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Developmental Gene-Environment Interactions and Premature Ovarian Failure

发育基因-环境相互作用和卵巢早衰

基本信息

批准号：
9751860
负责人：
Ulrike Luderer
金额：
$ 55.41万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-10 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751860
关键词：
Affect Age-Months Air Pollution American Antioxidants Apoptosis Apoptotic Aromatic Polycyclic Hydrocarbons Benzo(a)pyrene Biological Markers Biological Monitoring Caspase Cell Count Chemicals Cohort Effect Cultured Cells DNA DNA Methylation Data Daughter Development Developmental Gene Diagnosis Diagnostic Disease Dose Embryo Environmental Pollutants Enzymes Epigenetic Process Exposure to Female Fertility Fetus Food GCLM gene Gene Expression Generations Genotype Germ Cells Germ Lines Glutamate-Cysteine Ligase Glutathione Gonadal structure Heritability Human Maternal-Fetal Exchange Measurement Measures Mediating Meiosis Metabolism Methylation Modeling Mothers Mus Oils Oocytes Oral Administration Ovarian Ovarian Follicle Ovary Oxidative Stress Phenotype Pregnancy Premature Menopause Premature Ovarian Failure Prevention Proliferating Publishing Risk Assessment Smoke Structure of primordial sex cell Supplementation Testing Time Tobacco smoke Toxicant exposure Umbilical Cord Blood Woman Work cell motility early onset environmental tobacco smoke exposure epigenomics experience exposed human population exposure route fetal gene environment interaction genome-wide in utero in vivo innovation mRNA Expression male meetings offspring oocyte quality ovarian failure ovotoxicant ovotoxicity pollutant pregnant premature prenatal prenatal exposure prevent protective effect transcriptome sequencing transcriptomics transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT More than 1.5 million of the American women alive today have been or will be diagnosed with premature ovarian failure (POF) during their lifetimes and an unknown, probably much larger number will have early menopause without meeting the diagnostic criteria for POF. POF is characterized by accelerated depletion of ovarian follicles and decreased oocyte quality, but the causes remain unknown in 90% of cases. Polycyclic aromatic hydrocarbons (PAHs) are formed by the incomplete combustion of organic materials. Women are ubiquitously exposed to benzo[a]pyrene (BaP) and other PAHs via food, air pollution, and tobacco smoke. BaP is a potent ovotoxicant, and the developing ovary is particularly sensitive. Exposure to tobacco smoke, which contains high concentrations of BaP and other PAHs, is associated with decreased fecundity and earlier menopause in the daughters of women who smoked during pregnancy. We have shown that prenatal exposure of mice to BaP during primordial germ cell migration through the onset of meiosis causes POF in the F1 female offspring at doses that do not affect ovarian follicle numbers in the mothers. We further showed that embryos deficient in synthesis of the antioxidant glutathione (GSH) due to deficiency in the modifier subunit of glutamate cysteine ligase (Gclm) are more sensitive to the transplacental ovotoxicity of BaP than wild type littermates. Our preliminary data further show that BaP induces apoptosis in germ cells of cultured fetal ovaries and that Gclm null ovaries are more sensitive to the induction of germ cell apoptosis by BaP. In the current proposal we will test the hypothesis that BaP depletes germ cells in the prenatal ovary by inducing oxidative stress and apoptosis, while inducing heritable epigenetic changes in surviving germ cells to cause accelerated depletion of ovarian follicles in subsequent generations, and that GSH is protective against these effects. We will test this hypothesis in two aims: 1) To establish the critical window of development for and mechanisms of the transplacental ovotoxicity of BaP and to define the mechanism by which GSH modulates BaP-induced ovotoxicity during the critical window. We will use complementary in vivo transplacental exposure and cultured embryonic ovary models. We will test the potential protective effects of supplementation with GSH and other antioxidants. 2) Test whether the ovarian phenotype of prenatal exposure to BaP is transgenerational and is mediated by epigenetic changes in the germ line. We will utilize RNA- sequencing to examine genomewide gene expression and will assess global DNA methylation using MBD- Sequencing in F1, F2, and F3 primordial germ cells from BaP exposed compared to control lineages.

项目概要/摘要今天，超过 150 万美国女性已经或将被诊断为早产儿在他们的一生中卵巢衰竭（POF），并且未知的，可能更多的人会早期患有卵巢功能衰竭（POF）绝经但不符合 POF 诊断标准。 POF 的特点是加速耗尽卵泡和卵母细胞质量下降，但 90% 的病例原因仍不清楚。多环芳香烃（PAH）是由有机材料不完全燃烧形成的。女人是通过食物、空气污染和烟草烟雾，我们普遍接触苯并[a]芘 (BaP) 和其他多环芳烃。苯并芘是一种强效的卵毒剂，发育中的卵巢特别敏感。接触烟草烟雾，这含有高浓度的 BaP 和其他 PAH，与生育力下降和早产有关怀孕期间吸烟的妇女的女儿更年期。我们已经证明，产前暴露小鼠在减数分裂开始时原始生殖细胞迁移过程中转化为 BaP 导致 F1 雌性 POF 后代的剂量不会影响母亲的卵泡数量。我们进一步表明，胚胎由于谷氨酸修饰亚基的缺乏，导致抗氧化剂谷胱甘肽 (GSH) 的合成不足半胱氨酸连接酶 (Gclm) 对 BaP 的经胎盘卵毒性比野生型同窝动物更敏感。我们的初步数据进一步表明，BaP 会诱导培养的胎儿卵巢生殖细胞凋亡，并且 Gclm 无效卵巢对 BaP 诱导的生殖细胞凋亡更敏感。在当前的提案中，我们将检验 BaP 通过诱导氧化应激消耗产前卵巢生殖细胞的假设和细胞凋亡，同时诱导存活生殖细胞的可遗传的表观遗传变化，从而导致后代卵泡加速消耗，GSH 具有保护作用对抗这些影响。我们将通过两个目标来检验这个假设：1）建立临界窗口 BaP 经胎盘卵毒性的发展和机制，并通过以下方式定义该机制： GSH 在关键窗口期间调节 BaP 诱导的卵毒性。我们将使用体内互补经胎盘暴露和培养胚胎卵巢模型。我们将测试潜在的保护作用补充谷胱甘肽和其他抗氧化剂。 2) 检测卵巢表型是否有产前暴露 BaP 的转变是跨代的，并且由种系中的表观遗传变化介导。我们将利用 RNA- 测序以检查全基因组基因表达，并将使用 MBD- 评估全局 DNA 甲基化与对照谱系相比，BaP 暴露的 F1、F2 和 F3 原始生殖细胞的测序。