Placental transporter localization and expression in the Human: the importance of species, sex, and gestational age differences†

Abstract

The placenta is a critical organ during pregnancy, essential for the provision of an optimal intrauterine environment, with fetal survival, growth, and development relying on correct placental function. It must allow nutritional compounds and relevant hormones to pass into the fetal bloodstream and metabolic waste products to be cleared. It also acts as a semipermeable barrier to potentially harmful chemicals, both endogenous and exogenous. Transporter proteins allow for bidirectional transport and are found in the syncytiotrophoblast of the placenta and endothelium of fetal capillaries. The major transporter families in the human placenta are ATP-binding cassette (ABC) and solute carrier (SLC), and insufficiency of these transporters may lead to deleterious effects on the fetus. Transporter expression levels are gestation-dependent and this is of considerable clinical interest as levels of drug resistance may be altered from one trimester to the next. This highlights the importance of these transporters in mediating correct and timely transplacental passage of essential compounds but also for efflux of potentially toxic drugs and xenobiotics. We review the current literature on placental molecular transporters with respect to their localization and ontogeny, the influence of fetal sex, and the relevance of animal models. We conclude that a paucity of information exists, and further studies are required to unlock the enigma of this dynamic organ.

Keywords: human; ontogeny; placenta; placental transport.

Figure 1.

Transporting epithelium of the placenta and molecular transporter function. A molecule must be transported (or diffuse) through the syncytiotrophoblast and endothelium of the fetal capillary to access the fetal compartment. (A) Molecular transporter proteins are positioned in the maternal-facing apical and fetal-facing basolateral membranes and in the endothelium of fetal capillaries. (B) Possible pathways across the syncytiotrophoblast. A molecule can use transporter proteins, passive diffusion, or pinocytosis to cross the syncytiotrophoblast membranes. The molecule can be transported intact or may be metabolized first. The syncytiotrophoblast also retains certain molecules for its own use. (C) Superfamilies of genes coding for molecular transporters found in the placenta. SLC can be divided into gene subfamilies SLCO and SLC22A. ABC consist of seven gene subfamilies: ABCA, ABCB, ABCC, ABCD, ABCE, ABCF, ABCG although ABCE and ABCF are unlikely to have transporter function. A list of corresponding proteins can be found in Table 1. (D) Mechanism of transport for SLC proteins. Compounds can enter/exit the cell coupled to another molecule, passively down its concentration gradient or in exchange for another molecule. SLC transporters can be bidirectional although they mainly allow for placental uptake of molecules. (E) Mechanism of transport for ABC proteins. ABC transporters actively efflux compounds against their concentration gradient. ATP hydrolysis is required for a conformational change of the transporter protein to allow uptake and expulsion of the substrate from the cell.

Figure 2.

Molecular transporter transcripts with confirmed syncytiotrophoblast location in the human placenta and their direction of transport. SLC (orange) and ABC (blue) are found in both apical (maternal-facing) and basolateral (fetal-facing) membranes. As seen by the schematic, understanding of complete transplacental routes for compound movement is incomplete. Grey dashed line indicates the transporter has been found to be expressed on both membranes. It is likely that many molecules must use a combination of transporters to cross the membrane and as many transporters have common substrates, this is entirely possible. Substrates mentioned here are generalized substrates of the superfamilies.