Abstract
BackgroundNano-titanium dioxide (nano-TiO2) is amongst the most widely utilized engineered nanomaterials (ENMs). However, little is known regarding the consequences maternal ENM inhalation exposure has on growing progeny during gestation. ENM inhalation exposure has been reported to decrease mitochondrial bioenergetics and cardiac function, though the mechanisms responsible are poorly understood. Reactive oxygen species (ROS) are increased as a result of ENM inhalation exposure, but it is unclear whether they impact fetal reprogramming. The purpose of this study was to determine whether maternal ENM inhalation exposure influences progeny cardiac development and epigenomic remodeling.ResultsPregnant FVB dams were exposed to nano-TiO2 aerosols with a mass concentration of 12.09 ± 0.26 mg/m3 starting at gestational day five (GD 5), for 6 h over 6 non-consecutive days. Aerosol size distribution measurements indicated an aerodynamic count median diameter (CMD) of 156 nm with a geometric standard deviation (GSD) of 1.70. Echocardiographic imaging was used to assess cardiac function in maternal, fetal (GD 15), and young adult (11 weeks) animals. Electron transport chain (ETC) complex activities, mitochondrial size, complexity, and respiration were evaluated, along with 5-methylcytosine, Dnmt1 protein expression, and Hif1α activity. Cardiac functional analyses revealed a 43% increase in left ventricular mass and 25% decrease in cardiac output (fetal), with an 18% decrease in fractional shortening (young adult). In fetal pups, hydrogen peroxide (H2O2) levels were significantly increased (~ 10 fold) with a subsequent decrease in expression of the antioxidant enzyme, phospholipid hydroperoxide glutathione peroxidase (GPx4). ETC complex activity IV was decreased by 68 and 46% in fetal and young adult cardiac mitochondria, respectively. DNA methylation was significantly increased in fetal pups following exposure, along with increased Hif1α activity and Dnmt1 protein expression. Mitochondrial ultrastructure, including increased size, was observed at both fetal and young adult stages following maternal exposure.ConclusionsMaternal inhalation exposure to nano-TiO2 results in adverse effects on cardiac function that are associated with increased H2O2 levels and dysregulation of the Hif1α/Dnmt1 regulatory axis in fetal offspring. Our findings suggest a distinct interplay between ROS and epigenetic remodeling that leads to sustained cardiac contractile dysfunction in growing and young adult offspring following maternal ENM inhalation exposure.
Highlights
Nano-titanium dioxide is amongst the most widely utilized engineered nanomaterials (ENMs)
Mitochondria are a primary target of oxidant stress due to Reactive oxygen species (ROS) generation that arises from the electron transport chain (ETC), which can lead to peroxidation of biomembranes and impairment of ATP production [12]
We have previously reported that overexpression of a mitochondrially-targeted GPx4. By decreasing antioxidant defenses (GPx4), known as mPHGPX, in a transgenic mouse model, was capable of ameliorating H2O2 levels and improving mitochondrial and cardiac function in an acute nano-TiO2 inhalation exposure model [14], suggesting that it may be of particular relevance during ENM exposure
Summary
Nano-titanium dioxide (nano-TiO2) is amongst the most widely utilized engineered nanomaterials (ENMs). Reactive oxygen species (ROS) are increased as a result of ENM inhalation exposure, but it is unclear whether they impact fetal reprogramming. The purpose of this study was to determine whether maternal ENM inhalation exposure influences progeny cardiac development and epigenomic remodeling. Mitochondrial ultrastructure, including increased size, was observed at both fetal and young adult stages following maternal exposure. Recent studies have focused on the consequences of a baleful gestational environment, which include endocrine disruptors, toxic metals, and the subsequent increase in progeny developing cardiovascular, cancer, reproductive, immunological, and neurological diseases [5,6,7,8,9]. Nano-TiO2 exposure has been shown to have detrimental effects on mitochondrial bioenergetics and cardiovascular function, which are associated with increased levels of reactive oxygen species (ROS) [11]. Antioxidant defenses are critical for mitochondrial functional preservation
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