Placental CRH Research Articles

Promoter methylation changes in the placenta involved in the relationship between prenatal depression and small for gestational age

BackgroundRecent studies suggest that the incidence of small for gestational age (SGA) birth related to maternal depression, but the mechanism is unclear. The aim of this study was to explore the changes of promoter methylation in the placenta which may be involved in the relationship between prenatal depression and SGA.MethodsThree hundred forty-five pregnant women were enrolled in this prospective cohort study. Perinatal emotion and sleep quality in the second and third trimesters were assessed using self-rating depression scale, self-rating anxiety scale, and Pittsburgh sleep quality index. According to the exposure (depressed emotion of mother) and outcome (SGA), the placentas were divided into four groups. Methylation of the promoter regions of the placental CRH, HSD11β2, SLA16A10, DIO3, and MTNR1B genes was determined using next generation sequencing based on bisulfite sequencing PCR.ResultsThere were 97 (28.1%) and 95 (27.5%) pregnant women who had depression in the second trimester and third trimester, respectively. Thirty-five pregnant women had an SGA birth. The incidence of SGA births in this prospective cohort was 10.1%. The risk factors of SGA birth were low BMI of pregnancy women (RR = 0.71, 95%CI = 0.54 ~ 0.92), hypertensive disorder complicating pregnancy (HDCP, RR = 4.7, 95%CI = 1.18 ~ 18.72), and maternal depression in the second trimester (RR = 3.71, 95%CI = 1.31 ~ 12.16). We found that the CRH and HSD11β2 methylation levels were higher in the depression group than those in the non-depression group. Methylation levels of DIO3 were higher in SGA group than that in the non-SGA group. Higher methylation levels of CRH correlated with higher methylation levels of DIO3 in the placenta.ConclusionsMaternal depression in the second trimester may lead to the changes of methylation levels in the promoter region of CRH and HSD11β2 gene, while the changes of methylation of DIO3 in subsequent could related to SGA. This study suggests that maternal depressed emotion during pregnancy may result in SGA due to the epigenetic changes of placenta.

The role of corticoliberin concentration levels and placental CRH receptors 1 and 2 in the prolongation of pregnancy.

Objective To examine the changes in CRH concentrations in the blood serum of pregnant women and in the placenta of patients after the 41st week of gestation, and to determine its influence on the effectiveness of inducing labor and its progress. Materials and Methods The study group comprised pregnant patients who did not deliver until the 41 week of gestation (n = 114). The control group was divided into two subgroups: patients in whom delivery started spontaneously before the 41st week of gestation (n = 24) and pregnant patients in whom delivery started spontaneously after the 41st week of gestation (n = 23). Blood serum and placenta were obtained from the patients. Corticoliberin originating from blood serum was assessed with the use of ELISA Kit. Parts of the placenta were stained with monoclonal antibodies for the presence of corticoliberin, corticoliberin receptors 1 and 2. Results No statistically significant differences were found with regard to corticoliberin concentrations in the blood or during a qualitative assessment of the number of CRH R1 in the placenta between the research groups. However, corticoliberin receptor 2 had a statistically higher expression rate in the control group in which the delivery started spontaneously before the 41st week of gestation. Conclusion In post-term pregnancy, the up-regulation of CRH R2 receptor is disturbed with no change in CRH R1 expression, which complicates the initiation of labor despite correct corticoliberin levels in both blood serum and the placenta. Pregnancy duration over 41 weeks and the effectiveness of preinducing or inducing labor do not depend on corticoliberin concentrations.

Prenatal phthalate exposure in relation to placental corticotropin releasing hormone (pCRH) in the CANDLE cohort.

