Placental Drug Transporters Research Articles

Pharmacokinetics of Maternal Drug Administration: Insights into Placental Transfer and Fetal Exposure

ABSTRACT Pregnancy profoundly influences the pharmacokinetics of maternally administered drugs, necessitating a comprehensive understanding of placental transfer and fetal exposure for safe and effective drug therapy. This review provides an updated overview of recent advancements in the field, comprising placental anatomy and physiology, pharmacokinetic changes during pregnancy, factors affecting placental transfer, techniques for studying transfer mechanisms, and clinical implications for maternal and fetal health. Recent discoveries explaining placental structure, function, and molecular transport mechanisms underscore the complexity of drug transfer across the placental barrier. Advances in pharmacokinetic research reveal dynamic alterations in drug absorption, distribution, metabolism, and excretion during pregnancy, which impact therapeutic drug levels and maternal-fetal outcomes. Factors influencing placental transfer, including drug properties, placental transporters, and maternal-fetal physiology, are increasingly recognized as critical determinants of fetal exposure. Innovative methodologies and technologies facilitate the study of placental drug transport, offering insights into drug-specific transfer kinetics and developmental risks.

Targeted lipid nanoparticles to prevent trans-placental passage in the ex vivo human placental cotyledon perfusion model.

Medication use during pregnancy poses risks to both the mother and the fetus. These risks include an elevated potential for fetotoxicity due to placental drug transport. Nanomedicines offer a promising solution by potentially preventing trans-placental passage. Targeted nanomedicines could enhance safety and efficacy in treating maternal or placental pathophysiology. Our study investigates placental transfer kinetics of targeted lipid nanoparticles (LNPs) in an ex vivo human placenta cotyledon perfusion model. We collected human placentas for dual-side ex vivo placental perfusions. Targeted LNPs with a fluorescence tag were introduced into the maternal circuit of each placenta. To establish if there was trans-placental passage of LNPs to the fetal circuit, we collected samples from maternal and fetal circuits throughout the six hours of the perfusion. We determined the fluorescence signal using a multi-mode microplate reader and Multiphoton microscopy to localize the LNPs in the placenta tissue. Data from perfused placenta tissue showed no significant transfer of the fluorescently labeled LNPs across the placental barrier to the fetal circuit. Localization of targeted LNPs in tissue samples is mainly observed in the maternal blood space of the placenta. Our results suggest that targeted LNPs present a promising strategic approach to prevent trans-placental passage to the fetus. Our future perspectives involve investigating the efficacy of targeted LNPs as well as loading targeted LNPs with nucleic acid-based therapeutics to investigate their therapeutic potential.

Placental drug transport and fetal exposure during pregnancy is determined by drug molecular size, chemistry, and conformation

Pregnant people are unable to take many prescription and over-the-counter medications because of suspected or known risk to the fetus. This undermedication contributes to the high maternal mortality rate in the United States and detracts from the quality of life of pregnant people. As such, there is an urgent need to develop safe pharmaceutical formulations for use during pregnancy. Most drugs are small molecules that easily cross the placenta, which is the biological barrier that separates the maternal and fetal bloodstreams. One potential approach to preventing fetal drug accumulation is to design drug compounds that are excluded by the placenta; however, there is little understanding of how macromolecular drug properties affect transplacental transport. To address this knowledge gap, we examined the transport behavior of fluorescently-labeled polymers with varying size, conformation, and chemistry. We compared these polymers to unconjugated fluorescein, a small molecule model drug that readily crosses biological barriers. We found that molecular size affected transplacental transport in an in vitro model, BeWo b30 monolayers, as well as in pregnant mice, with larger polymers having lower permeability. In addition to size, polymer chemistry altered behavior, with polyethylene glycol (PEG) molecules permeating the placental barrier to a greater extent than dextrans of equivalent molecular weight. PEG molecules were also more readily taken up into placental cells in vivo. These findings will inform the future development of drug conjugates or other macromolecular medicines that can safely be used during pregnancy.

An update on placental drug transport and its relevance to fetal drug exposure.

