Developing A Link Between Cardiac Function and Maternal Engineered Nanomaterial Exposure in Growing Progeny
Authors: Hathaway Quincy Alexander , Nichols Cody , Shepherd Danielle , Stapleton Phoebe , McLaughlin Sarah , Stricker Janelle , Rellick Stephanie , Pinti Mark , Abukabda Alaeddin , McBride Carroll , Yi Jinghai , Stine Seth , Nurkiewicz Timothy , Hollander John 
Published: November 2023

New biomedical applications involving engineered nanomaterials, along with increasing use in consumer products, makes the evaluation of the toxicological properties of these materials very important. This study identified how gestational exposure to nano‐TiO2 can have an impact on cardiac function to growing progeny. Maternal exposure with nano‐TiO2 was conducted in Sprague Dawley rats which were exposed to aerosols (~10 mg/m3, 130 – 150 nm count median aerodynamic diameter) beginning at gestational day 5–6 for 7–8 nonconsecutive days. Three time points were used in the study, fetal (gestational day 20), neonatal (4–10 days), and young adult (6–12 weeks), to evaluate physiological, metabolic, and molecular consequences of nano‐TiO2 gestational exposure. Techniques were employed to assess Cardiac function (echocardiography, speckle‐tracking based strain, and cardiomyocyte contractility), cardiomyocyte metabolism (Seahorse bioanalysis and electron transport chain expression and activity), and molecular changes involved in fatty acid oxidation and cellular stress (Western blotting and quantitative PCR) evaluated functional differences in gestational exposed progeny. The results of the study showed a decrease in the cardiac function of the experimental group: decreased E and A wave velocities with a 15% higher E/A ratio and a ~30% decrease in total contractility, departure velocity, and area of contraction in cardiomyocytes. Metabolically, a significant increase in proton leak, accompanied by decreases in basal respiration, maximal respiration, and spare capacity and negatively impacted electron transport chain complex I and IV activities showed altered metabolic profiles in the gestational exposed progeny. Molecular data also suggested that an increase in fatty acid metabolism, uncoupling, and cellular stress proteins may be associated with functional deficits of the heart. In conclusion, gestational nano‐TiO2 exposure considerably impairs the functional capabilities of the heart through cardiomyocyte impairment, which is associated with mitochondrial dysfunction. Histone modifications through epigenetic regulation also show changes in progeny molecular expression after maternal exposure to nano‐TiO2, providing direction for future studies.Support or Funding InformationThis work was supported by a National Science Foundation IGERT: Research and Education in Nanotoxicology at West Virginia University Fellowship [1144676] awarded to QAH. This work was supported by the National Institutes of Health from the National Heart, Lung and Blood Institute [R56 HL128485] awarded to JMH. This work was supported by the National Institutes of Health from the National Institute of Environmental Safety and Health [R01 ES015022] awarded to TRN. This work was supported by an American Heart Association Predoctoral Fellowship (AHA 13PRE16850066) awarded to CEN. This work was supported by the National Institutes of Health from the National Institute of Environmental Safety and Health [K99 ES024783] awarded to PAS. Small animal imaging and image analysis were performed in the West Virginia University Animal Models & Imaging Facility (AMIF), which has been supported by the WVU Cancer Institute and NIH grants P20 RR016440, P30 GM103488 and S10 R026378. Seahorse data acquisition was supported by the West Virginia Stroke CoBRE [P20 GM109098].