The School of Marine Sciences, University of Maine, Orono, ME 04469, USA.
The School of Marine Sciences, University of Maine, Orono, ME 04469, USA.
Comp Biochem Physiol C Toxicol Pharmacol. 2020 Jul;233:108759. doi: 10.1016/j.cbpc.2020.108759. Epub 2020 Apr 4.
Mitochondria are integral to maintaining cellular homeostasis. Optimum mitochondrial function is critical during embryonic development, as they play a key role in early signaling cascades and epigenetic programming, in addition to sustaining an adequate energy production. Mitochondria are sensitive targets of environmental toxins, potentially even at levels considered safe under current regulatory limits. Most mitochondrial analyses have focused only on chemical exposure effects in vitro or in isolated mitochondria. However, comparatively little is known about mitochondrial effects of chemical exposure during vertebrate embryogenesis, especially during the recovery phase following a chemical insult. Here, we used the zebrafish (Danio rerio), in a 96-well plate system, to examine mitochondrial effects of 24 chemicals including pharmaceuticals, industrial chemicals, and agrochemicals. We used oxygen consumption rate (OCR) during embryogenesis as a proxy for mitochondrial function. Embryonic OCR (eOCR) was measured in clean egg water immediately following 24 h of chemical exposure and subsequently for an additional 8 h. Each chemical, dependent upon the concentration, resulted in a unique eOCR response profile. While some eOCR effects were persistent or recoverable over time, some effects were only detected several hours after being removed from the exposure. Non-monotonic dose response effects as well as mitochondrial hormesis were also detected following exposure to some chemicals. Collectively, our study shows that mitochondrial response to chemicals are highly dynamic and warrant careful consideration when determining mitochondrial toxicity of a given chemical.
线粒体对于维持细胞内稳态至关重要。在胚胎发育过程中，最佳的线粒体功能至关重要，因为它们在早期信号级联和表观遗传编程中发挥关键作用，此外还维持足够的能量产生。线粒体是环境毒素的敏感靶标，即使在当前监管限制下被认为安全的水平下，也可能如此。大多数线粒体分析仅集中于体外或分离的线粒体中的化学暴露效应。然而，对于化学暴露在脊椎动物胚胎发生期间，特别是在化学损伤后的恢复阶段对线粒体的影响，知之甚少。在这里，我们使用斑马鱼（Danio rerio）在 96 孔板系统中，研究了 24 种化学物质包括药物、工业化学品和农用化学品对线粒体的影响。我们使用胚胎期的耗氧量（OCR）作为线粒体功能的替代物。在化学暴露 24 小时后，立即在清洁的卵水中测量胚胎期的 OCR（eOCR），随后再测量 8 小时。每种化学物质根据浓度会导致独特的 eOCR 反应谱。虽然一些 eOCR 效应是持久的或随着时间的推移可恢复的，但有些效应仅在从暴露中去除数小时后才被检测到。一些化学物质暴露后还检测到非单调剂量反应效应和线粒体兴奋效应。总之，我们的研究表明，化学物质对线粒体的反应是高度动态的，在确定给定化学物质的线粒体毒性时需要仔细考虑。
