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Immunohistochemical localization of MDR1 and BCRP in human placentas . Results show MDR1 and BCRP localization to the membrane of the syncytiotrophoblast cells (arrows) in all tissue conditions (n 3/tissue group). BCRP was also localized to the fetal blood vessel endothelial cells (arrowheads). The MDR1 and BCRP controls are indicative of immunostaining without primary antibody. Original magnification, 100. Scale bars (in control), 120 m.
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Fetal drug exposure is determined by the type and concentration of placental transporters, and their regulation is central to the development of new treatments and delivery strategies for pregnant women and their fetuses. We tested the expression of several clinically important transporters in the human placenta associated with various pregnancy co...
Contexts in source publication
Context 1
... proper cellular localization is essential for transporters to perform their transport function. Immunohistochemical analysis ver- ified that the observed changes were due to MDR1 and BCRP (Fig. 2) expression at the membrane of the syncytiotrophoblast cells. BCRP was also localized to fetal blood vessel endothelial cells (Fig. ...
Context 2
... proper cellular localization is essential for transporters to perform their transport function. Immunohistochemical analysis ver- ified that the observed changes were due to MDR1 and BCRP (Fig. 2) expression at the membrane of the syncytiotrophoblast cells. BCRP was also localized to fetal blood vessel endothelial cells (Fig. ...
Citations
... The expression of the SV2C gene increases in exosomes in the blood of the mother with gestational diabetes compared with the group with normal pregnancy (Fang et al., 2021). Hypomethylation and high expression of the TICAM2 gene are also associated with preeclampsia and premature birth (Mason et al., 2011;Lim et al., 2020). ...
In humans, aneuploidy is incompatible with the birth of healthy children and mainly leads to the death of embryos in the early stages of development in the first trimester of pregnancy. Trisomy 16 is the most common aneup loidy among spontaneous abortions of the first trimester of pregnancy. However, the mechanisms leading to the death of embryos with trisomy 16 remain insufficiently investigated. One of these potential mechanisms is abnormal placental development, including aberrant remodeling of spiral arteries. Spiral artery remodeling involves the migration of trophoblast cells into the maternal spiral arteries, replacing their endothelium and remodeling to ensure a stable embryonic nutrition and oxygen supply. This is a complex process which depends on many factors from both the embryo and the mother. We analyzed the methylation level of seven genes ( ADORA2B , NPR3 , PRDM1 , PSG2 , PHTLH , SV2C, and TICAM2 ) involved in placental development in the chorionic villi of spontaneous abortions with trisomy 16 ( n = 14), compared with spontaneous abortions with a normal karyotype ( n = 31) and the control group of induced abortions ( n = 10). To obtain sequencing libraries, targeted amplification of individual gene regions using designed oligonucleot ide primers for bisulfite-converted DNA was used. The analysis was carried out using targeted bisulfite massive parallel sequencing. In the group of spontaneous abortions with trisomy 16, the level of methylation of the PRDM1 and PSG2 genes was significantly increased compared to induced abortions ( p = 0.0004 and p = 0.0015, respectively). In the group of spontaneous abortions, there was no increase in the level of methylation of the PRDM1 and PSG2 genes, but the level of methylation of the ADORA2B gene was significantly increased compared to the induced abortions ( p = 0.032). The results obtained indicate the potential mechanisms of the pathogenetic effect of trisomy 16 on the placental development with the participation of the studied genes.
... Placental MDR expression profiles in preterm labor pregnancies with chorioamnionitis has been investigated in different cohorts of patients. Increased expression of P-gp/ABCB1 and BCRP/ABCG2 was reported in preterm labor with infected chorioamnionitis compared to non-infective preterm labor placentas (Mason et al., 2011). Accordingly, P-gp expression was increased in infected preterm placentas compared to term controls in a larger cohort of patients (Scott et al., 2021). ...
... Importantly, MRP1 (ABCC1) and MRP2 (ABCC2) protein expression did not change in preterm labor infected placentae (compared to non-infected preterm labor placentae). Conversely, in the same cohort, placental MDR3 (ABCB4) protein levels increased in infected chorioamnionitis compared to non-infected preterm labor placentae (Mason et al., 2011). Since MDR3 is localized in the basolateral membrane of the syncytiotrophoblast, an increase of in MDR3 protein levels may favor the transfer of drug substrates into the fetal compartment. ...