Phthalates may disrupt maternal-fetal-placental endocrine pathways, affecting pregnancy outcomes and child development. Placental corticotropin releasing hormone (pCRH) is critical for healthy pregnancy and child development, but understudied as a target of endocrine disruption. To examine phthalate metabolite concentrations (as mixtures and individually) in relation to pCRH. Secondary data analysis from a prospective cohort study. Prenatal clinics in Tennessee, USA. 1018 pregnant women (61.4% non-Hispanic Black, 32% non-Hispanic White, 6.6% other) participated in the CANDLE study and provided data. Inclusion criteria included: low-medical-risk singleton pregnancy, age 16-40, and gestational weeks 16-29. None. Plasma pCRH at two visits (mean gestational ages 23.0 and 31.8weeks) and change in pCRH between visits (ΔpCRH). In weighted quantile sums (WQS) regression models, phthalate mixtures were associated with higher pCRH at Visit 1 (β=0.07, 95%CI: 0.02, 0.11) but lower pCRH at Visit 2 (β=-0.08, 95%CI: -0.14, -0.02). In stratified analyses, among women with gestational diabetes (n=59), phthalate mixtures were associated with lower pCRH at Visit 1 (β=-0.17, 95%CI: -0.35, 0.0006) and Visit 2 (β=-0.35, 95%CI: -0.50, -0.19), as well as greater ΔpCRH (β=0.16, 95%CI: 0.07, 0.25). Among women with gestational hypertension (n=102), phthalate mixtures were associated with higher pCRH at Visit 1 (β=0.20, 95%CI: 0.03, 0.36) and Visit 2 (β=0.42; 95%CI: 0.19, 0.64) and lower ΔpCRH (β=-0.17, 95%CI: -0.29, -0.06). Significant interactions between individual phthalate metabolites and pregnancy complications were observed. Phthalates may impact placental CRH secretion, with differing effects across pregnancy. Differences in results between women with and without gestational diabetes and gestational hypertension suggest a need for further research examining whether women with pregnancy complications may be more vulnerable to endocrine-disrupting effects of phthalates.

Associations Between Placental Corticotropin-Releasing Hormone, Maternal Cortisol, and Birth Outcomes, Based on Placental Histopathology.

Preterm birth remains the leading cause of neonatal morbidity and mortality, with complex biochemical pathways requiring continued understanding and assessment. The objective of this study is to assess the associations between maternal cortisol and placental corticotropin-releasing hormone (placental CRH) concentrations with birth outcomes when stratified by placental histopathology. We conducted an analysis of 112 singleton pregnancies who received betamethasone between 23 and 34weeks' gestation. Maternal blood and saliva were collected prior to betamethasone administration and samples assayed for plasma cortisol (pCort), salivary cortisol (sCort), and placental CRH levels. Placental findings were characterized as inflammatory, maternal vascular underperfusion (MVU), or no pathology, and compared for the outcomes of placental CRH, pCort, and sCort levels, gestational age at birth (GAB), and birthweight percentiles (BWP). Thirty-six subjects were characterized as inflammatory, 38 as MVU, and 38 without placental abnormalities. Histopathology groups differed significantly on placental CRH levels, GAB, and BWP. Post hoc tests suggested that the MVU group had higher placental CRH than the inflammatory or no pathology groups, and despite delivering earlier than the other two groups, the inflammatory group had infants with significantly higher BWP. No differences existed between groups in terms of mean plasma or sCort levels. Higher placental CRH and pCort levels were associated with earlier GAB in the overall sample, but when split by group, these associations remained significant only among the MVU group. Higher placental CRH was also associated with lower BWP in the overall sample but did not remain significant when split by group. Higher sCort was associated with lower BWP only in the MVU group. There is differentiation of placental CRH, cortisol, and birth outcomes when evaluated by placental histopathology. This highlights the importance of evaluating birth outcomes within the context of placental histopathology.

