Reactive oxygen species damage drives cardiac and mitochondrial dysfunction following acute nano-titanium dioxide inhalation exposure

<p>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 (<i>p</i> < 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 (<i>p</i> < 0.05) and decreased mitochondrial respiratory function (<i>p</i> < 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.</p

Microvascular and mitochondrial dysfunction in the female F1 generation after gestational TiO₂ nanoparticle exposure

<div><p></p><p>Due to the ongoing evolution of nanotechnology, there is a growing need to assess the toxicological outcomes in under-studied populations in order to properly consider the potential of engineered nanomaterials (ENM) and fully enhance their safety. Recently, we and others have explored the vascular consequences associated with gestational nanomaterial exposure, reporting microvascular dysfunction within the uterine circulation of pregnant dams and the tail artery of fetal pups. It has been proposed (<i>via</i> work derived by the Barker Hypothesis) that mitochondrial dysfunction and subsequent oxidative stress mechanisms as a possible link between a hostile gestational environment and adult disease. Therefore, in this study, we exposed pregnant Sprague-Dawley rats to nanosized titanium dioxide aerosols after implantation (gestational day 6). Pups were delivered, and the progeny grew into adulthood. Microvascular reactivity, mitochondrial respiration and hydrogen peroxide production of the coronary and uterine circulations of the female offspring were evaluated. While there were no significant differences within the maternal or litter characteristics, endothelium-dependent dilation and active mechanotransduction in both coronary and uterine arterioles were significantly impaired. In addition, there was a significant reduction in maximal mitochondrial respiration (state 3) in the left ventricle and uterus. These studies demonstrate microvascular dysfunction and coincide with mitochondrial inefficiencies in both the cardiac and uterine tissues, which may represent initial evidence that prenatal ENM exposure produces microvascular impairments that persist throughout multiple developmental stages.</p></div