Paternal preconception phthalates and reproductive health - potential mediation through sperm DNA methylation

父亲先入为主的邻苯二甲酸盐与生殖健康——通过精子 DNA 甲基化的潜在调节

• 批准号: 9917776
• 负责人: J. Richard Pilsner
• 金额: $ 53.07万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917776
• 关键词: Address; Adult; Affect; Animal Model; Area; Biological; Couples; DNA; DNA Methylation; DNA Sequence; Data; Development; Disease; Endocrine Disruptors; Environment; Environmental Health; Environmental Pollution; Epigenetic Process; Exposure to; Fertility; Fertilization; Fertilization in Vitro; General Population; Genome; Health; Human; Infertility; Investigation; Link; Live Birth; Measures; Mediation; Mediator of activation protein; Methylation; Nutritional; Outcome; Participant; Pathway interactions; Plastics; Population; Probability; Prospective cohort; Reproductive Health; Research; Resources; Role; Sampling; Seminal fluid; Testing; Toxicant exposure; Translational Research; androgenic; animal data; cohort; cost effective; embryo quality; epidemiologic data; epidemiology study; exposed human population; genome wide methylation; genome-wide; human male; innovation; methylome; mono-(2-ethylhexyl)phthalate; novel strategies; offspring; personal care products; phthalates; prevent; reproductive; reproductive success; research and development; sample collection; sperm cell; sperm quality; stem; time-to-pregnancy; toxicant; urinary

SUMMARY Phthalates, a class of endocrine disrupting compounds (EDCs) used in plastics and personal care products, are ubiquitous environmental contaminants resulting in widespread human exposure. Epidemiologic data implicate paternal phthalates with adverse reproductive health including poor sperm quality, and more recently, with longer time to pregnancy − the latter suggests a semen-derived effect. Traditionally, sperm have been considered vehicles only for the delivery of the paternal genome upon fertilization. However, compelling animal data demonstrate that environmental conditions in adulthood are embodied within sperm without altering the underlying DNA sequence, and in turn, these alterations affect offspring health and development. A biological pathway for this paternal contribution to reproductive success has been shown to include aberrations in sperm DNA methylation. To date, research in this area has been largely restricted to the effects of nutritional manipulations in animal models; therefore, relatively little is known about how adult exposures to toxicants affect epigenetic information in sperm – especially in human populations. We propose that a key to understanding how adult exposures to phthalates impact reproductive health lies within sperm DNA methylation. This application capitalizes on the concurrent sample collection from the Sperm Environmental Epigenetics and Development Study (SEEDS; PI: Richard Pilsner) and the Environmental and Reproductive Health Study (EARTH; PI Russ Hauser), two independent epidemiologic studies investigating the link between paternal phthalate exposure and adverse reproductive health among in vitro fertilization (IVF) populations. Moreover, to address potential generalizability issues stemming from IVF cohorts, we also include in our replication aim, sperm methylation analyses from samples collected from the Longitudinal Investigation of Fertility and the Environment (LIFE; PI Germaine Buck Louis) study, a prospective cohort of couples representing the general population. For our first aim, genome-wide methylation will be analyzed via Illumina’s EPIC array on isolated sperm remaining after in-vitro fertilization (IVF) from SEEDS. Next, we will determine the relationships of sperm methylome and on the reproductive outcomes of embryo quality and probability of a live birth in SEEDS. Finally, after completion of these objectives in SEEDS, we will perform replication studies in sperm samples from EARTH and LIFE to determine the concordance of findings across the three cohorts. The proposed research is expected to uncover pathways linking paternal phthalate exposures with adverse reproductive outcomes via sperm DNA methylation. Characterization of potential intermediate pathways between the exposure and outcome continuum is of significant importance because it will inform avenues of translational research for the development of novel approaches to treat and prevent adverse reproductive health.

概括 邻苯二甲酸盐是塑料和个人护理产品中使用的一类内分泌干扰化合物（EDC） 无处不在的环境污染物导致人类暴露宽度。流行病学数据隐含 父亲的邻苯二甲酸盐具有不良复制性健康，包括精子质量差，最近，较长的 怀孕的时间 - 后者表明了精液衍生的效果。传统上，精子被考虑 施肥后仅用于传递父亲基因组的车辆。但是，引人入胜的动物数据 证明成年中的环境条件在精子中体现而不改变 基本的DNA序列以及这些改变会影响后代的健康和发展。生物学 已经证明，这种模式为复制成功贡献的途径包括精子中的畸变 DNA甲基化。迄今为止，该领域的研究主要仅限于营养的影响 动物模型中的操纵；因此，关于成年人暴露于有毒物质的影响相对较少了解 精子中的表观遗传信息 - 尤其是在人群中。我们建议这是理解的关键 成年对邻苯二甲酸盐的暴露方式如何影响生殖健康。这 申请将精子环境表观遗传学的并发样品收集以及 开发研究（种子； PI：Richard Pilsner）和环境和生殖健康研究 （Earth; Pi Russ Hauser），两项独立的流行病学研究，研究了父亲之间的联系 体外受精（IVF）种群中的邻苯二甲酸盐暴露和不良生殖健康。而且， 解决IVF队列引起的潜在可推广性问题，我们还将复制目的包括 从纵向研究和 环境（Life; Pi Germaine Buck Louis）研究，代表一般夫妇的一群前瞻性队列 人口。对于我们的第一个目标，将通过Illumina的Epic阵列分析全基因组甲基化 从种子的体外受精（IVF）后仍保持精子。接下来，我们将确定精子的关系 甲基组以及种子中活出生的胚胎质量和概率的生殖结果。最后， 在种子中完成这些目标后，我们将对来自地球的精子样本进行复制研究 生命以确定三个同龄人中发现的一致性。预计拟议的研究 发现通过精子DNA将父亲邻苯二甲酸酯暴露与不良复制结果联系起来的途径 甲基化。表征暴露和结果连续性之间潜在中间途径的表征 非常重要，因为它将为发展新颖的途径提供转化研究的途径 治疗和预防不良复制健康的方法。