MON-346 A Rare Case of Recurring Adrenal Hemorrhage with Consecutive Pregnancies

Introduction - Adrenal hemorrhage (AH) during pregnancy is a rare condition with an incidence ranging from 0.14% to 1.1%. The objective of this report is to describe a case of recurring AH in successive pregnancies. Case Report - A 25-year-old female, G3P1011, 33 weeks of gestation, presented to the ER with the chief complaint of left flank pain. Her past medical history was pertinent for spontaneous abortion of first pregnancy, spontaneous right AH and adrenal insufficiency during the second pregnancy, with an eventual spontaneous vaginal delivery of viable child following medical management. History was negative for personal or family history of thromboembolic disease, anticoagulation use, trauma, signs or symptoms of infection. On admission, her vitals were stable. Pertinent physical exam findings were tenderness to deep palpation of the abdomen on the left upper quadrant. Laboratory results, including hemoglobin, were within normal limits. The US of abdomen revealed fat stranding surrounding the left adrenal gland. Given the concern for AH, after discussing risks and benefits, a CT abdomen without IV contrast was done and revealed abnormally enlarged left adrenal gland with high density, suggestive of hemorrhage. Her random serum cortisol level was low (0.7μg/dL; 7-28 μg/dL). Basal, 30-minute, and 60-minute serum cortisol with low dose ACTH stimulation testing were 0.6μg/dL (minimum 5.5μg/dL), 2.0μg/dL (minimum 7μg/dL), 3.1μg/dL (minimum 18μg/dL), confirming primary adrenal insufficiency and she was started on IV hydrocortisone. Work up for hypercoagulability and bleeding disorder comprising ANA, anticardiolipin antibody, protein C, protein S, antithrombin 3, von Willebrand assay, ristocetin cofactor, plasminogen activity, paroxysmal nocturnal hemoglobinuria panel, platelet function screen, and genetic studies were all normal. Obstetrical US showed single live intrauterine pregnancy, and given hemodynamic stability, she was managed medically. Discussion - This report highlights a case of recurrent AH in consecutive pregnancies, involving opposite adrenal glands and no identifiable hypercoagulable state, which has not been previously reported. During pregnancy, placental CRH stimulates the maternal pituitary gland, increasing ACTH, which subsequently leads to adrenal hypertrophy. The hypertrophied adrenal glands are prone to vascular congestion and can lead to AH. Pregnancy, being a hypercoagulable state, adds to the risk factor as well. AH should be included in the differential when evaluating abdominal pain in prenatal individuals. Emergent surgery and preterm delivery are warranted in patients with hemodynamic instability.

Differentiation of pathologic/neoplastic hypercortisolism (Cushing’s syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome): Letter to the Editor

I enjoyed reading Prof. Findling and Prof. Raff’s recent review article on hypercortisolism (1), and this letter provides further discussion on one sentence in that article. The review states that ‘CRH-binding protein also increases during pregnancy, which may prevent the stimulatory effects of placental CRH on the maternal pituitary gland (67 (2), 68 (3), 69 (4)).’ The references cited at the end of the aforementioned statement, however, do not report that plasma levels of CRH-binding protein increase during pregnancy, and indeed, CRH-BP plasma levels decrease in the last few weeks of pregnancy so the stimulatory effects of placental CRH on the maternal pituitary gland may be increased at this time. Sasaki and coworkers wrote, ‘CRH-binding protein did not increase during pregnancy’ (3) in reference to the paper by Suda and coworkers, which reported that the amount of binding of radiolabeled CRH to CRH-BP in pregnant women’s plasma (the plasma had been stripped of endogenous CRH) does not significantly change throughout pregnancy or become significantly different from non-pregnant controls (2). When endogenous CRH was not pre-stripped from plasma, levels of radiolabeled CRH binding to the CRH-BP stayed relatively stable for the first two trimesters, and then progressively decreased to reach approximately 40% of control non-pregnant levels shortly before parturition (2). The authors concluded that, (1) rises in CRH secretion from the placenta may have been displacing the radiolabeled CRH from the CRH-BP in later pregnancy plasma samples that did not have endogenous CRH removed, (2) the assay that they used does not show actual concentrations of CRH-BP and (3) the results suggest that hypothetically, even if there was a rise in CRH-BP levels at the end of pregnancy (noting that cortisol-binding protein levels show this pattern) that their assay did not reveal, it would be small (2).

Promoter Methylation Pattern Controls Corticotropin Releasing Hormone Gene Activity in Human Trophoblasts.

