Literature-Based Functional Annotation and Disease Associations of Solute Carriers and ATP-Binding Cassette Transporters in the Human Term Placenta: Integrating Bioinformatics with Ex-ploratory Functional Evaluation of OATP2B1

Abstract

Solute carrier (SLC) and ATP-binding cassette (ABC) transporters play critical roles in placental nutrient exchange, waste removal, and fetal protection by regulating the movement of endogenous compounds, nutrients, and xenobiotics across the placenta. Despite their physiological importance, our understanding of their expression patterns in the human placenta, as well as their involvement in early life disorders, remains incomplete. To address this knowledge gap, our laboratory recently performed RNA sequencing in term human placentas obtained from 10 healthy pregnancies. In the intervillous region, 276 SLC transporters were identified, with approximately 40% showing mod-erate to high expression. Thirty-seven ABC transporters were also detected, most of which were involved in lipid and xenobiotic transport. The goals of this study were to functionally annotate the top 110 SLC and 25 ABC transporter genes identified in our transcriptomic study and to investigate their association with genetic diseases in early development using public databases with verifica-tion by primary literature. Functional annotation revealed that amino acid, metal ion, and inorganic ion transporters each accounted for approximately 9% of the highly expressed SLCs, with vitamin and xenobiotic transporters also represented. Approximately 37% of the identified SLC transporters were localized to intracellular organelles, whereas 11% were classified as orphan transporters with unknown physiological functions. Similarly, functional annotation of intracellular ABC transporters showed that xenobiotic transporters represented the largest functional category, followed by lyso-somal transporters, with lipid/fatty acid and mitochondrial transporters also prominently represent-ed. Annotation of transporter-associated genetic diseases revealed that disrupted single transporter function is associated with distinct early-life developmental disorders. The 11 plasma membrane SLC transporters were primarily associated with disorders involving impaired transport of nutrients, hormones, neurotransmitters, metal ions, and inorganic ions, whereas 13 intracellular SLC trans-porters were associated with disorders involving lysosomal, mitochondrial, Golgi, and endoplasmic reticulum function. Similarly, 7 ABC transporters were primarily associated with disorders involv-ing lipid transport, surfactant homeostasis, heme and iron metabolism, bilirubin transport, peroxi-somal function, and vitamin B12 trafficking. Many of these disorders are present during fetal, neo-natal, or early childhood development, affecting fetal growth, neurodevelopment, neurologic func-tion, metabolism, and organ development To complement the transcriptomic annotation with functional evaluation, the highly expressed pla-cental uptake transporter OATP2B1 (SLCO2B1) which mediates the transport of steroid hormone conjugates, xenobiotics, and therapeutic drugs, was selected for an exploratory functional evalua-tion using fluorescence-based time-dependent uptake and cyclosporine A inhibition assays to char-acterize transporter activity and drug-transporter interactions. Overall, this integrated study combines literature-based functional annotation with an exploratory functional evaluation to advance the understanding of placental transporter biology. The findings provide a useful resource for further investigating placental SLC and ABC transporters and their roles in placental drug transport, fetal nutrient and xenobiotic exposure, as well as potential in-volvement in developmental disorders.