Determining how preconception exposure to phthalates impacts sperm function, the

总结 不孕症是最常见的生殖健康疾病之一，影响美国16%的夫妇。 令人担忧的是，新的荟萃分析数据显示，发达国家男性的精子数量 在过去的四十年里下降了超过50%。在大多数情况下， 近年来，我们可能不仅面临生育危机，而且精子数量低也影响了更广泛的公共健康。 影响包括发病率和死亡率风险增加（3，4）。考虑到精子数量的急剧减少 质量在短时间内，遗传影响可能不是归因于，而是环境因素 在生命历程中遇到的。特别是邻苯二甲酸酯，一类内分泌干扰化合物（EDCs） 在塑料和个人护理产品中使用，是普遍存在的环境污染物，导致广泛的 人体接触。ViCTER机制为加强跨学科和 翻译研究因此，我们的研究小组准备确定父亲的偏见 邻苯二甲酸酯影响精子功能，表观基因组和早期生命发育，利用正在进行的研究 在小鼠模型（R 01：ES 028214; PI：Dr. Pilsner）和接受体外受精（IVF）的夫妇中， 人类队列（精子环境表观遗传学和发育研究;种子：R 01：ES 028298; PI：Dr. Pilsner）。我们假设，了解成年人接触邻苯二甲酸酯如何影响生殖的关键是 健康在于精子表观遗传学和生理学。因此，我们的ViCTER目标是确定 成年男性暴露于邻苯二甲酸酯对：1）细胞外囊泡（EV）中的小非编码RNA（sncRNA）的影响 (Dr. Pilsner）; 2）精子组蛋白甲基化（Kimmins博士）;和3）精子获能，IVF和胚胎 （Visconti博士）。对于我们的第一个目标，我们将研究父亲的邻苯二甲酸酯暴露的协会， 来自小鼠和人的细胞外囊泡（EV）的sncRNA表达。接下来，我们将研究成年人的影响。 雄性暴露于邻苯二甲酸酯对小鼠和男性精子中组蛋白甲基化的影响。最后，我们将确定 DEHP、DBP及其混合物对成年小鼠精子获能、顶体反应和 随后的胚胎发育。这项拟议中的研究有望揭示父亲与母亲之间的联系途径。 通过精子生理学和表观遗传学，邻苯二甲酸酯暴露对生殖产生不良影响。 暴露和结果连续体之间的潜在中间途径的表征是 非常重要，因为它将为小说开发的转化研究提供信息 治疗和预防不良生殖健康的方法。

SUMMARY Infertility is one of the most common reproductive health disorders affecting 16% of couples in the U.S. Most concerning are the new meta-analysis data showing that sperm counts among men in developed countries have declined over 50% in the past four decades. With no sign of reversing this downward trajectory in the most recent years, we may not only be facing a fertility crisis, but low sperm count has also wider public health implications including increased risks in morbidity and mortality (3, 4). Given this dramatic decrease in sperm quality over a short period, genetic influences are likely not attributable, but rather, environmental factors encountered over the life-course. In particular, phthalates, a class of endocrine disrupting compounds (EDCs) used in plastics and personal care products, are ubiquitous environmental contaminants resulting in widespread human exposure. The ViCTER mechanism provides a unique opportunity to enhance cross-disciplinary and translational research. As such, our research team is poised to determine how paternal preconception phthalates impacts sperm function, the epigenome and early-life development by leveraging ongoing research in mice models (R01: ES028214; PI: Dr. Pilsner) and couples undergoing in vitro fertilization (IVF) as part of the human cohort (Sperm Environmental Epigenetics and Development Study; SEEDS: R01: ES028298; PI: Dr. Pilsner). We hypothesize that a key to understanding how adult exposures to phthalates affects reproductive health lies within sperm epigenetics and physiology. Therefore, our ViCTER objectives are to determine the effects of adult male exposure to phthalates on: 1) small noncoding RNA (sncRNA) in extracellular vesicles (EVs) (Dr. Pilsner); 2) sperm histone methylation (Dr. Kimmins); and 3) sperm capacitation, IVF and embryo development (Dr. Visconti). For our first aim, we will examine the associations of paternal phthalate exposure on sncRNA expression from extracellular vesicles (EVs) of mice and men. Next, we will examine the effect of adult male exposure to phthalates on histone methylation in sperm from mice and men. Finally, we will determine the effect of adult mouse exposure to DEHP, DBP and its mixture on sperm capacitation, acrosome reaction and subsequent embryo development. The proposed research is expected to uncover pathways linking paternal phthalate exposures with adverse reproductive outcomes via sperm physiology and epigenetics. 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.