Placental CRH production increases with advancing pregnancy in women and its course predicts gestational length. We hypothesized that CRH gene expression in the placenta is epigenetically controlled setting gestational trajectories characteristic of normal and pathological pregnancies. Here we determined histone modification and DNA methylation levels and DNA methylation patterns at the CRH promoter in primary trophoblast cultures by chromatin immunoprecipitation combined with clonal bisulfite sequencing and identified the transcriptionally active epialleles that associate with particular histone modifications and transcription factors during syncytialisation and cAMP-stimulation. CRH gene expression increased during syncytial differentiation and cAMP stimulation, which was associated with increased activating and decreased repressive histone modification levels at the promoter. DNA methylation levels remained unchanged. The nine CpGs of the CRH proximal promoter were partially and allele-independently methylated displaying many (>100) epialleles. RNA-polymerase-II (Pol-II) bound only to three particular epialleles in cAMP-stimulated cells, while phospho-cAMP response element-binding protein (pCREB) bound to only one epiallele, which was different from those selected by Pol-II. Binding of TATA-binding protein increased during syncytial differentiation preferentially at epialleles compatible with Pol-II and pCREB binding. Histone-3 acetylation was detected only at epialleles targeted by Pol-II and pCREB, while gene activating histone-4 acetylation and histone-3-lysine-4 trimethylation occurred at CRH epialleles not associated with Pol-II or pCREB. The suppressive histone-3-lysine-27 trimethyl and–lysine-9 trimethyl modifications showed little or no epiallele preference. The epiallele selectivity of activating histone modifications and transcription factor binding demonstrates the epigenetic and functional diversity of the CRH gene in trophoblasts, which is controlled predominantly by the patterns, not the overall extent, of promoter methylation. We propose that conditions impacting on epiallele distribution influence the number of transcriptionally active CRH gene copies in the trophoblast cell population determining the gestational trajectory of placental CRH production in normal and pathological pregnancies.

Maternal Exposure to Childhood Trauma Is Associated During Pregnancy With Placental-Fetal Stress Physiology

BackgroundThe effects of exposure to childhood trauma (CT) may be transmitted across generations; however, the time period(s) and mechanism(s) have yet to be clarified. We address the hypothesis that intergenerational transmission may begin during intrauterine life via the effect of maternal CT exposure on placental-fetal stress physiology, specifically placental corticotropin-releasing hormone (pCRH). MethodsThe study was conducted in a sociodemographically diverse cohort of 295 pregnant women. CT exposure was assessed using the Childhood Trauma Questionnaire. Placental CRH concentrations were quantified in maternal blood collected serially over the course of gestation. Linear mixed effects and Bayesian piece-wise linear models were employed to test hypothesized relationships. ResultsMaternal CT exposure (CT+) was significantly associated with pCRH production. Compared with nonexposed women, CT+ was associated with an almost 25% increase in pCRH toward the end of gestation, and the pCRH trajectory of CT+ women exhibited an approximately twofold steeper increase after the pCRH inflection point at 19 weeks gestation. ConclusionsTo the best of our knowledge, this finding represents the first report linking maternal CT exposure with placental-fetal stress physiology, thus identifying a potential novel biological pathway of intergenerational transmission that may operate as early as during intrauterine life.

Treatment with serotonin reuptake inhibitors during pregnancy is associated with elevated corticotropin-releasing hormone levels

Treatment with serotonin reuptake inhibitors (SSRI) has been associated with an increased risk of preterm birth, but causality remains unclear. While placental CRH production is correlated with gestational length and preterm birth, it has been difficult to establish if psychological stress or mental health problems are associated with increased CRH levels. This study compared second trimester CRH serum concentrations in pregnant women on SSRI treatment (n=207) with untreated depressed women (n=56) and controls (n=609). A secondary aim was to investigate the combined effect of SSRI treatment and CRH levels on gestational length and risk for preterm birth.Women on SSRI treatment had significantly higher second trimester CRH levels than controls, and untreated depressed women. CRH levels and SSRI treatment were independently associated with shorter gestational length. The combined effect of SSRI treatment and high CRH levels yielded the highest risk estimate for preterm birth.SSRI treatment during pregnancy is associated with increased CRH levels. However, the elevated risk for preterm birth in SSRI users appear not to be mediated by increased placental CRH production, instead CRH appear as an independent risk factor for shorter gestational length and preterm birth.

