Airborne pollutants pose a significant risk to pregnant individuals, as maternal inhalation of particulate matter (PM) has been associated with several pregnancy complications. PM represents a heterogenous mixture of aerosolized solid and liquid particles in the ambient air. PM is commonly generated from combustion sources like diesel exhaust, gasoline, and wildfire smoke. In this mixture, ultrafine PM, or particles less than 100 nm in diameter, represent a unique threat due to size-specific translocation from the lung to distal organs found in the reproductive system. Importantly, ultrafine PM is linked to the development of fetal growth restriction (FGR), an adverse pregnancy outcome characterized by low nutrient availability and significantly reduced fetal size. Increasing evidence implicates placental dysfunction as a key mechanism underlying FGR, as the placenta is a temporary organ with the responsibility of transporting growth-related nutrients to the developing baby. Glucose is the primary energy substrate for fetal growth and an essential energy source for placental function, emphasizing the importance of investigating placental glucose transport capacity to understand how environmental exposures contribute to FGR. Therefore, the purpose of this dissertation was to determine the effect of inhaling ultrafine PM during pregnancy on placental nutrient transport capacity and glucose handling to elucidate the mechanisms underlying PM-induced FGR. Engineered titanium dioxide nanoparticles (nano-TiO2) were used as a homogeneous proxy for ultrafine PM. Pregnant Sprague Dawley rats were exposed via whole-body inhalation to nano-TiO2 aerosols at a target concentration of 10 mg/m3. Following repeated exposure to nano-TiO2, it was determined that the inhalation of nanoparticles disrupted the size of the primary area for nutrient and waste exchange in the placenta, while simultaneously increasing the number of vascular spaces, an observation that indicates an adaptive response to improve nutrient exchange. Additional studies revealed that the placenta enhances glycolytic reliance under these conditions, suggesting greater glucose consumption, even in the presence of an overall decline in maximum metabolic function. This shift in metabolic phenotype was accompanied by a decrease in the overall expression of primary glucose transporter (GLUT) 1, but elevated membrane localization of both GLUT1 and GLUT4. These adaptations ultimately resulted in enhanced glucose transport across the placenta into the fetal compartment. Together, this project demonstrates the adaptive capacity of the placenta in the face of environmental insults like PM. Although the placenta was vulnerable to the toxicological effects of PM exposure during pregnancy, the observed compensation indicates that there are molecular changes that occur to rescue fetal nutrient access. Moreover, although glucose transport was improved, there remain concerns for the transport capacity of other important nutrients and oxygen delivery. This dissertation advances our understanding of environmentally driven placental dysfunction and provides a foundation for future efforts to improve pregnancy outcomes in at-risk populations.
Talia Nishay Seymore (Thu,) studied this question.