Pregnant women are often complicated with diseases that require treatment with medication. Most drugs administered to pregnant women are off-label without the necessary dose, efficacy, and safety information. Knowledge concerning drug transfer across the placental barrier is essential for understanding fetal drug exposure and hence drug safety and efficacy to the fetus. Transporters expressed in the placenta, including adenosine triphosphate (ATP)-binding cassette efflux transporters and solute carrier uptake transporters, play important roles in determining drug transfer across the placental barrier, leading to fetal exposure to the drugs. In this review, we provide an update on placental drug transport, including in vitro cell/tissue, ex vivo human placenta perfusion, and in vivo animal studies that can be used to determine the expression and function of drug transporters in the placenta as well as placental drug transfer and fetal drug exposure. We also describe how the knowledge of placental drug transfer through passive diffusion or active transport can be combined with physiologically based pharmacokinetic modeling and simulation to predict systemic fetal drug exposure. Finally, we highlight knowledge gaps in studying placental drug transport and predicting fetal drug exposure and discuss future research directions to fill these gaps.

Gestational Age Variation in Human Placental Drug Transporters.

Patient and providers’ fear of fetal exposure to medications may lead to discontinuation of treatment, disease relapse, and maternal morbidity. Placental drug transporters play a critical role in fetal exposure through active transport but the majority of data are limited to the 3rd trimester, when the majority of organogenesis has already occurred. Our objective was to define gestational age (GA) dependent changes in protein activity, expression and modifications of five major placental drug transporters: SERT, P-gp, NET, BCRP and MRP3. Apical brush border membrane fractions were prepared from fresh 1st, 2nd and 3rd trimester human placentas collected following elective pregnancy termination or planned cesarean delivery. A structured maternal questionnaire was used to identify maternal drug use and exclude exposed subjects. Changes in placental transporter activity and expression relative to housekeeping proteins were quantified. There was evidence for strong developmental regulation of SERT, NET, P-gp, BCRP and MRP3. P-gp and BCRP decreased with gestation (r = −0.72, p < 0.001 and r = −0.77, p < 0.001, respectively). Total SERT increased with gestation but this increase was due to a decrease in SERT cleavage products across trimesters. Uncleaved SERT increased with GA (r = 0.89, p < 0.001) while cleaved SERT decreased with GA (r = −0.94, p < 0.001). Apical membrane NET overall did not appear to be developmentally regulated (r = −0.08, p = 0.53). Two forms of MRP3 were identified; the 50 kD form did not change across GA; the 160 kD form was steady in the 1st and 2nd trimester and increased in the 3rd trimester (r = 0.24, p = 0.02). The 50 kD form was expressed at higher levels. The observed patterns of SERT, NET P-gp, BCRP and MRP3 expression and activity may be associated with transporter activity or decreased placental permeability in the 1st trimester to transporter specific substrates including commonly used psychoactive medications such as anti-depressants, anti-psychotics, and amphetamines, while transport of nutrients and serotonin is important in the 1st trimester. Overall these observations are consistent with a strong protective effect during organogenesis. 3rd trimester estimates of fetal exposure obtained from cord blood likely significantly overestimate early fetal exposure to these medications at any fixed maternal dose.

Overview of Drug Transporters in Human Placenta.

The transport of drugs across the placenta is a point of great importance in pharmacotherapy during pregnancy. However, the knowledge of drug transport in pregnancy is mostly based on experimental clinical data, and the underlying biological mechanisms are not fully understood. In this review, we summarize the current knowledge of drug transporters in the human placenta. We only refer to human data since the placenta demonstrates great diversity among species. In addition, we describe the experimental models that have been used in human placental transport studies and discuss their availability. A better understanding of placental drug transporters will be beneficial for the health of pregnant women who need drug treatment and their fetuses.

Organ-on-a-chip technology for the study of the female reproductive system.

Over the past decade, organs-on-a-chip and microphysiological systems have emerged as a disruptive in vitro technology for biopharmaceutical applications. By enabling new capabilities to engineer physiological living tissues and organ units in the precisely controlled environment of microfabricated devices, these systems offer great promise to advance the frontiers of basic and translational research in biomedical sciences. Here, we review an emerging body of interdisciplinary work directed towards harnessing the power of organ-on-a-chip technology for reproductive biology and medicine. The focus of this topical review is to provide an overview of recent progress in the development of microengineered female reproductive organ models with relevance to drug delivery and discovery. We introduce the engineering design of these advanced in vitro systems and examine their applications in the study of pregnancy, infertility, and reproductive diseases. We also present two case studies that use organ-on-a-chip design principles to model placental drug transport and hormonally regulated crosstalk between multiple female reproductive organs. Finally, we discuss challenges and opportunities for the advancement of reproductive organ-on-a-chip technology.

Role of Elevated SFLT-1 on the Regulation of Placental Transporters in Women With Pre-Eclampsia.