Fetal exposure to placental corticotropin-releasing hormone (pCRH) programs developmental trajectories

The maternal endocrine stress system is profoundly altered during the course of human pregnancy. The human placenta expresses the genes for CRH as early as the seventh week of gestation and it is the expotential increase in placental CRH (pCRH) over the course of human gestation that is responsible for the greatest modification in the maternal stress system. The bi-directional placental release of hormones into the maternal and fetal compartments has profound influences for both. The influential Fetal Programming model predicted that early or fetal exposures to maternal signals of threat or adverse conditions have lifelong consequences for health outcomes. A basic assumption of this model was that developing organisms play a dynamic role in their own construction. Data are reviewed and new data are presented that elevated pCRH over the course of human gestation plays a fundamental role in the organization of the fetal nervous system, modifies birth phenotype (the timing of the onset of spontaneous labor and delivery), and influences developmental, temperamental and metabolic trajectories. Evidence for sex differences and conserved function across species is presented. Finally, a model is presented that proposes several pathways that pCRH can program risk for health and disease.

Fetal programming of children's obesity risk

Childhood obesity affects nearly 17% of children and adolescents in the United States. Increasing evidence indicates that prenatal maternal stress signals influence fetal growth, child obesity, and metabolic risk. Children exhibiting catch-up growth, a rapid and dramatic increase in body size, within the first two years of life are also at an increased risk for developing metabolic disorder and obesity. We evaluate the potential role of the maternal hypothalamic-pituitary-adrenal (HPA) and placental axis in programming risk for child obesity. This prospective longitudinal study measured placental corticotropin-releasing hormone (pCRH) and maternal plasma cortisol at 15, 19, 25, 30, and 37 gestational weeks and collected child body mass index (BMI) at birth, 3, 6, 12, and 24 months. Participants included 246 mothers and their healthy children born full term. Each child's BMI percentile (BMIP) was determined using World Health Organization (WHO) standards based on age and sex. Child BMIP profiles from birth to two years of age were characterized using general growth mixture modeling (GGMM). We evaluated whether fetal exposure to placental CRH and maternal cortisol are associated with BMIP profiles. Placental CRH at 30 gestational weeks was highly associated with both BMIP (p<.05) and weight (p<.05) at birth when accounting for gestational age at birth and used as a predictor in modeling BMIP profiles. Maternal cortisol was not associated with child BMIP. GGMM analyses identified four distinct BMIP profiles: typical, rapid increase, delayed increase, and decreasing (See Fig. 2). The typical profile comprised the majority of the sample and maintained BMIP across the first two years. The rapid and delayed increase profiles each exhibit a period of reduced body size followed by BMI catch-up growth. The rapid increase profile exhibited catch-up within the first 12 months while the delayed group showed an initial decrease in BMIP at 3 months and a dramatic increase from 12 to 24 months. The decreasing profile exhibited normal birth weight and BMIP followed by persisting, low BMIP. The members of the rapid and delayed increase profiles were exposed to the highest concentrations of placental CRH at 30 gestational weeks compared to those in the typical profile group (Fig. 3). Exposure to elevated placental CRH concentrations during the third trimester is associated with catch-up growth. An early period of small body size followed by rapid catch-up growth is a profile associated with increased metabolic risk and increased obesity risk. Our findings suggest that placental CRH exposure makes a unique contribution to fetal programming of obesity risk.

Evaluation of the association between placental corticotrophin-releasing hormone and postpartum depressive symptoms.

