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: 9363201
• 负责人: Joel Newman Meyer
• 金额: $ 29.17万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9363201
• 关键词: Affect; Arsenic; Biogenesis; Biological Models; Caenorhabditis elegans; Caloric Restriction; Cell Proliferation; Cell physiology; Chemicals; Chronic Disease; Conceptions; Development; Diet; Disease; 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 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; 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很高 执着的。这很关键，因为线粒体功能会影响与慢性有关的有机表型 诸如代谢疾病，癌症，神经退行性疾病和生殖疾病之类的疾病。 因此，影响线粒体的暴露可能会导致这些条件。持久的可能性 影响可能对生殖细胞和配子的暴露尤其重要，因为线粒体发生 生物发生和种系增殖和配子产生期间的主要功能变化。此外， 可能对细胞功能产生长期影响的表观遗传模式在同一时间重新编程 框架。我们将检验以下假设，即污染物暴露于生殖细胞中的线粒体导致 在持续的表观遗传变化中，避免了胚胎重编程和改变的调节 统治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，烤面包酮，甲基汞，吡咯霉素，氯芬酸和有机磷酸盐火焰 阻燃三苯磷酸盐。我们还将测试饮食限制（改善线粒体的饮食限制）是否存在 功能和热量超载具有相反的效果，将改变这些结果。如果是这样，这两个 加强我们对这些化学物质毒性作用的机械理解，并提供可能 治疗方法。这项工作将在线虫秀丽隐杆线虫中进行，以利用 线粒体和表观遗传学工具非常发达的，寿命迅速，最关键的是 遗传和其他工具的可用性，这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的能力 预先预防的有害线粒体影响（即暴露减少） 和治疗（即，用于改变线粒体功能的药理和生活方式干预措施）。