Does exposure to mitochondrial toxicants during germ cell development result in lifelong alterations in mitochondrial function mediated by epigenetic changes?

在生殖细胞发育过程中接触线粒体毒物是否会导致由表观遗传变化介导的线粒体功能的终生改变？

• 批准号: 10246312
• 负责人: Joel Newman Meyer
• 金额: $ 30.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246312
• 关键词: Affect; Arsenic; Biogenesis; Biological Models; Caenorhabditis elegans; Caloric Restriction; Cell Proliferation; Cell physiology; Chemicals; Chronic Disease; Conceptions; Development; Elderly; Embryo; Environmental Exposure; Epigenetic Process; Etiology; Exercise; Exposure to; Flame Retardants; Genes; Genetic; Genetic Transcription; Genomic Segment; Germ Cells; Glucose; Health; Heritability; Homeostasis; Individual; Investigation; Knowledge; Lead; Life; Link; Long-Term Effects; Longevity; Maintenance; Malignant Neoplasms; Measures; Mediating; Meiosis; Membrane Potentials; Mercury; Messenger RNA; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Organophosphates; Outcome; Parents; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Ploidies; Predisposition; Prevention; Production; Regulation; Reproduction; Respiration; Role; Rotenone; Signal Pathway; Stress; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Work; combinatorial; diet and exercise; dietary; dietary restriction; egg; environmental chemical; environmental chemical exposure; epigenome; genetic manipulation; genome-wide; histone modification; improved; inorganic phosphate; knock-down; lifestyle intervention; middle age; mitochondrial metabolism; mutant; offspring; pollutant; reproductive system disorder; respiratory; sperm cell; tool; toxicant; transcriptome; transcriptomics; transmission process

Growing evidence suggests that the toxic effects of certain chemicals on mitochondrial function can be highly persistent. This is critical because mitochondrial function influences organismal phenotypes related to chronic diseases such as metabolic diseases, cancers, neurodegenerative diseases, and reproductive disorders. Therefore, exposures affecting mitochondria could contribute to these conditions. The likelihood of persistent effects may be especially great for exposures of germ cells and gametes, because mitochondria undergo biogenesis and major functional changes during germline proliferation and gamete production. Furthermore, epigenetic patterns that can have long-term effects on cellular function are reprogrammed in the same time frame. We will test the hypothesis that pollutant exposures targeting mitochondria in germ cells result in persistent epigenetic changes that escape embryonic reprogramming and alter regulation of pathways governing mitochondrial metabolism in offspring. We will test six important mitochondrial toxicants: arsenic, rotenone, methyl mercury, pyraclostrobin, chlorfenapyr, and the organophosphate flame retardant triphenyl phosphate. We will also test whether dietary restriction, which improves mitochondrial function, and caloric overload, which has the opposite effect, will alter these outcomes. If so, this would both reinforce our mechanistic understanding of the toxic effects of these chemicals, and provide a possible therapeutic approach. This work will be carried out in the nematode Caenorhabditis elegans to take advantage of very well-developed mitochondrial and epigenetic genetic tools, a rapid lifespan, and, most critically, the availability of genetic and other tools that will allow us to mechanistically test the causality of observed epigenetic and transcriptomic changes. Ultimately, this knowledge will improve our ability to reduce the deleterious mitochondrial impacts of preconception exposures both by prevention (i.e., reduced exposures) and treatment (i.e., pharmacological and lifestyle interventions to alter mitochondrial function).

越来越多的证据表明某些化学物质对线粒体功能的毒性作用可能非常严重 执着的。这是至关重要的，因为线粒体功能影响与慢性病相关的有机体表型 代谢性疾病、癌症、神经退行性疾病和生殖障碍等疾病。 因此，影响线粒体的暴露可能会导致这些情况。持续的可能性 对于生殖细胞和配子的暴露影响可能特别大，因为线粒体会经历 种系增殖和配子产生过程中的生物发生和主要功能变化。此外， 对细胞功能产生长期影响的表观遗传模式同时被重新编程 框架。我们将检验以下假设：针对生殖细胞中线粒体的污染物暴露会导致 持续的表观遗传变化逃避了胚胎重编程并改变了 控制后代线粒体代谢的途径。我们将测试六个重要的线粒体 有毒物质：砷、鱼藤酮、甲基汞、唑菌胺酯、虫螨腈和有机磷火焰 阻燃剂磷酸三苯酯。我们还将测试饮食限制是否会改善线粒体 功能和热量超负荷会产生相反的效果，会改变这些结果。如果是这样的话，这将既 加强我们对这些化学品毒性作用的机制理解，并提供可能的解决方案 治疗方法。这项工作将在线虫秀丽隐杆线虫中进行，以利用 非常发达的线粒体和表观遗传工具，快速的寿命，最重要的是， 遗传和其他工具的可用性将使我们能够机械地测试观察到的因果关系 表观遗传和转录组变化。最终，这些知识将提高我们减少 通过预防（即减少暴露）来预防孕前暴露对线粒体的有害影响 和治疗（即通过药物和生活方式干预来改变线粒体功能）。