Department of Animal Sciences, Michigan State University, East Lansing, Michigan 48824.
Department of Environmental Health Sciences, University of Michigan, Ann Arbor, Michigan 48109.
Toxicol Sci. 2020 Nov 1;178(1):16-25. doi: 10.1093/toxsci/kfaa129.
Recent studies implicate mitochondrial dysfunction in the development and progression of numerous chronic diseases, which may be partially due to modifications in mitochondrial DNA (mtDNA). There is also mounting evidence that epigenetic modifications to mtDNA may be an additional layer of regulation that controls mitochondrial biogenesis and function. Several environmental factors (eg, smoking, air pollution) have been associated with altered mtDNA methylation in a handful of mechanistic studies and in observational human studies. However, little is understood about other environmental contaminants that induce mtDNA epigenetic changes. Numerous environmental toxicants are classified as endocrine disrupting chemicals (EDCs). Beyond their actions on hormonal pathways, EDC exposure is associated with elevated oxidative stress, which may occur through or result in mitochondrial dysfunction. Although only a few studies have assessed the impacts of EDCs on mtDNA methylation, the current review provides reasons to consider mtDNA epigenetic disruption as a mechanism of action of EDCs and reviews potential limitations related to currently available evidence. First, there is sufficient evidence that EDCs (including bisphenols and phthalates) directly target mitochondrial function, and more direct evidence is needed to connect this to mtDNA methylation. Second, these and other EDCs are potent modulators of nuclear DNA epigenetics, including DNA methylation and histone modifications. Finally, EDCs have been shown to disrupt several modulators of mtDNA methylation, including DNA methyltransferases and the mitochondrial transcription factor A/nuclear respiratory factor 1 pathway. Taken together, these studies highlight the need for future research evaluating mtDNA epigenetic disruption by EDCs and to detail specific mechanisms responsible for such disruptions.
最近的研究表明，线粒体功能障碍与许多慢性疾病的发生和发展有关，这可能部分归因于线粒体 DNA（mtDNA）的修饰。越来越多的证据表明，mtDNA 的表观遗传修饰可能是控制线粒体生物发生和功能的另一个调节层。一些环境因素（例如吸烟、空气污染）已经在少数机制研究和观察性人类研究中与 mtDNA 甲基化的改变有关。然而，对于其他诱导 mtDNA 表观遗传变化的环境污染物知之甚少。许多环境毒物被归类为内分泌干扰化学物质（EDCs）。除了对激素途径的作用外，EDC 暴露还与氧化应激增加有关，氧化应激可能通过或导致线粒体功能障碍发生。尽管只有少数研究评估了 EDCs 对 mtDNA 甲基化的影响，但本综述提供了理由，认为 mtDNA 表观遗传破坏是 EDCs 的作用机制，并回顾了与现有证据相关的潜在局限性。首先，有足够的证据表明 EDCs（包括双酚类和邻苯二甲酸酯）直接靶向线粒体功能，需要更多的直接证据将其与 mtDNA 甲基化联系起来。其次，这些和其他 EDCs 是核 DNA 表观遗传学的有效调节剂，包括 DNA 甲基化和组蛋白修饰。最后，已经表明 EDCs 会破坏 mtDNA 甲基化的几个调节剂，包括 DNA 甲基转移酶和线粒体转录因子 A/核呼吸因子 1 途径。综上所述，这些研究强调了未来研究评估 EDC 对 mtDNA 表观遗传破坏的必要性，并详细说明负责这种破坏的具体机制。
