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Male preconception phthalates and offspring embryo and sperm allele-specific methylome programming.

男性孕前邻苯二甲酸盐和后代胚胎和精子等位基因特异性甲基化组编程。

基本信息

批准号：
10414482
负责人：
J. Richard Pilsner
金额：
$ 43.31万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414482
关键词：
Adult Adult Children Affect Alleles Animal Model Bioinformatics Biological Models Cells Conceptus DNA Methylation Data Development Dibutyl Phthalate Diethylhexyl Phthalate Disease Embryo Embryonic Development Endocrine Disruptors Environment Environmental Exposure Environmental Health Environmental Pollution Epigenetic Process Exposure to Female Fertilization Gene Expression Genetic Genome Genomics Germ Cells Goals Health Heritability Human Hybrids Interdisciplinary Study Knowledge Link Massachusetts Methylation Mus Nutritional Oocytes Partner in relationship Placenta Plastics Prevention Regulation Reporting Reproductive Health Research Spermatocytes Spermatogenesis Staging Time Tissues Toxicology Translational Research Universities androgenic animal data behavioral health bisulfite sequencing embryo tissue epidemiologic data exposed human population fetal frontier male methylome multidisciplinary novel strategies offspring personal care products phthalates prenatal reproductive reproductive hormone research and development sperm cell sperm quality time-to-pregnancy toxicant transcriptome sequencing whole genome

项目摘要

Project 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 objective is to determine the effects of adult exposure to di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DBP) and the mixture of DEHP and DBP on sperm DNA methylation and the persistence of sperm-derived changes on DNA methylation programming of the conceptus and F1 adult germ cells. We will exposure adult reproductive age male C57BL/6J mice with 0, 2.5 mg/kg/day of DEHP, 2.5 mg/kg/day of DBP, and its mixture (DEHP and DBP each at 2.5 mg/kg/day) for 70 days – approximately two spermatogenesis cycles. Epididymal sperm will be collected from mice in each group and will be analyzed for whole genome bisulfite sequencing (WGBS). Next, exposed C57BL/6J males will be mated with unexposed DBA/2Jfemales, which will allow for allele- specific analysis across the genome in the F1 hybrid embryos produced. We will perform RNA-seq and WGBS in embryonic and placental cells of gastrulating E6.5 embryos to determine the effects of paternal DEHP and/or DBP on each distinct lineage. Finally, we will analyze sperm quality parameters, oocyte follicle staging and reproductive hormones in male and female F1 offspring. We will also perform RNA-seq and WGBS on F1 sperm and oocytes. This research proposed is expected to identify an epigenetic understanding via sperm methylation of the effects of preconception male EDC exposure and offspring reproductive health. Understanding the involvement of sperm epigenetics within the exposure-disease paradigm will inform avenues of translational research for the development of novel approaches for the treatment and prevention of adverse reproductive health.

项目摘要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，最近，随着怀孕时间的延长-后者表明精子衍生的影响。越来越多的引人注目的数据表明环境暴露可以体现在发育中的男性生殖细胞中，表观遗传标记，这反过来又可以在受精时传递信息，影响健康的轨迹，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是一个重要的遗传学过程。特别是对环境暴露如邻苯二甲酸盐敏感的窗户。研究表明，这表明在生殖细胞发育过程中存在其他这样的易感窗口。我们的目标是确定成人暴露于邻苯二甲酸二（2-乙基己基）酯（DEHP）、邻苯二甲酸二正丁酯（DBP）和 DEHP和DBP混合对精子DNA甲基化的影响，精子源性变化的持续性孕体和F1成体生殖细胞的DNA甲基化编程。我们将暴露成年生殖年龄的雄性C57 BL/6 J小鼠，给予0、2.5 mg/kg/天DEHP、2.5 mg/kg/天DBP及其混合物（DEHP和 DBP各2.5 mg/kg/天）持续70天-约两个精子发生周期。附睾精子会从每组小鼠中收集，并分析全基因组亚硫酸氢盐测序（WGBS）。接下来，暴露的C57 BL/6 J雄性将与未暴露的DBA/2 J雌性交配，这将允许等位基因- 在所产生的F1杂种胚胎中进行跨基因组的特异性分析。我们将进行RNA测序和WGBS 在原肠形成E6.5胚胎的胚胎和胎盘细胞中，以确定父本DEHP和/或 DBP在每个不同的谱系上。最后，我们将分析精子质量参数、卵母细胞卵泡分期和雄性和雌性F1后代的生殖激素。我们还将在F1上进行RNA-seq和WGBS 精子和卵母细胞。这项研究预计将通过精子识别表观遗传理解甲基化对孕前男性EDC暴露和后代生殖健康的影响。了解精子表观遗传学在精子-疾病范例中的参与将为我们提供信息，转化研究的途径，以开发新的方法，用于治疗和预防有害生殖健康。