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

• 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
• 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

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.

项目总结/文摘

项目成果

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

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
• 作者: Liu J;Yu C;Doherty TM;Akbari O;Allard P;Rehan VK
• 通讯作者: Rehan VK

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
• 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

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

Challenging dogmas: How transgenerational epigenetics reshapes our views on life.

• DOI: 10.1002/jez.2465
• 发表时间: 2022-01
• 期刊: Journal of experimental zoology. Part A, Ecological and integrative physiology
• 作者: Wang HD;Allard P
• 通讯作者: Allard P