The placenta and fetal blood–brain barrier (BBB) play critical roles in protecting the fetus from potentially harmful substances in maternal circulation. Key to this protection are P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), initially identified in cancer cells but now recognized as essential components of physiological barrier systems. Our work has shown that P-gp expression declines markedly in the placenta in late gestation, while simultaneously increasing in the developing BBB—an adaptive shift that supports protection in the transition to neonatal life. We have investigated the molecular regulation of P-gp and BCRP and are currently elucidating the roles of astrocytes and pericytes in modulating BBB function. Importantly, we have identified novel factors that significantly influence transporter activity. Most recently, using preclinical models, we have demonstrated that antenatal corticosteroid exposure leads to sex-specific reductions in P-gp expression and function in the offspring BBB. These findings have substantial clinical implications: nearly half of the medications administered in neonatal intensive care units (NICUs) are substrates of P-gp. Collectively, this research is advancing our understanding of how protective mechanisms at the BBB are regulated during development. This knowledge is especially critical in the context of pregnancy complications, where the placental barrier may be compromised, and in preterm infants, who are particularly vulnerable to neurotoxicity.
