The effects of labor on differential gene expression in parturient women, placentas, and fetuses at term pregnancy

Peng, Hsiu-Huei; Kao, Chuan-Chi; Chang, Shuenn‐Dyh; Chao, An‐Shine; Wang, Chao‐Nin; Cheng, Po‐Jen; Lee, Yun‐Shien; Wang, Tzu‐Hao; Wang, Hsin-Shih

doi:10.1016/j.kjms.2011.06.012

Cited by 18 publications

(20 citation statements)

References 41 publications

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“…Such observations can be explained by the T1 and T2 placentae being closer in gestational age than term placentae (Table 1) and, hence, more similar in developmental processes. Additionally, induction of parturition-responsive genes can alter placental gene expression as the organ reaches term (Peng et al, 2011). Hence, at earlier gestational ages (T1 and T2), fetal drug exposure to transporter substrates may be more similar than at term.…”

Section: Discussionmentioning

confidence: 99%

Gestational Age–Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics

et al. 2020

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Some women take medication during pregnancy to address a variety of clinical conditions. Because of ethical and logistical concerns, it is impossible to determine fetal drug exposure, and therefore fetal risk, during pregnancy. Hence, alternative approaches need to be developed to predict maternal-fetal drug exposure throughout pregnancy. To do so, we previously developed and verified a maternalfetal physiologically based pharmacokinetic model, which can predict fetal exposure to drugs that passively cross the placenta. However, many drugs are actively transported by the placenta (e.g., human immunodeficiency virus protease inhibitors). To extend our maternal-fetal physiologically based pharmacokinetic model to these actively transported drugs, we determined the gestational age-dependent changes in the protein abundance of placental transporters. Total cellular membrane fractions from first trimester (T1; n = 15), second trimester (T2; n = 19), and term (n = 15) human placentae obtained from uncomplicated pregnancies were isolated by ultracentrifugation. Transporter protein abundance was determined by targeted quantitative proteomics using liquid chromatography tandem mass specrometry. We observed that breast cancer resistance protein and P-glycoprotein abundance significantly decreased from T1 to term by 55% and 69%, respectively (per gram of tissue). Organic anion-transporting polypeptide (OATP) 2B1 abundance significantly decreased from T1 to T2 by 32%. In contrast, organic cation transporter (OCT) 3 and organic anion transporter 4 abundance significantly increased with gestational age (2-fold from T1 to term, 1.6-fold from T2 to term). Serotonin transporter and norepinephrine transporter did not change with gestational age. The abundance of bile salt export pump, multidrug resistance-associated protein 1-5, Na +-taurocholate cotransporting polypeptide, OATP1B1, OATP1B3, OCTN1-2, concentrative nucleoside transporter 1-3, equilibrative nucleoside transporter 2, and multidrug and toxin extrusion 1 could not be quantified. These data can be incorporated into our maternal-fetal physiologically based pharmacokinetic model to predict fetal exposure to drugs that are actively transported across the placenta. SIGNIFICANCE STATEMENT We quantified the protein abundance of key placental uptake and efflux transporters [organic cation transporter (OCT) 3, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)] across gestational ages (first trimester, second trimester, and term) using quantitative targeted proteomics. We observed that the protein abundance of P-gp and BCRP decreased, whereas that of OCT3 increased with gestational age. Incorporating the protein abundance determined in this study into maternal-fetal physiologically based pharmacokinetic model can help us better predict fetal drug exposure to substrates of these transporters.

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Section: Discussionmentioning

confidence: 99%

Gestational Age–Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics

et al. 2020

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“…All the pregnant women were free of hypertension, diabetes mellitus, preterm labor, and other medical diseases. All neonates were born at term and with normal body weight and healthy vital signs that were evaluated with Apgar scores at 1 min and 5 min after delivery, as used previously [42]–[44].…”

Section: Resultsmentioning

confidence: 99%

“…Eleven normal placental tissues were obtained from 9 healthy individuals who underwent cesarean section without labor pain [42]. This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital (IRB#96-0630B).…”

