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

总结 邻苯二甲酸酯是一类用于塑料和个人护理产品的内分泌干扰化合物（EDCs）， 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 父亲的邻苯二甲酸酯与不利的生殖健康，包括精子质量差，最近，与更长的 怀孕时间-后者表明精液衍生的影响。传统上，精子被认为是 仅用于在受精时递送父本基因组的载体。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，而不改变精子的形态。 潜在的DNA序列，反过来，这些改变会影响后代的健康和发育。生物 这种父系对生殖成功的贡献的途径已被证明包括精子的畸变 DNA甲基化迄今为止，这一领域的研究主要限于营养的影响。 在动物模型中的操作;因此，关于成人暴露于有毒物质如何影响 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 成年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 该应用利用了来自精子环境表观遗传学的并行样本收集， 发展研究（SEEDS; PI：Richard Pilsner）和环境与生殖健康研究 （EARTH; PI Russ豪瑟），两项独立的流行病学研究调查了父亲与母亲之间的联系。 体外受精（IVF）人群中邻苯二甲酸酯暴露和不良生殖健康。此外，为了 解决IVF队列中潜在的普遍性问题，我们还将其纳入我们的复制目标， 精子甲基化分析从生育力纵向调查和 环境（LIFE; PI Germaine Buck Louis）研究，一项代表一般 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阵列分析分离的 体外受精（IVF）后剩余的精子。接下来，我们将确定精子之间的关系 甲基化和生殖结果的胚胎质量和概率的活产种子。最后， 在完成SEEDS的这些目标之后，我们将在来自地球的精子样本中进行复制研究 和LIFE，以确定三个队列结果的一致性。预计该研究将 通过精子DNA揭示父亲邻苯二甲酸酯暴露与不良生殖结果之间的联系 甲基化暴露和结果连续体之间潜在中间途径的表征 是非常重要的，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.