ROS promote epigenetic remodeling and cardiac dysfunction in offspring following maternal engineered nanomaterial (ENM) exposure

Abstract

Nano‐titanium dioxide (nano‐TiO2) is one of the most prevalently utilized ENMs. However, little is known regarding the ramifications that maternal inhalation exposure during gestation can have on growing progeny. Mitochondrial bioenergetics are critical for the maintenance of sufficient ATP for cardiac contractile function and data suggest that ENM exposure can cause deficits in this important mitochondrial role. Further, ENM inhalation exposure has been associated with an increase in mitochondrially‐derived reactive oxygen species (ROS). Nevertheless, it is unclear if such a dynamic occurs in the growing fetus or whether ROS is involved in fetal epigenome remodeling. The purpose of this study was to determine how maternal ENM exposure influences fetal ROS and epigenomic remodeling in a mouse model. Wild‐type pregnant dams were exposed to nano‐TiO2 with an aerodynamic diameter of 156 ± 2 nm and a mass concentration of 12 mg/m3 starting at gestational day 5 (GD 5), for 6 hours over 6 non‐consecutive days. Echocardiographic imaging was used to asses cardiac dysfunction in maternal, fetal (GD 16–19), and young adult (10–12 weeks) contexts. Electron transport chain complex (ETC) activities, mitochondrial size, complexity, and respiration were assessed. 5‐methylcytosine, and Dnmt1 protein and Hif1‐α activity, central contributors to epigenomic remodeling, were assessed. Cardiac function assessment revealed a 43% increase in left ventricular mass, 25% decrease in cardiac output in fetal pups, and 18.2% decrease in fractional shortening in young adult pups. In fetal pups, ROS levels were significantly increased (~10 fold) with a subsequent decrease in mitochondria phospholipid hydroperoxide glutathione peroxidase (mPHGPx) expression. ETC complex activity IV was decreased 68% and 46% in fetal and adult hearts, respectively. DNA Methylation was significantly increased in fetal pups following exposure, along with increased Hif1‐α activity and Dnmt1 protein expression. Significant increases in mitochondrial size and internal complexity persisted into adulthood following exposure. Maternal exposure to nano‐ TiO2 during gestation results in adverse effects on cardiac function by causing an increase in ROS levels and associated dysregulation via a Hif1‐α/Dnmt1 regulatory axis in the fetal offspring. The elevated ROS levels results in mitochondrial dysfunction at the fetal stage, which precipitates alterations in mitochondrial structure and persistent cardiac dysfunction. Our findings suggest a distinct interplay between ROS signaling and epigenetic remodeling that lead to sustained cardiac contractile dysfunction in growing and adult offspring mice following maternal ENM exposure. Support or Funding Information Supported by: RO1 HL‐128485 (JMH), RO1‐ES015022 (TRN), AHA‐17PRE33660333 (QAH). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Nanopolystyrene translocation and fetal deposition after acute lung exposure during late-stage pregnancy

“…We, and others, have identified that maternal exposures to metallic and carbonaceous ENM during gestation can initiate developmental onset of disease within the maturing fetus. In laboratory studies, young and adult offspring have been reported to exhibit coronary dysfunction [33][34][35][36][37][38], vascular perturbations [38,39], negative reproductive health outcomes [40][41][42], and neurological outcomes [43][44][45] after maternal inhalation of engineered nanomaterials during pregnancy. It is also plausible that these findings represent a snapshot of time, wherein the particles reach the fetal tissues within 24 h of exposure but are removed from the fetal circulation prior to birth.…”

Nanopolystyrene Translocation and Fetal Deposition After Acute Lung Exposure During Late-Stage Pregnancy

“…We, and others, have identi ed that maternal exposures to ENM during gestation can initiate developmental onset of disease within the maturing fetus. In laboratory studies, young and adult offspring have been reported to exhibit coronary dysfunction [40,41,42,43,44,45], vascular perturbations [27,45], reproductive consequences [46,47,48,49,50], and neurodevelopmental delays [51,52] after maternal inhalation of engineered nanomaterials during pregnancy. Therefore, particle deposition, and likely particle accumulation and retention, impact offspring health after birth and into adulthood.…”

Rethinking Nano‐TiO2 Safety: Overview of Toxic Effects in Humans and Aquatic Animals

“…The meta-analysis showed that nano-TiO 2 exposure via different routes tend to reduce the cardiac output albeit the effect depends on the life stage and the genetic background ( Figure 1C). Thus, fetal mice (prenatally exposed to ≈10 mg m −3 of nano-TiO 2 [54,59] ) showed negligible change in cardiac output. In adult isogenic [59] and heterozygous mice, [56] nano-TiO 2 caused more significant increased cardiac output, whereas in adult wild type and MiRNA-378a knockout mice the cardiac output notably decreased in response to nano-TiO 2 inhalation ( Figure 1).…”

“…[64,65] The cardiac contractile dysfunction in the offspring of mice gestationally exposed to nano-TiO 2 was a result of the oxidative stress and inflammation in the heart as well as the direct effects on the fetal vasculature. [59,65]…”