Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA.
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA.
Toxicology. 2021 Apr 30;454:152744. doi: 10.1016/j.tox.2021.152744. Epub 2021 Mar 4.
Mitochondria are intracellular organelles responsible for biological oxidation and energy production. These organelles are susceptible to damage from oxidative stress and compensate for damage by increasing the number of copies of their own genome, mitochondrial DNA (mtDNA). Cancer and environmental exposure to some pollutants have also been associated with altered mtDNA copy number. Since exposures to polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have been shown to increase oxidative stress, we hypothesize that mtDNA copy number will be altered with exposure to these compounds. mtDNA copy number was measured in DNA from archived frozen liver and lung specimens from the National Toxicology Program (NTP) study of female Harlan Sprague Dawley rats exposed to TCDD (3, 10, or 100 ng/kg/day), dioxin-like (DL) PCB 126 (10, 100, or 1000 ng/kg/day), non-DL PCB 153 (10, 100, or 1000 μg/kg/day), and PCB 126 + PCB 153 (10 ng/kg/day + 10 μg/kg/day, 100 ng/kg/day + 100 μg/kg/day, or 1000 ng/kg/day + 1000 μg/kg/day, respectively) for 13 and 52 weeks. An increase in mtDNA copy number was observed in the liver and lung of rats exposed to TCDD and the lung of rats exposed to the mixture of PCB 126 and PCB 153. A statistically significant positive dose-dependent trend was also observed in the lung of rats exposed to PCB 126 and a mixture of PCB 153 and PCB 126, although in neither case was the control copy number significantly exceeded at any dose level. These exposures produced a range of pathological responses in these organs in the two-year NTP studies. Conversely, there was a significant decrease or no change in mtDNA copy number in the liver and lung of rats exposed to non-DL PCB 153. This is consistent with a general lack of PCB 153 mediated liver or lung injury in the NTP study, with the exception of liver hypertrophy. Together, the results suggest that an increase in mtDNA copy number may serve as a sensitive, early biomarker of mitochondrial injury and oxidative stress that contributes to the development of the toxicity of dioxin-like compounds.
线粒体是负责生物氧化和能量产生的细胞内细胞器。这些细胞器容易受到氧化应激的损害，并通过增加自身基因组（线粒体 DNA，mtDNA）的拷贝数来补偿损伤。癌症和环境暴露于某些污染物也与 mtDNA 拷贝数的改变有关。由于多氯联苯（PCBs）和 2,3,7,8-四氯二苯并对二恶英（TCDD）的暴露已被证明会增加氧化应激，我们假设暴露于这些化合物会改变 mtDNA 拷贝数。在国家毒理学计划（NTP）研究中，从冷冻的肝脏和肺组织的 DNA 中测量了暴露于 TCDD（3、10 或 100ng/kg/天）、类二恶英（DL）PCB126（10、100 或 1000ng/kg/天）、非-DL PCB153（10、100 或 1000μg/kg/天）和 PCB126+PCB153（分别为 10ng/kg/天+10μg/kg/天、100ng/kg/天+100μg/kg/天和 1000ng/kg/天+1000μg/kg/天）的雌性哈兰斯普拉格道利大鼠的 mtDNA 拷贝数。暴露于 TCDD 的大鼠的肝脏和肺以及暴露于 PCB126 和 PCB153 混合物的大鼠的肺中观察到 mtDNA 拷贝数增加。暴露于 PCB126 和 PCB153 混合物的大鼠的肺中还观察到统计学上显著的阳性剂量依赖性趋势，尽管在任何剂量水平下，对照拷贝数均未显著超过。这些暴露在两年的 NTP 研究中在这些器官中产生了一系列病理反应。相反，在暴露于非-DL PCB153 的大鼠的肝脏和肺中，mtDNA 拷贝数显著减少或没有变化。这与 NTP 研究中 PCB153 介导的肝脏或肺部损伤一般缺乏一致，除了肝肥大。总的来说，结果表明 mtDNA 拷贝数的增加可能作为线粒体损伤和氧化应激的敏感早期生物标志物，有助于二恶英样化合物毒性的发展。
