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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：
10223303
负责人：
Ulrike Luderer
金额：
$ 52.93万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223303
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 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 Hereditary Disease 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 Spermatocytes 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.

项目总结/摘要今天活着的美国妇女中有150多万人已经或将要被诊断为早产儿。卵巢功能衰竭（POF）在他们的一生中，一个未知的，可能更大的数字将有早期绝经期不符合POF的诊断标准。POF的特征是加速消耗卵泡和卵母细胞质量下降，但90%的病例原因不明。多环芳香烃（PAH）是由有机材料的不完全燃烧形成的。妇女通过食物、空气污染和烟草烟雾无处不在地暴露于苯并[a]芘（BaP）和其他多环芳烃。bap 是一种强效的卵毒素，发育中的卵巢特别敏感。接触烟草烟雾，含有高浓度的BaP和其他多环芳烃，与生殖力下降和早期在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在F1雌性小鼠中，在原始生殖细胞迁移期间，通过减数分裂的开始，以不影响母体卵泡数量的剂量给后代注射。我们进一步表明，由于谷氨酸修饰亚基缺乏，导致抗氧化剂谷胱甘肽（GSH）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仔更敏感。我们的初步数据进一步表明BaP诱导培养的胎儿卵巢生殖细胞凋亡， Gclm基因敲除卵巢对BaP诱导的生殖细胞凋亡更敏感。在目前的提案中，我们将检验苯并（a）芘通过诱导氧化应激消耗产前卵巢生殖细胞的假设和凋亡，同时诱导存活生殖细胞的遗传表观遗传变化，加速了后代卵泡的耗竭，GSH具有保护作用，对抗这些影响。我们将从两个方面来检验这一假设：1）建立一个临界窗口，苯并（a）芘经胎盘卵毒性的发展和机制，并通过以下方法确定其机制： GSH在关键窗口期间调节BaP诱导的卵毒性。我们将在体内使用互补的经胎盘暴露和培养的胚胎卵巢模型。我们将测试补充GSH和其他抗氧化剂。2)产前检查卵巢表型是否暴露 BaP是跨代的，由生殖系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评估整体DNA甲基化，与对照谱系相比，来自BaP暴露的F1、F2和F3原始生殖细胞的测序。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glutathione deficiency sensitizes cultured embryonic mouse ovaries to benzo[a]pyrene-induced germ cell apoptosis.

DOI：
10.1016/j.taap.2018.05.024
发表时间：
2018-08-01
期刊：
Toxicology and applied pharmacology
影响因子：
3.8
作者：
Lim J;Luderer U
通讯作者：
Luderer U

DNA methylome of human neonatal umbilical cord: Enrichment of differentially methylated regions compared to umbilical cord blood DNA at transcription factor genes involved in body patterning and effects of maternal folate deficiency or children's sex.

人类新生儿脐带的 DNA 甲基化组：与脐带血 DNA 相比，转录因子基因的差异甲基化区域富集，这些转录因子基因涉及身体模式以及母体叶酸缺乏或儿童性别的影响。

DOI：
10.1371/journal.pone.0214307
发表时间：
2019
期刊：
PloS one
影响因子：
3.7
作者：
Sakurai,Kenichi;Shioda,Keiko;Eguchi,Akifumi;Watanabe,Masahiro;Miyaso,Hidenori;Mori,Chisato;Shioda,Toshi
通讯作者：
Shioda,Toshi