Pre‐eclampsia (PE) is an obstetric complication associated with elevated levels of fms‐like tyrosine kinase 1 (sFlt‐1) and dysregulated trophoblast differentiation. However, limited information exists on the expression and regulation of placental drug transporters in PE. Transporter mRNA and protein expression were analyzed in human placentas diagnosed with PE (n = 34) and gestational age‐matched controls (n = 24), whereas placental BeWo cells were treated with angiogenic factors in vitro. Significant downregulation of breast cancer resistance protein (BCRP) and several other transporters were seen in placentas complicated by PE compared with controls, whereas mRNA levels of sFlt‐1 were induced by 2.5‐fold in PE placentas (P < 0.01). Treatment of BeWo cells with sFlt‐1 resulted in an 85–90% downregulation of BCRP, which was attenuated by vascular endothelial growth factor. Our findings suggest that placental function is compromised during PE due to altered expression of clinically important transporters. Furthermore, our in vitro results show that sFlt‐1 is involved in the regulation of BCRP.

Chapter 8 - Perinatal pharmacology and safety profiles

Most medications are not adequately evaluated for use during pregnancy, delivery, or the postpartum period, and package inserts fail to provide clear instructions for use in these contexts, despite major concerns among health-care providers and the community as to how to practice evidence-based pharmacotherapy. Valproate fetopathy hereby serves as one of the more recent illustrations of the scope of the problem. At its best, evidence-based pharmacotherapy is driven by a balanced decision between disease-related risks (natural course of the disease) and any risks related to exposure to medications for mother, fetus, or infant. This chapter aims to describe the general patterns of changes in pharmacokinetics (absorption, distribution, metabolism, elimination) in pregnant women and postpartum, with specific emphasis on placental drug transport and additional focus on lactation. The relevance of these changes is illustrated by discussing medications commonly prescribed to treat neurologic conditions.

Biomimetic Micropatterned Adhesive Surfaces To Mechanobiologically Regulate Placental Trophoblast Fusion.

The placental syncytiotrophoblast is a giant multinucleated cell that forms a tree-like structure and regulates transport between mother and baby during development. It is maintained throughout pregnancy by continuous fusion of trophoblast cells, and disruptions in fusion are associated with considerable adverse health effects including diseases such as preeclampsia. Developing predictive control over cell fusion in culture models is hence of critical importance in placental drug discovery and transport studies, but this can currently be only partially achieved with biochemical factors. Here, we investigate whether biophysical signals associated with budding morphogenesis during development of the placental villous tree can synergistically direct and enhancetrophoblast fusion. We use micropatterning techniques to manipulate physical stresses in engineered microtissues and demonstrate that biomimetic geometries simulating budding robustly enhance fusion and alter spatial patterns of synthesis of pregnancy-related hormones. These findings indicate that biophysical signals play a previously unrecognized and significant role in regulating placental fusion and function, in synergy with established soluble signals. More broadly, our studies demonstrate that biomimetic strategies focusing on tissue mechanics can be important approaches to design, build, and test placental tissue cultures for future studies of pregnancy-related drug safety, efficacy, and discovery.

Chemotherapy in pregnancy: exploratory study of the effects of paclitaxel on the expression of placental drug transporters.

Introduction The use of paclitaxel in pregnant cancer patients is feasible in terms of fetal safety, but little is known about the effects of paclitaxel on the placenta. Using three experimental models, we aimed to assess the effects of paclitaxel on the expression of placental drug transporters. Methods In the in vitro model (human primary trophoblast culture), trophoblasts were isolated from normal term placentas and subsequently exposed to paclitaxel. The transcriptional regulation of 84 genes encoding for drug transporters, and the protein expression of ABCB1/P-gp and ABCG2/BCRP were assessed. In the in vivo model, placental tissues isolated from pregnant cancer patients treated with paclitaxel were analyzed to assess the protein expression of ABCB1/P-gp and ABCG2/BCRP. The same parameters were assessed in extracts from human placental cotyledons perfused ex vivo with paclitaxel. Results In the in vitro model, the expression of twelve drug-transporters genes was found to be significantly down-regulated after exposure to paclitaxel, including ABCC10, SLC28A3, SLC29A2, and ATP7B (involved in the transport of taxanes, antimetabolites, and cisplatin, respectively). The protein expression of ABCB1/P-gp increased by 1.3-fold after paclitaxel administration. Finally, the protein expression of ABCB1/P-gp and ABCG2/BCRP was higher in cotyledons from mothers treated with multiple doses of paclitaxel during pregnancy than in cotyledons perfused with a single dose of paclitaxel. Discussion Paclitaxel modulates the expression of placental drug transporters involved in the disposition of various anticancer agents. Further studies will be needed to assess the impact of repeated or prolonged exposure to paclitaxel on the expression and function of placental drug transporters.