P-glycoprotein (P-gp, encoded by the ABCB1) and breast cancer resistance protein (BCRP/ABCG2) are efflux multidrug resistance (MDR) transporters localized at the syncytiotrophoblast barrier of the placenta and protect the conceptus from drug and toxin exposure throughout pregnancy. Infection is an important modulator of MDR expression and function. This review comprehensively examines the effect of infection on the MDR transporters, P-gp and BCRP in the placenta. Infection PAMPs such as bacterial lipopolysaccharide (LPS) and viral polyinosinic–polycytidylic acid (poly I:C) and single-stranded (ss)RNA, as well as infection with Zika virus (ZIKV), Plasmodium berghei ANKA (modeling malaria in pregnancy – MiP) and polymicrobial infection of intrauterine tissues (chorioamnionitis) all modulate placental P-gp and BCRP at the levels of mRNA, protein and or function; with specific responses varying according to gestational age, trophoblast type and species (human vs. mice). Furthermore, we describe the expression and localization profile of Toll-like receptor (TLR) proteins of the innate immune system at the maternal-fetal interface, aiming to better understand how infective agents modulate placental MDR. We also highlight important gaps in the field and propose future research directions. We conclude that alterations in placental MDR expression and function induced by infective agents may not only alter the intrauterine biodistribution of important MDR substrates such as drugs, toxins, hormones, cytokines, chemokines and waste metabolites, but also impact normal placentation and adversely affect pregnancy outcome and maternal/neonatal health.
... However, studies to demonstrate their functional role in vivo in determining fetal drug exposure, through in vitro or perfused human placenta studies, are limited. The placental transporters show gestational agedependent abundance/expression, for example, the abundance/expression of P-gp, BCRP, organic anion transporting polypeptide (OATP) 1A2, OATP2B1, OATP1B1, and organic cation/carnitine transporter 2 decreases from the first trimester to term 21,22,[37][38][39][40][41][42][43][44][45] while that of MRP2, organic anion transporter 4, and organic cation transporter 3 increases as gestation progresses. 22,[46][47][48][49] The abundance/expression of OATP4A1, MRP1, MRP3, and multidrug and toxin extrusion 1 shows no change throughout pregnancy. ...
... 22,[46][47][48][49] The abundance/expression of OATP4A1, MRP1, MRP3, and multidrug and toxin extrusion 1 shows no change throughout pregnancy. 37,43,46,48,49 It is important to note that where the abundance of transporters per gram of placental tissue decreases (e.g., P-gp), the overall abundance of the transporters in the whole placenta increases with gestational age because the placenta significantly increases in size with gestational age. Unfortunately, literature reports are controversial regarding the ontogeny of several placental transporters (e.g., Pgp, MRP1, OATP1B1, organic cation transporter 3), 21,37,46,[48][49][50] and additional studies are needed to clarify their ontogeny. ...
... 37,43,46,48,49 It is important to note that where the abundance of transporters per gram of placental tissue decreases (e.g., P-gp), the overall abundance of the transporters in the whole placenta increases with gestational age because the placenta significantly increases in size with gestational age. Unfortunately, literature reports are controversial regarding the ontogeny of several placental transporters (e.g., Pgp, MRP1, OATP1B1, organic cation transporter 3), 21,37,46,[48][49][50] and additional studies are needed to clarify their ontogeny. ...
Medication (drug) use in human pregnancy is prevalent. Determining fetal safety and efficacy of drugs is logistically challenging. However, predicting (not measuring) fetal drug exposure (systemic and tissue) throughout pregnancy is possible through maternal‐fetal physiologically based pharmacokinetic (PBPK) modeling and simulation. Such prediction can inform fetal drug safety and efficacy. Fetal drug exposure can be quantified in 2 complementary ways. First, the ratio of the steady‐state unbound plasma concentration in the fetal plasma (or area under the plasma concentration–time curve) to the corresponding maternal plasma concentration (ie, Kp,uu). Second, the maximum unbound peak (Cu,max,ss,f) and trough (Cu,min,ss,f) fetal steady‐state plasma concentrations. We (and others) have developed a maternal‐fetal PBPK model that can successfully predict maternal drug exposure. To predict fetal drug exposure, the model needs to be populated with drug specific parameters, of which transplacental clearances (active and/or passive) and placental/fetal metabolism of the drug are critical. Herein, we describe in vitro studies in cells/tissue fractions or the perfused human placenta that can be used to determine these drug‐specific parameters. In addition, we provide examples whereby this approach has successfully predicted systemic fetal exposure to drugs that passively or actively cross the placenta. Apart from maternal‐fetal PBPK models, animal studies also have the potential to estimate fetal drug exposure by allometric scaling. Whether such scaling will be successful is yet to be determined. Here, we review the above approaches to predict fetal drug exposure, outline gaps in our knowledge to make such predictions and map out future research directions that could fill these gaps.
