Effects of inhaled nanoparticles on placental nutrient transfer and energy metabolism
Creators: name: D'Errico, Jeanine Nicole
Publisher: name: No Publisher Supplied
Year: 2022

description: Inhalation of ultrafine particulate matter (PM0.1), otherwise known as nanoparticles (NPs), during pregnancy is of emerging concern due to known distribution throughout the body and impact on the developing offspring (i.e. fetal growth restriction). During pregnancy, the placenta serves as a protective barrier and conduit of glucose for the fetus. As a highly metabolically active tissue, the placenta needs a significant amount of glucose-derived energy to function. Together, this raises concern for NP-mediated placental toxicity with consequences for placental function and fetal development. Further, developmental growth patterns differ depending on the sex of the fetus, therefore there may be sex-dependent risk after gestational NP exposure. The hypothesis of this dissertation was that inhaled NP translocate to the placenta and impact placental glucose transfer and metabolism in a sex-dependent manor. Three specific aims were put forth; 1) characterize the distribution of NP aerosols in a pregnancy model, 2) evaluate maternal and fetal blood glucose concentrations and placental glucose transfer, and 3) assess placental energetic status and glucose metabolism. To recapitulate maternal NP exposure, pregnant Sprague-Dawley rats were administered whole-body exposure to titanium dioxide nanoparticle (nano-TiO2) aerosols. TiO2 is a naturally occurring ore manufactured at the nanoscale for application in personal care products, pharmaceuticals, food and drink, and an array of other consumer products. Additionally, due to low reactivity profile, nano-TiO2 is used to model toxicity for PM air pollution exposure. The findings of this dissertation demonstrate the systemic distribution of Ti in maternal, placental, and fetal tissues after gestational inhalation exposure to nano-TiO2 aerosols. NPs were visualized intracellularly at the syncytiotrophoblast barrier inside nuclei, lysosomes, and embedded among rough endoplasmic reticulum organelles. A significant reduction in glucose was identified in fetal blood. When stratifying the data by fetal sex, male fetuses had a significant lowering of blood glucose where females did not. Using ex-vivo placental perfusion a significant reduction in fluid flow through the uterine vasculature, but no change in placental glucose transfer to the umbilical vein, was identified. It was also determined that exposure does not reduce placental glucose transporter protein (GLUT1, GLUT3, GLUT4) expression or membrane localization. However, GLUT4 mRNA expression and fetal blood vessel area in the labyrinth zone were significantly reduced. Upon further investigation, changes in glucose metabolizing enzyme activity and energetic status in response to gestational nano-TiO2 exposure were found; females significantly reduced glycolytic enzyme activity, whereas in male placentas enzyme activity was unchanged and energy status was compromised. Presented are the first evidence of sex-dependent reductions in glycolytic metabolism and energy in the placenta after maternal nano-TiO2 inhalation. Altogether, the dissertation data support that inhaled NPs translocate to the placenta and lead to uterine vascular dysfunction. These may contribute to poor placental delivery of glucose, reduced placental glucose metabolism, and lowered fetal blood glucose transfer. Inadequate intrauterine conditions could lead to impaired fetal growth and predispose to life-long health consequences, particularly for males. The next research questions surround the sex-dependent changes to placental mitochondrial function and alternate nutrient metabolic pathways in response to gestational NP exposure. Offspring metabolic reprogramming and glucose tolerance from the intrauterine experience should also be explored. Overall, the information presented here is critical for educating the public and policy makers on the hazards of repeated NP inhalation exposure for pregnant women and their developing offspring.