Postpartum depression (PPD) represents a significant threat to maternal-child health. Although PPD is common, with an estimated prevalence of 10% to 15%, critical questions concerning its etiology remain unanswered. Existing studies seem to provide conflicting evidence regarding the relation between placental corticotrophin-releasing hormone (pCRH) and the development of PPD. The purpose of the present investigation was to determine whether maternal prepartum hypothalamic-pituitary-adrenal and placental dysregulation, in particular elevated midgestational pCRH, represent markers of risk for the development of PPD symptoms. One hundred seventy adult women with singleton, term pregnancies were recruited during the first trimester and participated in study visits at 15, 19, 25, 31, and 36+ weeks' gestation and at 3 and 6 months postpartum. At each prenatal visit, blood samples were obtained and assayed to determine maternal cortisol, adrenocorticotropic hormone, and pCRH concentrations. Depressive symptoms were assessed at all visits. Depressive symptoms at 3 months postpartum were associated with elevated midgestational pCRH (partial r = 0.26; p < .01) and also accelerated trajectories of pCRH (B values ranged from 6.9 to 8.3, p < .05). Placental CRH was not predictive of PPD symptoms at 6 months postpartum. Furthermore, prepartum cortisol and corticotrophin profiles were not associated with PPD symptoms. The current prospective study provides results that reconcile both the positive and negative findings in the existing literature and identifies elevated pCRH as a marker of risk for the development of PPD symptoms.

Negative Effects of Progesterone Receptor Isoform-A on Human Placental Activity of the Noncanonical NF-κB Signaling

Progesterone (P4)contributes to the maintenance of human pregnancy, in part by inhibiting activity of the human pro-labor genes CRH and cyclooxygenase-2 (COX-2). However, the molecular mechanisms underlying the action of P4 remain poorly defined. We have shown that in human placenta, the constitutively activated noncanonical nuclear factor (NF)-κB pathway positively regulates CRH and COX-2, which is further stimulated by glucocorticoid receptor signaling. We investigated the role of P4 receptor (PR) in the regulation of nuclear activity of v-rel avian reticuloendotheliosis viral oncogene homolog B (RelB)/NF-κB2 and, in turn, expression of placental CRH and COX-2. We used a variety of techniques including gene silencing, ectopic expression, chromatin immunoprecipitation, Western blot, quantitative RT-PCR, and immunohistochemical staining assays in human placental tissues and primary culture of human cytotrophoblast. We identified PR isoform-A (PR-A) as the only isoform of PR produced in human placenta. PR-A levels were lower in term placenta than in midterm placenta. Depletion of PR-A by short interfering RNA derepressed inhibition of CRH and COX-2 by P4 and the synthetic progestin 17α-hydroxyprogesterone caproate. Overexpression of PR-A inhibited transcription of CRH and COX-2, which was further downregulated by treatment with P4 or 17α-hydroxyprogesterone caproate. Such an inhibition was mediated by a negative functional interaction of PR-A with the activity of RelB/NF-κB2. P4 inhibits the pro-labor genes CRH and COX-2 via PR-A repression of the noncanonical NF-κB signaling in human placenta. Characterization of these pathways may identify potential drug targets for prevention of preterm birth.

Pulsatile Interleukin-6 Leads CRH Secretion and Is Associated With Myometrial Contractility During the Active Phase of Term Human Labor

Our objective was to investigate IL-6 and CRH secretion during the active phase of human labor and to define their potential involvement in myometrial contractility. Twenty-two primigravid women were studied for 90 minutes during the active phase of term labor by serial plasma sampling every 3 minutes for measurement of IL-6 and CRH concentrations. Uterine contractions, measured by cardiotocograph, were evaluated in Montevideo units. Basic, quantitative, pulsatility, and time cross-correlation statistical analyses were performed. By linear regression analysis, a positive correlation was observed between IL-6 and CRH total mean area under the curve above 0 (r = 0.76184, P = .006). Mean number of pulses was 2.00 ± 0.70 and 3.33 ± 1.29 for IL-6 and CRH, respectively. There was a significant positive correlation between IL-6 and CRH over time, peaking at the 12-minute interval, with IL-6 leading CRH. Also, there was a significant positive correlation between myometrial contractility expressed in Montevideo units and IL-6 concentrations over time, starting at +51 minutes and ending at +57 minutes with myometrial contractility leading IL-6. No significant correlation was found between myometrial contractility and CRH concentrations over time. IL-6 and CRH are both secreted in a pulsatile fashion during the active phase of human labor. The time-integrated concentrations of the two hormones are positively correlated, with IL-6 leading CRH secretion. It appears, thus, that proinflammatory mediators may be direct and/or indirect promoters of placental CRH release. Furthermore, the secretion of IL-6, which is a myokine, seems to be associated positively with uterine contractility. Additional studies are needed to elucidate the combined effect of inflammation, placental CRH release, and/or the receptors of the latter in parturition.