... The resulting increase in systemic levels of proinflammatory cytokines as well as placental hypoxia have each been shown to impact transporter regulation [181,187,192]. Indeed, changes in expression of numerous transporters along with alterations in transcript levels of cytokines and growth factors were seen in placenta obtained from women with preeclampsia [170,174]. These samples compared to gestation age-matched controls, displayed significantly decreased transcript levels of BCRP, MRP1, OCT3, OAT4, and ENT2, along with increased levels of OATP2B1 [174]. ...
Drug transporters play an important role in the maintenance of chemical balance and homeostasis in different tissues. In addition to their physiological functions, they are crucial for the absorption, distribution, and elimination of many clinically important drugs, thereby impacting therapeutic efficacy and toxicity. Increasing evidence has demonstrated that infectious, metabolic, inflammatory, and neurodegenerative diseases alter the expression and function of drug transporters. However, the current knowledge on transporter regulation in critical protective barriers, such as the brain and placenta, is still limited and requires more research. For instance, while many studies have examined P-glycoprotein, it is evident that research on the regulation of highly expressed transporters in the blood-brain barrier and blood-placental barrier are lacking. The aim of this review is to summarize the currently available literature in order to better understand transporter regulation in these critical barriers.
... The present study focuses on the human breast cancer resistance protein (BCRP/ ABCG2), an ATP-binding cassette efflux transporter protein previously identified in the placenta [10,17]. BCRP is a well-expressed drug transport protein throughout the human body, including the apical surface of the placental syncytiotrophoblasts, liver hepatocytes, the intestinal tract epithelium, the endothelial cells of the brain, and the proximal renal tubules [18]. ...
... BCRP was localized in the basal side of amnion epithelium (1) and predominantly expressed in CTCs (2) ( Figure 1B). As reported in previous studies, and used here as a positive control ( Figure 1B), BCRP was localized in the syncytiotrophoblast of the placenta, where it functions primarily to protect the developing fetus by effluxing the xenobiotics present back to the maternal circulation [10,17]. To confirm the relative expression levels of BCRP in FM, WB was performed. ...
During pregnancy, the placenta is established as a primary organ for drug transport at the maternal-fetal interface. The fetal membranes (FM) also form an interface with maternal tissues; however, their role in drug transport has not been previously investigated. Knowledge of drug transport across this feto-maternal interface along with the placenta can improve new drug development and testing for use during pregnancy. We also hypothesize that extracellular vesicles (exosomes 30–160 nm) released from the FM and placental cells may also contain drug transport proteins and might impact drug trafficking across the feto-maternal interfaces. The objectives were to (1) localize the breast cancer resistance protein (BCRP) in human FM; (2) determine the drug transport function of BCRP in chorion trophoblast cells (CTCs) of the FM; and (3) investigate the presence of BCRP in FM cell-derived exosomes, as a paracrine modifier of the tissue environment for transport functions. The gene and protein expressions of ABCG2/BCRP in FMs were determined by quantitative real-time PCR (qRT-PCR) and western blotting (WB) and were localized by immunohistochemistry (IHC). The surface expression of BCRP in FM cells was determined by flow cytometry. The functional role of BCRP was assessed by an EFFLUX dye multidrug resistance assay. The presence of BCRP in exosomes derived from CTCs and BeWo cells was examined using ExoView®. Data derived from CTCs are compared with placental trophoblast cells (BeWo). BCRP is expressed and localized in the fetal membrane, primarily in the chorion trophoblast cell layer and scarcely in the amnion epithelial layer (AEC), and primarily localized on both AEC and CTC cell surfaces. Efflux assay data showed that FM cells have similar drug resistance activity as BeWo cells, suggesting that FM also have drug transportation capabilities. BeWo- and CTC-derived exosomes expressed limited BCRP protein on the surface, so it was predominantly contained in the exosomal lumen. As far as we are aware, this is the first study to report BCRP expression in fetal membrane cells and as cargo in fetal membrane-derived exosomes. We report that fetal membrane cells are capable of drug transportation. Based on these results, investigational drug trials should include the FM and its exosomes as possible drug transportation routes in pregnancy.
