Glutathione Peroxidase Influence on Cardiac Remodeling in Progeny of Dams Exposed to Engineered Nanomaterials during Gestation

Abstract

Vulnerable populations, like the developing fetus, may be more susceptible to sustained detriments elicited by inhaled engineered nanomaterials (ENMs) entering the bloodstream and prompting systemic effects. Previous studies have demonstrated diminished mitochondrial bioenergetics in progeny following maternal exposure to a highly utilized ENM, nano‐titanium dioxide (nano‐TiO2). Cardiac dysfunction and reduced ROS scavenging ability were observed with decreased mitochondria phospholipid hydroperoxide glutathione peroxidase (mPHGPx) expression. This study aimed to elucidate whether overexpression of mPHGPx could provide sufficient antioxidant protection to attenuate cardiac dysfunction in pregnant dams and progeny following gestational ENM inhalation exposure. Wild‐type (WT) and transgenic (mPHGPx) female mice were bred with transgenic and WT males, respectively, to delineate maternal vs progeny protection. Pregnant dams were exposed to nano‐TiO2 (6 hrs/day for 6 days) with a primary particle size of 21nm and mass concentration of 12mg/m3 or sham air. Conventional (M‐Mode) and speckle tracking stress‐strain echocardiographic parameters were assessed in pregnant dams, as well as in fetal (gestational day 14) and adult (11 wks) offspring. Following inhalation exposure to nano‐TiO2 during gestation, WT dams exhibited signs of concentric remodeling marked by significantly decreased (left ventricular) LV diastolic diameter (12%) and volume (26%), and significant increases in both LV posterior wall thickness (23%) and relative wall thickness (39%), which were preserved in mPHGPx pregnant dams. Fetal offspring of mPHGPx dams had significantly enhanced cardiac output (87%) and stroke volume (43%) compared to fetal offspring of WT dams. Stress‐strain analysis revealed that fetal WT offspring of nano‐TiO2–exposed mPHGPx dams had significantly higher short‐axis systolic circumferential strain rate (~3 fold) and displacement (~2 fold) than WT offspring of WT dams. Adult WT offspring of transgenic dams presented with a significantly lower ejection fraction (6% and 8%) and fractional shortening (18% and 22%) than sham WT and nano‐TiO2 transgenic offspring, respectively. This may suggest that in offspring lacking the transgene, enhanced maternal antioxidant defense alone may not provide sufficient protection into adulthood. This study highlights the beneficial role of enhanced antioxidant defense (during fetal development and adulthood) on cardiac dysfunction following gestational ENM exposure.Support or Funding InformationSupported by: R01 HL‐128485 (JMH), CFO for the Ohio Valley Whipkey Trust (JMH), R01‐ES015022 (TRN), AHA‐17PRE33660333 (QAH).