Bisphenol A differentially activates protein kinase C isoforms in murine placental tissue

Bisphenol A is utilized to make polycarbonate plastics and is an environmental pollutant. Recent research has indicated that it is an endocrine disruptor and may interfere with reproductive processes. Our lab has previously shown that bisphenol A could regulate corticotrophin releasing hormone and aromatase in cultured placental cells. In the present study, the effect of bisphenol A on these two genes in the placenta was investigated in mice. Pregnant ICR mice were gavaged with bisphenol A at 2, 20 and 200mg/kg body weight/day from E13 to E16 and were euthanized at E17. Compared to the control mice, increased plasma estrogen and corticotrophin releasing hormone were observed in bisphenol A-treated mice. Messenger RNA quantification indicated that placental crh but not cyp19 was induced in mice treated with bisphenol A. Tracking the related signaling pathway, we found that protein kinase C ζ/λ and δ were activated in the placentas of bisphenol A-treated mice. As the gene promoter of crh contains CRE and the half site of ERE, either phospho-PKC or estrogen could stimulate the gene transactivation. These results indicate that bisphenol A might increase plasma concentrations of estradiol, testosterone, corticotrophin releasing hormone and placental phospho-PKC ζ/λ and δ in mice. Ultimately, the incidence of premature birth in these mice could increase.

Glucocorticoid Receptor Signaling Contributes to Constitutive Activation of the Noncanonical NF-κB Pathway in Term Human Placenta

Our recent study demonstrated that constitutively activated RelB/NF-κB2 positively regulates the CRH in the human placenta. In the current study, we explored the role of the glucocorticoid receptor (GR) signaling in constitutive activation of the noncanonical NF-κB pathway. A glucocorticoid response element (GRE) motif search suggests that both NF-κB inducing kinase (NIK) and RelB genes, which are key regulators of the noncanonical NF-κB pathway, have a putative GRE within their promoter, approximately 1 kb upstream from the transcription start site. By using chromatin immunoprecipitation assay we identified that the GR and phosphorylated GR at Ser211 were associated with the GREs of both NIK and RelB. Dexamethasone stimulated expression of NIK, RelB, NF-κB2 as well as CRH and cyclooxygenase-2 (COX-2). Repression of GR by short interfering RNA resulted in inhibition of NIK, RelB, NF-κB2, CRH, and COX-2. In addition, depletion of GR attenuated glucocorticoid-mediated up-regulation of NIK, RelB, NF-κB2, CRH, and COX-2. Furthermore, siRNA specifically targeting NIK down-regulated CRH and COX-2. Taken together, these results suggest that constitutive activation of the noncanonical NF-κB pathway in term human placenta is driven by the GR signaling, which in turn up-regulates placental CRH and other NF-κB-responsive genes.

Exposure to childhood trauma among pregnant women is associated with increased placental CRH production over gestation

EUROPEAN JOURNAL OF PSYCHO- TRAUMATOLOGY Supplement 1, 2012 Effects of Traumatic Stress Molecular and Hormonal Mechanism Abstracts from 42 nd Annual Conference New York, September 11–14, 2012

