Adenosine triphosphate-binding cassette transporters: key players in maintaining fetal health during pregnancy

ATP binding cassette (ABC) transporters are active efflux proteins that move substrates against the gradient via hydrolysis of ATP, and regulate fetal metabolic homeostasis and chemical exposure. The maternal-fetal interface represents a barrier for key transporters involved in xenobiotic efflux, reverse cholesterol transport, bile acid handling, metabolism of steroid hormones and immune tolerance. We combine recent data from cryo-electron microscopy-based structure with recent single-cell transcriptomic data and ex vivo studies of placenta pharmacology to explore the underlying mechanism of transporter dysfunction in preeclampsia, intrahepatic cholestasis of pregnancy, preterm birth, gestational diabetes mellitus, intrauterine growth restriction, and early miscarriage. NRF2-dependent antioxidant signaling, HIF-1α-dependent suppression of BCRP under hypoxia, cytokine-dependent downregulation by TNF-α and IL-1β, and autophagy. Key translation opportunities in clinical pharmacogenomics are highlighted, such as near-term ABCG2 Q141K genotyping for glyburide prescribing in gestational diabetes, and ABCB4 variant profiling for cholestasis risk.