Mechanisms of environmental epigenetic disruption and memory of exposure in germ cells

环境表观遗传破坏机制和生殖细胞暴露记忆

基本信息

批准号：
10112905
负责人：
Patrick Allard
金额：
$ 40.81万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112905
关键词：
Address Affect Biological Models Caenorhabditis elegans Candidate Disease Gene Cell Death Cell Differentiation process Cell model Cell physiology Cells Chemical Exposure Chemicals Chromatin Complex Congenital Abnormality DNA DNA Methylation Defect Development Dissection Dose Embryo Embryonic Development Environmental Exposure Environmental Impact Epigenetic Process Exposure to Failure Flame Retardants Generations Genes Genetic Genetic Models Genetic Transcription Genomic Instability Germ Cells Goals Health Heritability Histones Human Hypogonadism In Vitro Infertility Lead Maintenance Mediating Memory Methods Modeling Molecular Monitor Mus Nematoda Organism Outcome Parents Pathway interactions Pattern Pharmaceutical Preparations Physiological Plant Roots Regulation Repetitive Sequence Reporting Reproduction Research Retrotransposon Sterility Structure of primordial sex cell Testing Time Tissues Toxic effect Toxicology United States Work bisphenol A demethylation embryonic stem cell environmental agent environmental chemical epigenome experimental study genome-wide histone modification infant death innovation novel prevent programs reproductive reproductive fitness reproductive function reproductive outcome response screening transcriptome transgenerational epigenetic inheritance transmission process

项目摘要

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to identify the mechanisms of germ cell sensitivity to environmental exposures and their long-lasting, transgenerational effects. Germ cells are the bridge between generations and their integrity is paramount to the health and viability of all organisms. As such, the dysregulation of germ cells development and function significantly contributes to infertility and is also the leading cause of birth defects and infant deaths in the United States. While the intricate steps of germ cell development have long been hypothesized to provide unique windows of sensitivity to environmental insults, little is known of the effect of chemical exposure on the epigenome of germ cells and of the mechanisms of inheritance of these effects. This gap is particularly significant as embryonic germ cells undergo an extensive remodeling of their chromatin which includes genome-wide demethylation and the establishment of a complex pattern of histone modifications. The failure to properly regulate these histone marks leads to spurious repetitive element expression, germ cell death and infertility. Furthermore, preliminary evidence gathered in the powerful genetic model system C. elegans indicates that exposure to chemicals such as Bisphenol A leads to a heritable, transgenerational defect in chromatin silencing of repetitive DNA. Here, we propose to leverage two complementary germ cell models, the nematode C. elegans and in vitro generated mouse germ cells, to elucidate the molecular mechanisms underlying the epigenetic effects of Bisphenol A. We will achieve this goal by (1) Characterizing the sensitivity of early mammalian germ cells to BPA exposure and establish the long term, transgenerational outcome on reproduction in C. elegans; (2) Providing a comprehensive and detailed examination of epimutations caused by BPA and of their transcriptional consequence; and finally by (3) Identifying the genetic requirements for both germ cell sensitivity to direct exposure as well as for the transmission of epigenetic effects across generations. We expect this research to provide a much-needed examination of the pathways implicated in the sensitivity of early germ cells to environmental insults and at the root of infertility.

项目摘要/摘要该项目的长期目标是确定生殖细胞的机制对环境暴露及其持久的转世效应的敏感性。生殖细胞是世代之间的桥梁，其完整性对所有生物的健康和生存能力。因此，生殖细胞的失调发展和功能显着促进不育，也是领先的美国出生缺陷和婴儿死亡的原因。而复杂的步骤长期以来，生殖细胞发育已被假设提供了独特的窗户对环境侮辱的敏感性，对化学暴露对化学的影响知之甚少生殖细胞的表观组和这些作用遗传的机制。由于胚胎细胞经历广泛染色质的重塑，包括全基因组脱甲基和建立复杂的组蛋白修饰模式。无法正确地调节这些组蛋白标记会导致虚假的重复元件表达，生殖细胞死亡和不育。此外，在强大的遗传中收集的初步证据模型系统C.秀丽隐杆线虫表明暴露于Bisphenol A等化学物质导致重复DNA的染色质沉默中可遗传的跨代缺陷。在这里，我们建议利用两个互补的生殖细胞模型，即线虫C.秀丽隐杆线虫和体外产生的小鼠生殖细胞，以阐明双酚A的表观遗传作用背后的分子机制。我们将通过（1）表征早期哺乳动物生殖细胞对 BPA暴露并建立长期的跨代结果在秀丽隐杆线虫中；（2）提供全面详细的评估检查由BPA及其转录后果引起；最后是（3）识别生殖细胞对直接暴露的敏感性以及世代相传的表观遗传效应的传播。我们希望这项研究能够对途径进行急需的检查与早期生殖细胞对环境侮辱的敏感性有关不育。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Perinatal nicotine exposure-induced transgenerational asthma: Effects of reexposure in F1 gestation.

DOI：
10.1096/fj.201902386r
发表时间：
2020-09
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Liu J;Yu C;Doherty TM;Akbari O;Allard P;Rehan VK
通讯作者：
Rehan VK

Histone Modifications: Epigenetic Mediators of Environmental Exposure Memory.

DOI：
10.1177/2516865718803641
发表时间：
2018
期刊：
Epigenetics insights
影响因子：
2.2
作者：
Camacho J;Allard P
通讯作者：
Allard P

A Vault-Encapsulated Enzyme Approach for Efficient Degradation and Detoxification of Bisphenol A and Its Analogues.

DOI：
10.1021/acssuschemeng.8b05432
发表时间：
2019-02
期刊：
ACS sustainable chemistry & engineering
影响因子：
8.4
作者：
Meng Wang;Yichang Chen;V. Kickhoefer;L. Rome;P. Allard;Shaily Mahendra
通讯作者：
Meng Wang;Yichang Chen;V. Kickhoefer;L. Rome;P. Allard;Shaily Mahendra

Protocol for nuclear dissociation of the adult C. elegans for single-nucleus RNA sequencing and its application for mapping environmental responses.

DOI：
10.1016/j.xpro.2023.102756
发表时间：
2023-12-15
期刊：
STAR PROTOCOLS
影响因子：
0
作者：
Levenson, Max T.;Barrere-Cain, Rio;Truong, Lisa;Chen, Yen-Wei;Shuck, Karissa;Panter, Blake;Reich, Ella;Yang, Xia;Allard, Patrick
通讯作者：
Allard, Patrick

Strength of Cu-efflux response in Escherichia coli coordinates metal resistance in Caenorhabditis elegans and contributes to the severity of environmental toxicity.