Approach for differentiating trophoblast cell lineage from human induced pluripotent stem cells with retinoic acid in the absence of bone morphogenetic protein 4

IntroductionPlacental transport is the first step in chemotherapeutic safety evaluations during pregnancy. However, a well-established in vitro model is not available. We previously reported that a trophoblast layer model using differentiating choriocarcinoma JEG-3 cells (DJEGs) can be used for placental drug transport studies. However, it was necessary to increase the similarities between the syncytiotrophoblast, the main layer of the placental barrier, and the in vitro evaluation model in order for the model to be useful for placental drug transport evaluations. We focused on in vivo similarities of differentiating induced pluripotent stem cells (iPSCs). iPSCs can achieve a syncytiotrophoblast-like form and secrete human chorionic gonadotropin (hCG) following bone morphogenetic protein 4 (BMP4) treatment. However, BMP4-treated iPSCs can differentiate into several cell types. In the placental transport model, a dense syncytiotrophoblast cell layer is necessary for appropriate differentiation. MethodsThe conditions permitting differentiation of iPSCs into syncytiotrophoblasts with retinoic acid (RA) treatment without BMP4 were investigated. The presence of syncytiotrophoblast-like cells was confirmed by measurement of mRNA expression levels of breast cancer resistance protein (BCRP) and paternally expressed 10 (PEG10) in syncytiotrophoblasts. In addition, immunofluorescence imaging of cytokeratin 7 (CK7) induced in trophoblasts was performed. Resultsand Discussion: RA-induced iPSCs exhibited these syncytiotrophoblast-like features and hCG secretion was maintained for at least 28 days after treatment with RA (500 nM) without BMP4. These results suggest that RA-induced iPSCs are a suitable in vitro syncytiotrophoblast model that can be used as an indicator of drug placental transport for pharmacotherapy during pregnancy.

Regulation of human placental drug transporters in HCV infection and their influence on direct acting antiviral medications

IntroductionThe objectives of this study were to determine how HCV infection affects placental drug transporters, and to determine the role of drug transporters on the cellular accumulation of direct-acting antiviral drugs in human trophoblasts. MethodsEighty-four ABC and SLC transporter genes were first screened in normal and HCV infected pregnant women using PCR profiler array. The changes in expression were confirmed by qPCR and Western blot. The impact of selected drug transporters on the cellular accumulation of radiolabeled antiviral drugs sofosbuvir, entecavir, and tenofovir was measured in primary human trophoblasts (PHT) and BeWo b30 cells in the presence or absence of transporter-specific inhibitors. PHT were then treated with CL097, ssRNA40, and imquimod to determine the impact of Toll-like receptor (TLR) 7/8 activation on drug transporter expression. ResultsThe expression of the ABC efflux transporters ABCB1/P-gp and ABCG2/BCRP was increased in placenta of women with HCV, while the nucleoside transporters SLC29A1/ENT1 and SLC29A2/ENT2 remained unchanged. The accumulation of sofosbuvir and tenofovir was unaffected by inhibition of these transporters in trophoblast cells. Entecavir accumulation was decreased by the inhibition of ENT2. P-gp and BCRP inhibition enhanced entecavir accumulation in BeWo b30, but not PHT. Overall, there was little effect of TLR7/8 activation on these drug transporters, and the accumulation of entecavir in PHT. DiscussionThe data suggest that expression of placental drug transporters and selection of antiviral drug may impact fetal drug exposure in pregnancies complicated by HCV infections.

Effect of Histone Deacetylase Inhibition on the Expression of Multidrug Resistance-associated Protein 2 in a Human Placental Trophoblast Cell Line.