... In one study, women with CA exhibited a 50% reduction in placental BCRP expression in the third trimester . Other studies have shown differential BCRP and MDR1 expression in preterm CA placentas (Mason et al., 2011;do Imperio et al., 2018) and no change in MDR1 in term CA placentas . Notably, all three of these studies had fairly small sample sizes. ...
As a result, the placenta offers support and protection to the developing fetus by delivering crucial nutrients and removing waste and xenobiotics. ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP), remove chemicals through active efflux and are considered the primary transporters within the placental barrier. Altered transporter expression at the barrier could result in fetal exposure to chemicals and/or accumulation of xenobiotics within trophoblasts. Emerging data demonstrate that expression of these transporters is changed in women with pregnancy complications, suggesting potentially compromised integrity of placental barrier function. The purpose of this review is to summarize the regulation of placental efflux transporters during medicalcomplications of pregnancy including: (1) placental inflammation/infection and chorioamnionitis, (2) hypertensive disorders of pregnancy, (3) metabolic disorders including gestational diabetes and obesity, and (4) fetal growth restriction/altered fetal size forgestational age. For each disorder, we review the basic pathophysiology and consider impacts on the expression and function ofplacental efflux transporters. Mechanisms of transporter dysregulation and implications for fetal drug and toxicant exposure are discussed. Understanding how transporters are up- or down-regulated during pathology is important in assessing possible exposures of the fetus to potentially harmful chemicals in the environment as well as the disposition of novel therapeutics intended to treat placental and fetal diseases. Significance Statement Diseases of pregnancy are associated with reduced expression of placental barrier transporters that may impact fetal pharmacotherapy and exposure to dietary and environmental toxicants.
... BCRP is localized to the syncytiotrophoblast, cytotrophoblast, and endothelial cells of fetal blood vessels, and transports endogenous steroids, antibiotics (beta-lactams, fluoroquinolones), antivirals, sulfonylureas, nutrients, and toxins from the fetus back into the maternal circulation (28,31). The expression of placental P-gp and BCRP transporters varies throughout gestation, and may be higher in preterm placentae, and decrease with gestational age (32). Proinflammatory cytokines such as IL-6, TNF-α, and interferon-γ have been shown to modulate P-gp and BCRP expression and function in placentae/placental cells (33,34), suggesting that BMI, possibly through its contributions to the inflammatory milieu, has the potential to influence placental MDR transporter expression. ...
... PTB and chorioamnionitis thus alter the expression of key placental transporters and inflammatory regulators, which may impact placental development and function. Our observations that placental transporter expression levels were increased in all preterm pregnancies is consistent with previous findings that suggest the expression of P-gp and BCRP transporters in the placenta decrease with gestational age (32,50). Placental ABCB1 mRNA and syncytiotrophoblast P-gp protein levels are higher in first trimester compared with term (49,51), supporting the important role of P-gp in fetal exchange and protection, especially at earlier stages of pregnancy (49). ...
... We did, however, find increased BCRP protein expression in preterm placentae, suggesting a disconnect between gene and protein level results, which could be in part explained by the semi-quantitative nature of immunohistochemistry, or may suggest a functional adaptation in protein translation in response to other regulating factors, such as placental oxygen levels (49). Placental P-gp and BCRP expression have also been shown to be increased in mothers exhibiting high white blood cell count, which may be an indication of infection (32), in line with our findings of increased transporter expression in preterm pregnancies with chorioamnionitis. While results were not significant at the mRNA level, placental P-gp protein expression in the syncytiotrophoblast was highest in preterm pregnancies with chorioamnionitis compared with term pregnancies. ...
Context
Preterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition, however few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected pro-inflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype.
Objective
To determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1) and breast cancer resistance protein (BCRP/ABCG2), and pro-inflammatory cytokine levels are altered by PTB and maternal BMI.
