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将表观遗传学作为机械途径的中间步骤，将表观遗传学作为中间步骤，将母亲和父亲环境暴露与生殖成功以及随后的后代健康与发展联系起来。作为新任命的助理教授，我获得了必要的设施和资源，以建立一个可靠的高吞吐量实验室，用于针对大型人群研究量身定制的表观遗传分析。该K22应用的目的是建立一项对250对寻求体外施肥的副夫妇的队列研究，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，我确定了特定领域的额外发展将增强我作为独立研究人员的成功。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）队列和生物座席实施以及4）表观遗传信息学和计算生物学。 EDC邻苯二甲酸盐是无处不在的环境污染物，用于塑料和个人护理产品。邻苯二甲酸酯的暴露与多种生殖结果相关，包括男性生殖健康，出生结果和后代神经发育；但是，对这些关联的机械理解尚未清楚地阐明。表观遗传重编程对于精子成熟至关重要，代表了对环境诱发的表观遗传误差易感性的关键窗口，这可能会影响生殖健康。新兴动物和人类数据表明，男性生殖健康与精子中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富含发育和印记基因，这表明精子中的表观遗传模式对于受精后的胚胎发育可能很重要。为了实现我们的研究目标，我们将：1）检查邻苯二甲酸尿素对烙印基因上精子DNA甲基化的关系与Illumina的450K表观基因组阵列之间的关系； 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一种途径，父亲邻苯二甲酸盐会影响精子和胚胎质量。这项研究具有创新性，因为：1）虽然人类中的许多表观遗传学研究受到混合细胞类型（例如白细胞）的DNA的阻碍，但我们的研究利用了单个细胞类型 - 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来提供有关邻苯二甲酸盐暴露和精子DNA甲基化之间关联的第一个人类数据； 3）它可能通过为生殖成功提供有关父亲环境贡献的新数据来挑战当前生殖健康的教条。