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 邻苯二甲酸盐是一类用于塑料和个人护理产品的内分泌干扰化合物 (EDC)， 普遍存在的环境污染物导致人类广泛接触。流行病学数据暗示 父系邻苯二甲酸盐对生殖健康不利，包括精子质量差，最近，时间更长 怀孕时间——后者表明精液产生的影响。传统上，精子被认为 仅用于在受精时传递父本基因组的载体。然而，令人信服的动物数据 证明成年期的环境条件体现在精子中，而不会改变 潜在的 DNA 序列，反过来，这些改变会影响后代的健康和发育。一个生物 父系对生殖成功的贡献已被证明包括精子的畸变 DNA甲基化。迄今为止，该领域的研究主要局限于营养的影响。 动物模型的操作；因此，对于成人接触有毒物质如何影响我们知之甚少。 精子中的表观遗传信息——尤其是在人类中。我们提出理解的关键 成人接触邻苯二甲酸盐如何影响生殖健康取决于精子 DNA 甲基化。这 应用程序利用精子环境表观遗传学的并发样本收集和 发展研究（SEEDS；PI：Richard Pilsner）以及环境和生殖健康研究 （EARTH；PI Russ Hauser），两项独立的流行病学研究调查了父系之间的联系 邻苯二甲酸盐暴露和体外受精 (IVF) 人群的生殖健康不良。此外，为了 解决 IVF 队列产生的潜在普遍性问题，我们还将其纳入我们的复制目标中， 对生育力纵向调查收集的样本进行精子甲基化分析 环境（LIFE；PI Germaine Buck Louis）研究，一组代表一般情况的夫妇的前瞻性研究 人口。对于我们的第一个目标，将通过 Illumina 的 EPIC 阵列对分离的基因组进行分析。 SEEDS 体外受精 (IVF) 后剩余的精子。接下来，我们将确定精子的关系 甲基化组以及 SEEDS 中胚胎质量和活产概率的生殖结果。最后， 在 SEEDS 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 和 LIFE 来确定三个队列中研究结果的一致性。拟议的研究预计 通过精子 DNA 揭示父亲邻苯二甲酸盐暴露与不良生殖结果之间的联系途径 甲基化。暴露和结果连续体之间潜在中间途径的表征 具有重要意义，因为它将为小说开发的转化研究提供途径 治疗和预防不良生殖健康的方法。