Design and Outcomes
A cross-sectional study was conducted to assess the effect of PTB (+/- chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin [IL]-6 and 8 expression in 60 preterm and 36 term pregnancies.
Results
ABCB1 expression was increased in preterm compared to term placentae (p=0.04). P-gp (p=0.008) and BCRP (p=0.01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, p=0.007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (p=0.0005), and PTC associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes.
Conclusions
PTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6. This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.
... BCRP is localized to the syncytiotrophoblast, cytotrophoblast, and endothelial cells of fetal blood vessels, and transports endogenous steroids, antibiotics (betalactams; doxorubicin; fluoroquinolones), antivirals, sulfonylureas, nutrients, and toxins from the fetus back into the maternal circulation 17,21 . The expression of placental P-gp and BCRP transporters varies throughout gestation, and may be higher in preterm placentae, and decrease with gestational age 22 . The effects of maternal BMI on the expression of placental efflux transporters are not well understood, but are critical to study, as in many regions of the world these conditions coexist with other infectious and inflammatory diseases and increased medication use, for which MDR transporters may be affected. ...
... Our observations that placental transporter expression levels were increased in all preterm pregnancies is consistent with previous findings that suggest the expression of P-gp and BCRP transporters in the placenta decrease with gestational age 22,32 . Placental ABCB1 mRNA and syncytiotrophoblast P-gp protein levels are higher in first trimester compared to term 30,33 , supporting the important role of P-gp in fetal exchange and protection, especially at earlier stages of pregnancy 30 . ...
... We did, however, find increased BCRP protein expression in preterm placentae, suggesting a disconnect between gene and protein level results, which could be in part explained by the semi-quantitative nature of immunohistochemistry, or may suggest a functional adaptation in protein translation in response to other regulating factors, such placental oxygen levels 30 . Placental P-gp and BCRP expression have also been shown to be increased in mothers exhibiting high white blood cell count, which may be an indication of infection 22 , in line with our findings of increased transporter expression in preterm pregnancies with chorioamnionitis. While results were not significant at the mRNA level, placental P-gp protein expression in the syncytiotrophoblast was highest in preterm pregnancies with chorioamnionitis compared to term pregnancies. ...
Context
Preterm birth (PTB) and suboptimal prepregnancy body mass index (BMI) operate through inflammatory pathways to impair fetoplacental development. Placental efflux transporters mediate fetal protection and nutrition, however few studies consider the effect of both PTB and BMI on fetal protection. We hypothesized that PTB would alter the expression of placental multidrug resistance (MDR) transporters and selected pro-inflammatory cytokines, and that maternal underweight and obesity would further impair placental phenotype.
Objective
To determine whether placental MDR transporters P-glycoprotein (P-gp, encoded by ABCB1 ) and breast cancer resistance protein (BCRP/ ABCG2 ), and pro-inflammatory cytokine levels are altered by PTB and maternal BMI.
Design and Outcomes
A cross-sectional study was conducted to assess the effect of PTB (+/- chorioamnionitis), or the effect of maternal prepregnancy BMI on placental MDR transporter and interleukin [IL]-6 and 8 expression in 60 preterm and 36 term pregnancies.
Results
ABCB1 expression was increased in preterm compared to term placentae (p=0.04). P-gp (p=0.008) and BCRP (p=0.01) immunolabeling was increased among all preterm compared to term placentae, with P-gp expression further increased in preterm pregnancies with chorioamnionitis (PTC, p=0.007). Placental IL-6 mRNA expression was decreased in PTC compared to term placentae (p=0.0005), and PTC was associated with the greatest proportion of anti-inflammatory medications administered during pregnancy. Maternal BMI group did not influence placental outcomes.
Conclusions
PTB and infection, but not prepregnancy BMI, alter placental expression of MDR transporters and IL-6 . This may have implications for fetal exposure to xenobiotics that may be present in the maternal circulation in pregnancies complicated by PTB.
... In turn, ABCA1 effluxes cholesterol and cytotoxic oxysterols in the placental barrier towards the maternal side [19]. Of importance, infection and inflammation are potent modulators of placental multidrug resistance and ABC-lipid transporters expression and function [10,[19][20][21][22], demonstrating that infective challenges alter the fetal accumulation of nutrient, cytokines, hormones, drugs, environmental toxins and cytotoxic oxysterols, which may severely impact pregnancy outcome. ...
