Placentation and barrier transporters: regulation by endogenous and exogenous factors

During pregnancy, the placenta serves as a critical interface between the fetal and maternal circulations and facilitates nutrient-waste exchange to support normal fetal development. Once established, the placenta regulates hormone secretion, xenobiotic metabolism, and expression of transporters to maintain overall barrier integrity. Uptake and efflux transporters are localized to the syncytiotrophoblast cells and in part regulate the disposition of endogenous signaling molecules, hormones, chemicals, and drugs across the placenta. Development of the placenta can be affected by both endogenous (i.e. low oxygen, cyclic nucleotide signaling) and xenobiotic (i.e. mycotoxin zearalenone) influences. Due to the critical role of the placenta in supporting normal fetal development, more work is urgently needed to further characterize its physiology and susceptibility to insults. The purpose of this dissertation was to investigate the impact of endogenous (i.e. hypoxia, cyclic nucleotide signaling) and exogenous (i.e. zearalenone) factors on placentation with a focus on endobiotic and xenobiotic disposition through transporter-mediated mechanisms. Physiologically relevant low oxygen tension, observed during the 1st and 2nd trimesters, altered the transcriptional regulatory pathways and drug transporter profiles in two in vitro placental models (BeWo choriocarcinoma cells, human placental explants). Altered functionality of drug transporters may not only impact the disposition of xenobiotics but also endogenous molecules that activate/regulate downstream signaling cascades and overall placentation. Cyclic adenosine monophosphate (cAMP)-mediated signaling regulates the process of syncytialization whereby giant multinucleated syncytiotrophoblasts arise from the fusion of progenitor cytotrophoblast cells. Multidrug resistance-associated protein (MRP) transporters are localized to the syncytiotrophoblast cell layer and regulate intracellular cAMP levels through active efflux. Studies using both pharmacological and genetic loss-of-function approaches targeting the MRP5 transporter revealed enhanced intracellular concentration of cAMP and syncytialization in placental explants and/or BeWo cells. Zearalenone, an estrogenic mycotoxin, is a known substrate of the BCRP efflux drug transporter. In vivo studies using Bcrp heterozygous mice demonstrated that zearalenone increased maternal weight gain and embryo resorption as well as decreased placental weight and area. Further examination revealed that markers responsible for placental differentiation were globally down-regulated in zearalenone-treated placentas. Zearalenone exposure differentially regulated placental xenobiotic transporter expression and decreased placental antioxidant defense genes. Together, these data demonstrate that endogenous and exogenous factors may influence placental transporter expression and function, and in turn, lead to altered disposition of endobiotics and xenobiotics and impact placenta and fetal development.Ph.D.Includes bibliographical reference