Section: Methodsmentioning

confidence: 99%

“…The approximate 2.5-cm thickness of the placental cross section was divided into three equal parts: maternal (includes thin basal plate), middle, and fetal (includes the chorionic plate) [32]. We analyzed the middle part of the placental tissues in all of our placental studies [42], [44]. The tissues were snap frozen in liquid nitrogen and stored at −80°C.…”

Section: Methodsmentioning

confidence: 99%

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Intra- and Inter-Individual Variance of Gene Expression in Clinical Studies

Cheng

Shu

et al. 2012

PLoS ONE

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Background Variance in microarray studies has been widely discussed as a critical topic on the identification of differentially expressed genes; however, few studies have addressed the influence of estimating variance. Methodology/Principal Findings To break intra- and inter-individual variance in clinical studies down to three levels–technical, anatomic, and individual–we designed experiments and algorithms to investigate three forms of variances. As a case study, a group of “inter-individual variable genes” were identified to exemplify the influence of underestimated variance on the statistical and biological aspects in identification of differentially expressed genes. Our results showed that inadequate estimation of variance inevitably led to the inclusion of non-statistically significant genes into those listed as significant, thereby interfering with the correct prediction of biological functions. Applying a higher cutoff value of fold changes in the selection of significant genes reduces/eliminates the effects of underestimated variance. Conclusions/Significance Our data demonstrated that correct variance evaluation is critical in selecting significant genes. If the degree of variance is underestimated, “noisy” genes are falsely identified as differentially expressed genes. These genes are the noise associated with biological interpretation, reducing the biological significance of the gene set. Our results also indicate that applying a higher number of fold change as the selection criteria reduces/eliminates the differences between distinct estimations of variance.

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“…Importantly, a number of studies have reported differences in gene expression between labouring and non-labouring placentas [26–29] , which may arise from a decrease in placental oxygen supply during contractions [10] and/or differences in exposure to hormones associated with labour [30] . PHLDA2 is known to be responsive to hypoxia [31–33] but it is not known whether placental expression of PHLDA2 , CDKN1C , PEG3 or PEG10 is altered in response to labour.…”

Section: Introductionmentioning

confidence: 99%

Placental expression of imprinted genes varies with sampling site and mode of delivery

Janssen¹,

Tunster²,

Savory³

et al. 2015

Placenta

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Imprinted genes, which are monoallelically expressed by virtue of an epigenetic process initiated in the germline, are known to play key roles in regulating fetal growth and placental development. Numerous studies are investigating the expression of these imprinted genes in the human placenta in relation to common complications of pregnancy such as fetal growth restriction and preeclampsia. This study aimed to determine whether placental sampling protocols or other factors such as fetal sex, gestational age and mode of delivery may influence the expression of imprinted genes predicted to regulate placental signalling.MethodsTerm placentas were collected from Caucasian women delivering at University Hospital of Wales or Royal Gwent Hospital within two hours of delivery. Expression of the imprinted genes PHLDA2, CDKN1C, PEG3 and PEG10 was assayed by quantitative real time PCR. Intraplacental gene expression was analysed (N = 5). Placental gene expression was compared between male (N = 11) and female (N = 11) infants, early term (N = 8) and late term (N = 10) deliveries and between labouring (N = 13) and non-labouring (N = 21) participants.ResultsThe paternally expressed imprinted genes PEG3 and PEG10 were resilient to differences in sampling site, fetal sex, term gestational age and mode of delivery. The maternally expressed imprinted gene CDKN1C was elevated over 2-fold (p < 0.001) in placenta from labouring deliveries compared with elective caesarean sections. In addition, the maternally expressed imprinted gene PHLDA2 was elevated by 1.8 fold (p = 0.01) in samples taken at the distal edge of the placenta compared to the cord insertion site.ConclusionThese findings support the reinterpretation of existing data sets on these genes in relation to complications of pregnancy and further reinforce the importance of optimising and unifying placental collection protocols for future studies.

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The effects of labor on differential gene expression in parturient women, placentas, and fetuses at term pregnancy

Cited by 18 publications

References 41 publications

Gestational Age–Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics

Gestational Age–Dependent Abundance of Human Placental Transporters as Determined by Quantitative Targeted Proteomics

Intra- and Inter-Individual Variance of Gene Expression in Clinical Studies

Placental expression of imprinted genes varies with sampling site and mode of delivery

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