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

摘要 邻苯二甲酸酯，一类用于塑料和个人护理产品的内分泌干扰化合物(EDCs)，是 无处不在的环境污染物导致人类广泛接触。流行病学数据表明 父性邻苯二甲酸酯，生殖健康不良，包括精子质量差，最近， −指的是由精液产生的影响。传统上，精子被认为是 仅用于在受精时传递父系基因组的工具。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，这些变化会影响后代的健康和发育。一种生物学的 父系对生殖成功的贡献途径已被证明包括精子中的畸形。 DNA甲基化。到目前为止，这一领域的研究主要局限于营养的影响。 动物模型中的操纵；因此，对成人接触毒物如何影响的了解相对较少。 精子中的表观遗传信息--特别是在人类群体中。我们认为理解的关键是 成人接触邻苯二甲酸盐对生殖健康的影响在于精子DNA甲基化。这 应用程序利用同时从精子环境表观遗传学和 发展研究(Seed；PI：Richard Pilsner)和环境与生殖健康研究 (Earth；Pi Russ Hauser)，两项独立的流行病学研究，调查了父亲和母亲之间的联系 体外受精(IVF)人群中邻苯二甲酸盐暴露与生殖健康不良。此外，为了 解决来自试管受精队列的潜在泛化问题，我们还在复制目标中包括 从生育力纵向调查中收集的精子甲基化分析 环境(生活；皮杰曼·巴克·路易斯)研究，代表一般情况的夫妇的预期队列 人口。对于我们的第一个目标，全基因组甲基化将通过Illumina的EPIC阵列在分离的 种子体外受精(IVF)后残留的精子。接下来，我们将确定精子之间的关系 甲基组和胚胎质量的生殖结果以及种子活产的可能性。最后， 在种子中完成这些目标后，我们将在来自地球的精子样本中进行复制研究 和生命来确定三个队列中发现的一致性。拟议的研究是可望完成的。 通过精子DNA揭示父亲邻苯二甲酸盐暴露与不良生殖结局之间的联系 甲基化。暴露和结果连续体之间的潜在中间途径的特征 它具有重要的意义，因为它将为小说的发展提供翻译研究的途径 治疗和预防不良生殖健康的方法。

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.