... LPS treatment of first trimester human placental explants and HTR8/SVneo (human extravillous trophoblast-like) cells, inhibited the expression BCRP/ABCG2 with concomitant increase in mRNA levels of IL-6, IL-8 and CCL2 [32,33]. Conversely, BCRP/ABCG2 levels were found elevated in human preterm placental fragments from patients with chorioamnionitis [20,22]. These divergent results from cell culture and ex-vivo experiments were probably a result of the considerable heterogeneity of human chorioamnionitis when compared to the TLR4-targeted effect of LPS [8,22]. ...
Bacterial infection alters placental ABC transporters expression. These transporters provide fetal protection against circulating xenobiotics and environmental toxins present in maternal blood. We hypothesized that lipopolysaccharide (LPS-bacterial mimic) alters the yolk sac morphology and expression of key ABC transporters in a gestational-age dependent manner. Yolk sac samples from C57BL/6 mice were obtained at gestational ages (GD) 15.5 and GD18.5, 4 or 24 hours after LPS exposure (150ug/kg; n = 8/group). Samples underwent morphometrical, qPCR and immunohistochemistry analysis. The volumetric proportions of the histological components of the yolk sac did not change in response to LPS. LPS increased Abcg2 expression at GD15.5, after 4 h of treatment (p < 0.05). No changes in Abca1, Abcb1a/b, Abcg1, Glut1, Snat1, Il-1β, Ccl2 and Mif were observed. Il-6 and Cxcl1 were undetectable in the yolk sac throughout pregnancy. Abca1, breast cancer resistance protein (Bcrp, encoded by Abcg2) and P-glycoprotein (P-gp/ Abcb1a/b) were localized in the endodermal (uterine-facing) epithelium and to a lesser extent in the mesothelium (amnion-facing), whereas Abca1 was also localized to the endothelium of the yolk sac blood vessels. LPS increased the labeling area and intensity of Bcrp in the yolk sac's mesothelial cells at GD15.5 (4 h), whereas at GD18.5, the area of Bcrp labeling in the mesothelium (4 and 24 h) was decreased (p < 0.05). Bacterial infection has the potential to change yolk sac barrier function by affecting Bcrp and Abcg2 expression in a gestational-age dependent-manner. These changes may alter fetal exposure to xenobiotics and toxic substances present in the maternal circulation and in the uterine cavity.
... The TLR4-mediated immune response at the maternal-fetal interface contributes to poor early placentation and may culminate into a PElike syndrome. In a previous study investigating ATPbinding cassette transporter expression in the human placenta as a function of pregnancy, gene expression of TICAM2 was upregulated in the placentas of women who delivered preterm compared with those women who delivered at term [29]. In this study, PE with severe feature was accompanied with preterm delivery. ...
Background:
Preeclampsia (PE) is an obstetric disorder with significant morbidities for both the mother and fetus possibly caused by a failure of the placental trophoblast invasion. However, its pathophysiology largely remains unclear. Here, we performed DNA methylation profiling to determine whether differential patterns of DNA methylation correlate with PE and severe features of PE.
Materials and methods:
We extracted DNA from placental tissues of 13 normal, five PE, and eight PE pregnant women with severe features. Genome-wide DNA methylation analysis was performed using the Illumina HumanMethylation 850K BeadChip. New functional annotations of differentially methylated CpGs (DMCs) in PE were predicted using bioinformatics tools.
Results:
Significant differences were evident for 398 DMCs, including 243 DMCs in PE and 155 DMCs in PE with severe features, compared with normal placental tissues. Of these, 12 hypermethylated DMCs and three hypomethylated DMCs were observed in both PE groups, thus were independent from severe features. Three hundred seventy-nine DMCs were identified by the presence or absence of severe features. Two hundred genes containing these DMCs were associated with developmental processes and cell morphogenesis. These genes were significantly associated with various PE complications such as disease susceptibility, viral infections, immune system diseases, endocrine disturbance, seizures, hematologic diseases, and thyroid diseases.
Conclusions:
This is the first study to investigate the genome-scale DNA methylation profiles of PE placentas according to severe features. The epigenetic variation in the placentas probably resulted in altered developmental processes and immune dysregulation, contributing to PE. This study provides basic information to refine the clinical and pathological mechanisms of the severe features in placenta-mediated PE.