Background:Placental multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene in human, plays a significant role in regulating drugs’ transplacental transfer rates. Studies on placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases (HDACs) inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC1/2/3 are preliminarily involved in this process.Methods:The human choriocarcinoma-derived trophoblast cell line (Bewo cells) was treated with the HDAC inhibitors-trichostatin A (TSA) at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 μmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA (siRNA) specific for HDAC1/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC1/2/3/ABCC2 messenger RNA (mRNA) and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively.Results:TSA could inhibit total HDAC activity and HDAC1/2/3 expression in company with increase of MRP2 expression in Bewo cells. Reduction of HDAC1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 μmol/L (vs. vehicle group, all P < 0.001), accompanied with dose-dependent induction of MRP2 expression (P = 0.045 for 1.0 μmol/L, P = 0.001 for 3.0 μmol/L, and P < 0.001 for 5.0 μmol/L), whereas no significant differences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells were week, and no significant differences were noticed among these three groups (all P > 0.05). However, MRP2 expression was remarkably elevated in HDAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells (P < 0.001).Conclusions:HDACs inhibition could up-regulate placental MRP2 expression in vitro, and HDAC1 was probably to be involved in this process.

Impact of endotoxin on the expression of drug transporters in the placenta of HIV-1 transgenic (HIV-Tg) rats

BackgroundInflammatory responses in HIV (+) patients may be exacerbated due to reports of subclinical endotoxemia and existing immune dysregulation. As inflammation has been reported to mediate changes in the expression of transporters, this could be potentiated in pregnant HIV (+) women. Similar to humans, the HIV-Tg rat model develops immune dysregulation and chronic AIDS-like conditions. Our objective was to examine the expression of placental drug transporters in HIV-Tg rats in response to low-dose endotoxin. MethodsPregnant HIV-Tg rats or wild-type littermates (WT) were treated with low dose bacterial endotoxin 0.1mg/kg (n=8) or 0.25mg/kg (n=4–6) on GD18 and placentas were harvested 18h later. Placental and hepatic expression of transporters and cytokines were examined using qRT-PCR and Western blotting. ResultsAs compared to WT, endotoxin administration increased the hepatic and placental expression of IL-6 and TNF-α to a greater extent in HIV-Tg rats (p<0.05). The placental mRNA and protein expression of Abcb1a and Slco2b1 was significantly decreased in endotoxin-treated HIV-Tg but not WT rats and downregulation of Slco4a1 mRNA was more pronounced in the HIV-Tg group (p<0.05). These changes significantly correlated with the placental expression of pro-inflammatory cytokines. Abcc3 mRNA expression was increased in the placenta of endotoxin treated WT rats only, while placental expression of Abcc1, Abcc2 and Abcc4 was not significantly affected in both WT and HIV rats. Endotoxin imposed a pronounced downregulation in the hepatic expression of Abcb1a, Abcc2, Abcc4, Abcg2, Slco1a1, Slco1b2 and Slc29a1 in both HIV-Tg and WT rats; however, Abcb1b expression was increased in HIV but not WT rats. ConclusionOur results indicate that low-dose endotoxin resulted in an augmented inflammatory response in HIV-Tg rats accompanied with significant changes in the placental expression of several drug transporters. Our data suggests that subclinical endotoxemia and other co-existing infections may alter the placental transfer of drugs in the HIV population.

531: Chemotherapy and pregnancy: effects of taxanes exposure on placental drug transporters expression

531: Chemotherapy and pregnancy: effects of taxanes exposure on placental drug transporters expression

Drug transporter expression during in vitro differentiation of first-trimester and term human villous trophoblasts

Drug transporters interfere with drug disposition during pregnancy by actively transporting drugs from mother to fetus, and vice versa. Data on their placental expression are scarce, especially during the first trimester of pregnancy. The aim of our study was to assess mRNA expression of more than 80 drug transporters by using an RT-qPCR array in primary cytotrophoblastic cells isolated from first-trimester and term human placentas and cultured for 72 h to form syncytiotrophoblasts. This original expression panel of human placental drug transporters should help to understand transplacental drug transfer and to ensure more rational drug use during pregnancy.

