Determining how preconception exposure to phthalates impacts sperm function, the

摘要 不孕不育是美国最常见的生殖健康疾病之一，影响着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40年里下降了50%以上。在最大程度上没有扭转这一下降轨迹的迹象 近年来，我们可能不仅面临着生育危机，而且精子数量低也会影响更广泛的公共健康 影响包括发病率和死亡率增加的风险(3、4)。鉴于精子数量的急剧减少 在短期内，遗传影响可能不是环境因素造成的，而是环境因素造成的 在一生中遇到过的。尤其是邻苯二甲酸酯，一类内分泌干扰化合物(EDCs) 用于塑料和个人护理产品，是普遍存在的环境污染物，导致广泛的 人体接触。维克特机制提供了一个独特的机会，以加强跨学科和 翻译研究。因此，我们的研究团队准备确定父亲的先入为主 利用正在进行的研究，邻苯二甲酸酯影响精子功能、表观基因组和早期生命发育 在小鼠模型(R01：ES028214；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：R01：ES028298；PI：Dr. 皮尔斯纳)。我们假设，理解成人接触邻苯二甲酸盐如何影响生殖的关键 健康在于精子的表观遗传学和生理学。因此，我们的胜利者目标是确定 成年男性接触邻苯二甲酸盐对：1)细胞外小泡中非编码小RNA(SNcRNA)的影响 (皮尔斯纳博士)；2)精子组蛋白甲基化(金明斯博士)；以及3)精子获能、试管受精和胚胎 发展(维斯康蒂博士)。为了我们的第一个目标，我们将研究父亲接触邻苯二甲酸盐与 小鼠和人细胞外小泡(EVS)SNcRNA的表达。接下来，我们将考察成人的影响 男性暴露于邻苯二甲酸盐对小鼠和男性精子组蛋白甲基化的影响。最后，我们将确定 成年小鼠暴露于DEHP、DBP及其混合物对精子获能、顶体反应和精子的影响 随后的胚胎发育。这项拟议中的研究有望揭示连接父亲和父亲的路径 邻苯二甲酸盐暴露通过精子生理学和表观遗传学产生不良生殖后果。 暴露和结果连续体之间的潜在中间途径的特征是 非常重要，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 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.