RelB/NF-κB2 Regulates Corticotropin-Releasing Hormone in the Human Placenta

Placental CRH may be part of a clock that governs the length of human gestation. The mechanism underlying differential regulation of CRH in the human placenta is poorly understood. We report here that constitutively activated RelB/nuclear factor-κB2 (NF-κB)-2 (p100/p52) acts as an endogenous stimulatory signal to regulate CRH by binding to an NF-κB enhancer of CRH gene promoter in the human placenta. Nuclear staining of NF-κB2 and RelB in villous syncytiotrophoblasts and cytotrophoblasts was coupled with cytoplasmic CRH in syncytial knots of cytotrophoblasts. Chromatin immunoprecipitation identified that CRH gene associated with both RelB and NF-κB2 (p52). Dexamethasone increased synthesis and nuclear translocation of RelB and NF-κB2 (p52) and their association with the CRH gene. In contrast, progesterone, a down-regulator of placental CRH, repressed NF-κB2 (p100) processing, nuclear translocation of RelB and NF-κB2 (p52), and their association with the CRH gene. Luciferase reporter assay determined that the NF-κB enhancer of CRH was sufficient to regulate transcriptional activity of a heterologous promoter in primary cytotrophoblasts. RNA interference-mediated repression of RelB or NF-κB2 resulted in significant inhibition of CRH at both transcriptional and translational levels and prevented the dexamethasone-mediated up-regulation of CRH transcription and translation. These results suggest that the noncanonical NF-κB pathway regulates CRH production in the human placenta and is responsible for the positive regulation of CRH by glucocorticoids.

On the function of placental corticotropin‐releasing hormone: a role in maternal‐fetal conflicts over blood glucose concentrations

Throughout the second and third trimesters, the human placenta (and the placenta in other anthropoid primates) produces substantial quantities of corticotropin-releasing hormone (placental CRH), most of which is secreted into the maternal bloodstream. During pregnancy, CRH concentrations rise over 1000-fold. The advantages that led selection to favour placental CRH production and secretion are not yet fully understood. Placental CRH stimulates the production of maternal adrenocorticotropin hormone (ACTH) and cortisol, leading to substantial increases in maternal serum cortisol levels during the third trimester. These effects are puzzling in light of widespread theory that cortisol has harmful effects on the fetus. The maternal hypothalamic-pituitary-adrenal (HPA) axis becomes less sensitive to cortisol during pregnancy, purportedly to protect the fetus from cortisol exposure. Researchers, then, have often looked for beneficial effects of placental CRH that involve receptors outside the HPA system, such as the uterine myometrium (e.g. the placental clock hypothesis). An alternative view is proposed here: the beneficial effect of placental CRH to the fetus lies in the fact that it does stimulate the production of cortisol, which, in turn, leads to greater concentrations of glucose in the maternal bloodstream available for fetal consumption. In this view, maternal HPA insensitivity to placental CRH likely reflects counter-adaptation, as the optimal rate of cortisol production for the fetus exceeds that for the mother. Evidence pertaining to this proposal is reviewed.

Maternal choline intake alters the epigenetic state of fetal cortisol‐regulating genes in humans

The in utero availability of methyl donors, such as choline, may modify fetal epigenetic marks and lead to sustainable functional alterations throughout the life course. The hypothalamic-pituitary-adrenal (HPA) axis regulates cortisol production and is sensitive to perinatal epigenetic programming. As an extension of a 12-wk dose-response choline feeding study conducted in third-trimester pregnant women, we investigated the effect of maternal choline intake (930 vs. 480 mg/d) on the epigenetic state of cortisol-regulating genes, and their expression, in placenta and cord venous blood. The higher maternal choline intake yielded higher placental promoter methylation of the cortisol-regulating genes, corticotropin releasing hormone (CRH; P=0.05) and glucocorticoid receptor (NR3C1; P=0.002); lower placental CRH transcript abundance (P=0.04); lower cord blood leukocyte promoter methylation of CRH (P=0.05) and NR3C1 (P=0.04); and 33% lower (P=0.07) cord plasma cortisol. In addition, placental global DNA methylation and dimethylated histone H3 at lysine 9 (H3K9me2) were higher (P=0.02) in the 930 mg choline/d group, as was the expression of select placental methyltransferases. These data collectively suggest that maternal choline intake in humans modulates the epigenetic state of genes that regulate fetal HPA axis reactivity as well as the epigenomic status of fetal derived tissues.