Inhalation of titanium dioxide nanoparticles during gestation alters placental bioenergetics in a sex-related manner in rats

Introduction: Epidemiological and experimental studies support an association between exposure to particulate matter during pregnancy and the development of fetal growth restriction (FGR). The etiology of FGR is often attributed to poor nutrient delivery. Glucose is the primary energy substrate for fetal growth and an important energy source for placental tissue function; therefore, the health of the feto-placental unit depends on sufficient delivery of this nutrient to the tissue. Preeclampsia and FGR are associated with altered placental metabolism; moreover, the underlying causes and progression of these pathologies are influenced by fetal sex. The goal of this study was to investigate sex-related metabolic changes in the placenta after gestational exposure to particulate matter. Methods: Sprague Dawley rats were exposed to nano-titanium dioxide (nano-TiO₂) aerosols throughout pregnancy [gestational day (GD) 6-GD20]. For these studies, we developed a novel precision-cut placenta slice model for analysis of tissue bioenergetics using an Agilent Seahorse Analyzer. Results: Exposure of pregnant rats to nano-TiO₂ aerosols (9.74 ± 0.11 mg/m³) resulted in an overall decrease in placental metabolic function with an increased reliance on glycolytic ATP production. Reductions in maximum metabolic function were sex-related, revealing that female placentas are more sensitive to environmentally induced metabolic changes. Discussion: These data show that there are sex-related mechanisms within the glycolytic pathway for increased glucose utilization. As increased metabolism of glucose by the placenta can reduce fetal glucose delivery, it may contribute to adverse effects on fetal growth induced by nano-TiO₂.