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

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是非常严重的。 坚持不懈这是至关重要的，因为线粒体功能影响与慢性炎症相关的生物体表型。 疾病如代谢疾病、癌症、神经变性疾病和生殖障碍。 因此，影响线粒体的暴露可能导致这些情况。持续的可能性 对生殖细胞和配子的影响可能特别大，因为线粒体经历了 生殖细胞增殖和配子产生过程中的生物发生和主要功能变化。此外，委员会认为， 对细胞功能有长期影响的表观遗传模式在同一时间被重新编程， frame.我们将检验以下假设，即针对生殖细胞中线粒体的污染物暴露导致 在持续的表观遗传变化，逃避胚胎重编程和改变调节 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、吡唑醚菌酯、溴虫腈和有机磷火焰 阻燃剂磷酸三苯酯我们还将测试是否饮食限制，这改善线粒体 功能和热量过载，具有相反的效果，将改变这些结果。如果是这样的话， 加强我们对这些化学物质的毒性作用的机械理解，并提供一个可能的 治疗方法这项工作将在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，使我们能够机械地测试所观察到的因果关系， 表观遗传学和转录组学变化。最终，这些知识将提高我们减少 通过预防（即，减少暴露） 和治疗（即，药理学和生活方式干预以改变线粒体功能）。

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).