational biology. Phthalates, an EDC, are ubiquitous environmental contaminants that are used in plastics and personal care products. Phthalate exposure is associated with a diverse set of reproductive outcomes, including male reproductive health, birth outcomes, and offspring neurodevelopment; however, a mechanistic understanding of these associations has not been clearly elucidated. Epigenetic reprogramming is essential for sperm maturation and represents a critical window of susceptibility to environmentally-induced epigenetic errors that may, in turn, influence reproductive health. Emerging animal and human data indicate that male reproductive health is associated with epigenetic dysregulation in sperm. Moreover, recent evidence indicates that epigenetic information retained in mature sperm is enriched at developmental and imprinted genes, signifying that epigenetic patterns in sperm may be important for embryonic development after fertilization. To achieve our research objectives, we will: 1) examine the relationships between paternal urinary phthalate exposure on sperm DNA methylation at imprinted genes and by Illumina's 450K epigenomic array; 2) examine the influence of paternal phthalate exposure on sperm quality and embryo development; 3) use statistical mediation to examine if sperm methylation is a pathway by which paternal phthalates influence sperm and embryo quality. This study is innovative because: 1) while many epigenetic studies in humans are hampered by DNA from mixed cell types (e.g., leukocytes), our study utilizes a single cell type - sperm germ cells; 2) it will provide, to our knowledge, the first human data on the association between phthalate exposure and sperm DNA methylation through the use of both targeted gene and epigenomic approaches; and 3) it may challenge the current dogma of reproductive health by providing novel data on paternal environmental contributions to reproductive success.

描述（由申请人提供）： 这个K22职业发展奖的目的是促进跨学科分子流行病学家J. Richard Pilsner博士的职业发展。一个长期的研究目标是描绘表观遗传学的作用，作为一个中间步骤的机制途径连接母亲和父亲的环境暴露，生殖成功和随后的后代健康和发展。作为一名新任命的助理教授，我获得了必要的设施和资源，以建立一个强大的高通量实验室，用于针对大型人群研究的表观遗传分析。本K22申请的目的是建立一项队列研究，纳入250对寻求体外受精的低生育力夫妇，以检查父亲邻苯二甲酸酯暴露、精子表观遗传学和生殖健康之间的关联。为此，我已经确定了额外的发展将提高我作为一个独立研究人员的成功的具体领域。其中包括：1）内分泌干扰物化合物（EDCs）; 2）精子生物学和男性生殖健康; 3）队列和生物储存库的实施和4）表观遗传信息学和计算生物学。邻苯二甲酸酯是一种EDC，是普遍存在的环境污染物，用于塑料和个人护理产品。邻苯二甲酸酯暴露与多种生殖结局相关，包括男性生殖健康、出生结局和后代神经发育;然而，对这些相关性的机械理解尚未明确阐明。表观遗传重编程对精子成熟至关重要，代表了对环境诱导的表观遗传错误易感性的关键窗口，这些错误可能反过来影响生殖健康。新的动物和人类数据表明，男性生殖健康与精子的表观遗传失调有关。此外，最近的证据表明，保留在成熟精子中的表观遗传信息在发育和印记基因中富集，这意味着精子中的表观遗传模式可能对受精后的胚胎发育很重要。为了实现我们的研究目标，我们将：1）通过Illumina的450 K表观基因组阵列检查父亲尿液邻苯二甲酸酯暴露对精子DNA甲基化的关系; 2）检查父亲邻苯二甲酸酯暴露对精子质量和胚胎发育的影响; 3）使用统计中介来检查精子甲基化是否是父亲邻苯二甲酸酯影响精子和胚胎质量的途径。这项研究是创新的，因为：1）虽然许多人类表观遗传学研究受到来自混合细胞类型的DNA的阻碍（例如，白细胞），我们的研究利用单细胞类型-精子生殖细胞; 2)据我们所知，它将通过使用靶向基因和表观基因组方法提供关于邻苯二甲酸酯暴露与精子DNA甲基化之间关联的第一个人类数据; 3）它可能通过提供关于父亲环境对生殖成功贡献的新数据来挑战当前生殖健康的教条。