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.

概括不育是影响美国16％的最常见的生殖健康障碍之一关于新的荟萃分析数据，表明发达国家中的精子计数在过去的四十年中，下降了50％以上。没有最大的迹象逆转这种向下的轨迹近年来，我们不仅可能面临生育危机，而且精子数量低下也更广泛的公共卫生含义包括发病率和死亡率的风险增加（3，4）。考虑到精子的这种急剧减少质量在短时间内，遗传影响可能不是可归因于遗传的，而是环境因素在生命过程中遇到。特别是邻苯二甲酸盐，一类内分泌破坏化合物（EDC）用于塑料和个人护理产品，无处不在的环境污染物导致广泛人类暴露。 Victer机制为增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率如何邻苯二甲酸盐通过利用正在进行的研究来影响精子功能，表观基因组和早期发展在小鼠模型（R01：ES028214; PI：PILSNER博士）和经过体外受精（IVF）的夫妻中人类队列（精子环境表观遗传学和发展研究；种子：R01：es028298; pi：Dr. 皮尔斯纳）。我们假设了解成年人对邻苯二甲酸盐如何影响生殖的关键健康位于精子表观遗传学和生理学中。因此，我们的维克特目标是确定成年男性暴露于邻苯二甲酸盐的影响：1）细胞外囊泡中的小非编码RNA（SNCRNA）（EV）（比尔斯纳博士）； 2）精子组蛋白甲基化（Kimmins博士）； 3）精子电容，IVF和胚胎开发（维斯科蒂博士）。为了我们的第一个目的，我们将研究父亲邻苯二甲酸盐的关联小鼠和男性细胞外囊泡（EV）的SncRNA表达。接下来，我们将研究成人的效果雄性暴露于小鼠和男性精子中组蛋白甲基化的邻苯二甲酸盐。最后，我们将确定成年小鼠暴露于DEHP，DBP及其混合物对精子电容，Adrosos反应和随后的胚胎发育。预计拟议的研究将发现与父亲联系的途径通过精子生理学和表观遗传学的邻苯二甲酸盐暴露，具有不良生殖结果。暴露和结果连续体之间潜在的中间途径的表征是重要的重要性，因为它将为转化研究的途径提供详尽的发展治疗和预防不良生殖健康的方法。