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

Preventing and treating malaria in pregnancy is a global health priority. However little is known regarding the impact of malaria infection on the maternal and fetal disposition of pharmaceuticals and other xenobiotics. Our objective was to characterize expression of key determinants of drug-disposition in maternal and fetal tissues in a validated murine model of experimental placental malaria. Balb/c mice were infected with Plasmodium berghei at mid gestation [gestational day (GD) 13] and maternal, placental, and fetal tissues were collected at GD19. Expression of key ABC drug transporters and Cyp3a11 was examined by quantitative polymerase chain reaction. Western blotting was used to examine the protein expression of multidrug resistance protein 1 (MDR1, ABCB1). Compared with controls, placental mRNA expression of Abcb1a, Abcb1b, Abcc1, Abcc2, Abcc3, and Abcg2 were significantly downregulated in the malaria-infected group (P < 0.05), as was placental MDR1 protein (P < 0.05). Significantly decreased hepatic expression of Abcc2, Abcg2, and Abcb11 and significantly increased expression of Abcb1b, Abcc1, and Abcc3 were seen in malaria-infected dams (P < 0.05) in comparison with uninfected controls. The expression of Abcb1a and Abcg2 was significantly decreased in fetal liver of infected dams, whereas levels of Abcb1b were increased (P < 0.05). Maternal and fetal hepatic expression of Cyp3a11 was significantly downregulated in the malaria group (P < 0.05). Together, malaria-induced alterations in the expression of transporters and drug-metabolizing enzymes in maternal and fetal tissues may alter the disposition of endogenous and therapeutic substrates, potentially impacting maternal and fetal outcomes.

Prenatal Endotoxemia and Placental Drug Transport in The Mouse: Placental Size-Specific Effects

Lipopolysaccharide (LPS) in high doses inhibits placental multidrug resistance P-glycoprotein (P-gp - Abcb1a/b) and breast cancer resistance protein (BCRP - Abcg2). This potentially impairs fetal protection against harmful factors in the maternal circulation. However, it is unknown whether LPS exposure, at doses that mimic sub-lethal clinical infection, alters placental multidrug resistance. We hypothesized that sub-lethal (fetal) LPS exposure reduces placental P-gp activity. Acute LPS (n = 19;150 µg/kg; ip) or vehicle (n = 19) were given to C57BL/6 mice at E15.5 and E17.5. Placentas and fetal-units were collected 4 and 24 h following injection. Chronic LPS (n = 6; 5 µg/kg/day; ip) or vehicle (n = 5) were administered from E11.5–15.5 and tissues were collected 4 h after final treatment. P-gp activity was assessed by [3H]digoxin accumulation. Placental Abcb1a/b, Abcg2, interleukin-6 (Il-6), Tnf-α, Il-10 and toll-like receptor-4 (Tlr-4) mRNA were measured by qPCR. Maternal plasma IL-6 was determined. At E15.5, maternal IL-6 was elevated 4 h after single (p<0.001) and chronic (p<0.05) LPS, but levels had returned to baseline by 24 h. Placental Il-6 mRNA was also increased after acute and chronic LPS treatments (p<0.05), whereas Abcb1a/b and Abcg2 mRNA were unaffected. However, fetal [3H]digoxin accumulation was increased (p<0.05) 4 h after acute LPS, and maternal [3H]digoxin myocardial accumulation was increased (p<0.05) in mice exposed to chronic LPS treatments. There was a negative correlation between fetal [3H]digoxin accumulation and placental size (p<0.0001). Acute and chronic sub-lethal LPS exposure resulted in a robust inflammatory response in the maternal systemic circulation and placenta. Acute infection decreased placental P-gp activity in a time- and gestational age-dependent manner. Chronic LPS decreased P-gp activity in the maternal myocardium and there was a trend for fetuses with smaller placentas to accumulate more P-gp substrate than their larger counterparts. Collectively, we demonstrate that acute sub-lethal LPS exposure during pregnancy impairs fetal protection against potentially harmful xenobiotics in the maternal circulation.

Placental drug transporters and their role in fetal protection

The human placenta has a number of protective mechanisms that help to prevent potentially harmful compounds from entering the fetal compartment. Two important transporter proteins are phospho-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) which are mainly expressed in the syncytiotrophoblast where they actively extrude a wide range of xenobiotics. The expression profile of these transporters varies with advancing gestation. P-gp has been shown to decline near term, leaving the fetus susceptible to potentially teratogenic drugs commonly administered to pregnant women (i.e. synthetic glucocorticoids, selective serotonin reuptake inhibitors, glyburide, antiretrovirals, etc.). Drug transporter expression is regulated by a number of transcription factors, and steroid hormones present during pregnancy, such as progesterone, estrogen and corticosteroids. Drug transporter levels have also been found to be altered in pathological pregnancies (preterm, pre-eclampsia, growth restriction and infection). Genetic variation in the genes that encode these drug transporters can significantly alter transporter function and may play a significant role in determining the susceptibility of a fetus to maternally-administered therapeutic drugs. Understanding the regulation of placental drug transporters in normal and pathological pregnancies is critical to further our knowledge of fetal development, and may lead to the development of more selectively-targeted maternal and fetal drug treatments.