Nanotechnology offers innovation in products from cosmetics to drug delivery, leading to increased engineered nanomaterial (ENM) exposure. Unfortunately, health impacts of ENM are not fully realized. Titanium dioxide (TiO₂) is among the most widely produced ENM due to its use in numerous applications. Extrapulmonary effects following pulmonary exposure have been identified and may involve reactive oxygen species (ROS). The goal of this study was to determine the extent of ROS involvement on cardiac function and the mitochondrion following nano-TiO₂ exposure. To address this question, we utilized a transgenic mouse model with overexpression of a novel mitochondrially-targeted antioxidant enzyme (phospholipid hydroperoxide glutathione peroxidase; mPHGPx) which provides protection against oxidative stress to lipid membranes. MPHGPx mice and littermate controls were exposed to nano-TiO₂ aerosols (Evonik, P25) to provide a calculated pulmonary deposition of 11 µg/mouse. Twenty-four hours following exposure, we observed diastolic dysfunction as evidenced by E/A ratios greater than 2 and increased radial strain during diastole in wild-type mice (p < 0.05 for both), indicative of restrictive filling. Overexpression of mPHGPx mitigated the contractile deficits resulting from nano-TiO₂ exposure. To investigate the cellular mechanisms associated with the observed cardiac dysfunction, we focused our attention on the mitochondrion. We observed a significant increase in ROS production (p < 0.05) and decreased mitochondrial respiratory function (p < 0.05) following nano-TiO₂ exposure which were attenuated in mPHGPx transgenic mice. In summary, nano-TiO₂ inhalation exposure is associated with cardiac diastolic dysfunction and mitochondrial functional alterations, which can be mitigated by the overexpression of mPHGPx, suggesting ROS contribution in the development of contractile and bioenergetic dysfunction.

中文翻译：

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急性纳米二氧化钛吸入暴露后，活性氧的破坏导致心脏和线粒体功能障碍

纳米技术可提供从化妆品到药物输送的创新产品，从而增加了工程纳米材料（ENM）的暴露。不幸的是，ENM对健康的影响尚未完全实现。由于其在众多应用中的使用，二氧化钛（TiO ₂）是生产最广泛的ENM之一。已经确定了肺暴露后的肺外作用，可能涉及活性氧（ROS）。这项研究的目的是确定纳米TiO ₂后ROS对心脏功能和线粒体的参与程度接触。为了解决这个问题，我们利用了转基因小鼠模型，该模型具有过量表达的新型线粒体靶向抗氧化酶（磷脂氢过氧化物谷胱甘肽过氧化物酶； mPHGPx），可为脂质膜提供抗氧化应激的保护作用。将MPHGPx小鼠和同窝幼仔对照组暴露于纳米TiO ₂气雾剂（赢创，P25），以提供每只小鼠11 µg的经计算肺沉积量。暴露后二十四小时，我们观察到舒张功能障碍，如E / A大于2所证明，并且野生型小鼠在舒张期期间径向张力增加（ 两者均p <0.05），这表明限制性填充。mPHGPx的过表达减轻了纳米TiO ₂引起的收缩缺陷接触。为了研究与观察到的心脏功能障碍相关的细胞机制，我们将注意力集中在线粒体上。我们观察到 纳米TiO ₂暴露后ROS产量显着增加（p  <0.05）和线粒体呼吸功能下降（p <0.05），而在mPHGPx转基因小鼠中这种作用减弱了。总之，纳米TiO ₂吸入暴露与心脏舒张功能障碍和线粒体功能改变有关，这可以通过mPHGPx的过表达缓解，这表明ROS在收缩性和生物能功能障碍发展中的作用。