Determining how preconception exposure to phthalates impacts sperm function, the

确定孕前接触邻苯二甲酸盐如何影响精子功能，

基本信息

批准号：
10017234
负责人：
J. Richard Pilsner
金额：
$ 53.28万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-12 至 2021-03-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017234
关键词：
Acrosome Reaction Adult Affect Animal Model Bioinformatics Biological Biology Birth ChIP-seq Clinical Couples DNA Methylation DNA Sequence Data Data Analyses Developed Countries Development Diagnostic Dibutyl Phthalate Diethylhexyl Phthalate Disease Embryonic Development Endocrine Disruptors Environment Environmental Pollution Environmental Risk Factor Epigenetic Process Exposure to Extracellular Fluid Female Fertility Fertilization in Vitro Genetic Genetic Transcription Genome Genomic Segment Health Histone H3 Human In Vitro Infertility Knowledge Life Life Cycle Stages Link Lysine Meta-Analysis Metaphase Morbidity - disease rate Mus Nutritional Oocytes Outcome Pathway interactions Physiology Plastics Pregnancy Protocols documentation Public Health Publishing RNA RNA methylation Reproductive Biology Reproductive Health Research Risk Sampling Seminal Plasma Seminal fluid Sperm Capacitation Sperm Count Procedure Spermatogenesis Testing Toxicant exposure Translational Research Untranslated RNA androgenic base blastocyst chromatin immunoprecipitation cohort egg embryo quality epigenetic marker epigenome exposed human population extracellular vesicles functional genomics histone methylation human male male men mortality mouse model novel strategies offspring personal care products phthalates pregnant prevent pup reproductive reproductive tract research and development sperm analysis sperm cell sperm function sperm quality time-to-pregnancy toxicant transcriptome sequencing zygote

项目摘要

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.

概括不孕不育是最常见的生殖健康疾病之一，影响着美国 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已经下降过去四十年下降了50%以上。在大多数情况下都没有扭转这种下降趋势的迹象近年来，我们可能不仅面临生育危机，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)。鉴于精子数量急剧减少短期内的质量，可能不是遗传影响，而是环境因素生命历程中所遇到的。特别是邻苯二甲酸盐，一类内分泌干扰化合物 (EDC) 用于塑料和个人护理产品，是普遍存在的环境污染物，导致广泛人类暴露。 ViCTER 机制提供了一个独特的机会来加强跨学科和转化研究。因此，我们的研究团队准备确定父亲的先入之见如何邻苯二甲酸盐利用正在进行的研究影响精子功能、表观基因组和早期生命发育在小鼠模型（R01：ES028214；PI：Pilsner 博士）和接受体外受精 (IVF) 作为一部分的夫妇中人类队列（精子环境表观遗传学和发育研究；SEEDS：R01：ES028298；PI：Dr. 比尔森啤酒）。我们假设了解成人接触邻苯二甲酸盐如何影响生殖的关键精子的健康取决于表观遗传学和生理学。因此，我们的 ViCTER 目标是确定成年男性接触邻苯二甲酸盐对以下方面的影响： 1) 细胞外囊泡 (EV) 中的小非编码 RNA (sncRNA) （比尔森博士）； 2) 精子组蛋白甲基化（Kimmins 博士）； 3) 精子获能、体外受精和胚胎发展（维斯康蒂博士）。对于我们的第一个目标，我们将检查父亲邻苯二甲酸盐暴露与小鼠和人的细胞外囊泡 (EV) 的 sncRNA 表达。接下来我们来看看成人的效果男性接触邻苯二甲酸盐对小鼠和男性精子中组蛋白甲基化的影响。最后，我们将确定成年小鼠接触 DEHP、DBP 及其混合物对精子获能、顶体反应和随后的胚胎发育。拟议的研究预计将揭示父系之间的联系途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结果。暴露和结果连续体之间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途径治疗和预防不良生殖健康的方法。