Embryonic inheritance of sperm methylome after adult exposure to phthalates

成人接触邻苯二甲酸盐后精子甲基化组的胚胎遗传

• 批准号: 9315151
• 负责人: Jesse Mager
• 金额: $ 20.97万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9315151
• 关键词: Adult; Adverse effects; Affect; Age; Alleles; Animal Model; Animals; Area; Biological Models; Body Weight; Cells; Conceptus; Couples; DNA Methylation; Data; Development; Diethylhexyl Phthalate; Disease; Embryo; Endocrine Disruptors; Environmental Exposure; Environmental Health; Environmental Pollution; Epigenetic Process; Exposure to; Female; Fertilization; Future; Gene Expression; Gene Expression Profiling; Genetic; Genome; Genomics; Germ Cells; Goals; Health; Heritability; Hybrids; Infertility; Interdisciplinary Study; Investigational Therapies; Knowledge; Massachusetts; Mus; Newborn Infant; Nutritional; Parents; Partner in relationship; Phenotype; Placenta; Plasticizers; Plastics; Pregnancy; Prevention; Regulation; Reporting; Reproductive Health; Research; Time; Tissues; Toxicology; Universities; adverse outcome; bisulfite sequencing; epidemiologic data; epigenomics; exposed human population; fetal; frontier; genome-wide; high reward; high risk; male; methylome; multidisciplinary; offspring; personal care products; phthalates; prenatal; reproductive; reproductive success; sperm cell; sperm quality; toxicant; transcriptome sequencing; whole genome

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 sperm-derived effect. A growing body of compelling data demonstrates that environmental exposures can be embodied within the developing male germ cell through epigenetic marks, which in turn, can impart information at fertilization to affect the trajectory of health and development of offspring. It is known that prenatal epigenetic reprogramming of male germ cells is a particularly susceptible window to environmental exposures such as phthalates. Research has now emerged demonstrating that other such susceptible windows exist during germ cell development. Our long- term goal is to provide an epigenetic understanding of how paternal EDC exposure affects reproductive and offspring health – in both embryonic and placental tissue. The objective here is to determine the effects of adult exposure to di(2-ethylhexyl) phthalate (DEHP) on sperm DNA methylation and the persistence of these sperm-derived changes on DNA methylation programming of the conceptus. Our central hypothesis is that adult DEHP exposure confers DNA methylation changes in sperm that persist in F1 conceptus. Adult reproductive age (7-8 wks old) male PWD mice will be treated with 0, 2.5 and 250 mg/kg body weight/day of DEHP for 60 days. Epididymal sperm will be collected and will be analyzed for whole genome bisulfite sequencing. Using parental strains that will allow for allele specific analysis across the genome, we will perform RNA-seq and whole genome bisulfite sequencing in embryonic and extraembryonic (placenta) tissues of E6.5 embryos. The research proposed in the above aims is expected to identify a DNA methylation signature in sperm as well as in the developing conceptus as a consequence of DEHP exposure in adult male mice. Such results are the first step to significantly advance our understanding of the mechanisms by which paternal environmental exposures in adulthood affect reproductive health, successful development and offspring health.

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）， 是普遍存在的环境污染物，导致人类广泛接触。流行病学数据 邻苯二甲酸盐与不良生殖健康有关，包括精子质量差等 最近，随着怀孕时间的延长-后者表明精子来源的影响。越来越多的 令人信服的数据表明，环境暴露可以体现在发展中的男性 生殖细胞通过表观遗传标记，这反过来又可以在受精时传递信息，影响轨迹 健康和后代的发展。众所周知，男性生殖细胞的产前表观遗传重编程 细胞是对环境暴露如邻苯二甲酸盐特别敏感的窗口。研究已经 这表明在生殖细胞发育过程中存在其他此类易感窗口。我们长久以来- 长期目标是提供一个表观遗传学的理解，如何父亲EDC暴露影响生殖和 后代的健康-在胚胎和胎盘组织中。这里的目标是确定 成人暴露于邻苯二甲酸二（2-乙基己基）酯（DEHP）对精子DNA甲基化的影响及其持续性 精子来源的变化对孕体DNA甲基化编程的影响。我们的核心假设是， 成人DEHP暴露导致精子DNA甲基化改变，并持续存在于F1孕体中。成人 将用0、2.5和250 mg/kg体重/天的 DEHP 60天。将收集附睾精子，并分析全基因组亚硫酸氢盐 测序使用允许在基因组中进行等位基因特异性分析的亲本菌株，我们将 在胚胎和胚外（胎盘）中进行RNA-seq和全基因组亚硫酸氢盐测序 E6.5胚胎。在上述目的中提出的研究有望鉴定DNA甲基化 由于成年男性暴露于DEHP，精子和发育中的孕体中的特征 小鼠这样的结果是第一步，以显着推进我们的机制， 成年期父亲的环境暴露影响生殖健康、成功发育和 后代健康